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Question ID: WS-128
Submitted By Robert Giuntoli on May 14, 2012 (0 comments)

Why haven’t we won the war on cancer? Background: In 1971, President Richard Nixon declared war on cancer. Despite significant investment in conducting this conflict, we have failed to eradicate this disease. While our understanding of the biology of cancer has improved exponentially, many breakthrough treatments have failed to live up to expectations and screening tests such as mammograms and prostate specific antigen have been called into question. There are notable exceptions with great strides occurring in the treatment of a limited number of cancers. What makes an advanced testicular cancer different from an advanced ovarian cancer? Feasibility: The ability of a particular malignancy to evade a certain treatment most likely lies in molecular differences specific to that cancer type. By using techniques such as micro arrays, the genetic alterations between cancers can be compared and variations between cancer types can be identified. Implications: The recognition of specific genetic alterations associated with poor prognosis malignancies would allow for several avenues of improvement in cancer care. Initially, these alterations may provide the basis of screening tests for the cancer in question. As our experience grows, exploitation of these differences may well hold the key to the reversal of resistance to a specific therapy. (Review or Add Comments)

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Question ID: WS-127
Submitted By Robert Giuntoli on May 14, 2012 (0 comments)

Can Immunotherapy reliably cure cancer? Background: Given the presence of genetic mutations, virtually all malignancies should present novel antigens capable of immune recognition. The development of a clinically apparent cancer suggests either an evasion of host immune responses or creation of an immunosuppressive environment. Manipulation of the host immune system should result in the generation of an anti-tumor response. At this time, reliable immunotherapeutic approaches to malignancies have been limited to vaccines against oncogenic viruses such as human papillomavirus and hepatitis B. Anecdotal reports have been presented of isolated patients successfully treated with adoptive immunotherapy. Can immunotherapy be used to effectively and consistently treat patients with metastatic cancers? Feasibility: Malignancies have limited methods available to escape destruction by the host immune system. Techniques are available to better understand both a tumor’s response to the immune system and the immune system’s response to a malignancy. Implications: By better understanding the limitations of host immune response to malignancy, we can design better more reliable immune based approaches to the treatment of malignancy. These approaches a most likely to be successful as part of adjuvant treatment or in patients with metastatic or recurrent cancer with minimal residual disease. (Review or Add Comments)

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Question ID: WS-126
Submitted By Marc Wathelet on April 2, 2012 (0 comments)

Targeting the Warburg effect: sponsoring clinical trials for dichloroacetate with public funds BACKGROUND: cancer cells often display abnormal metabolism and mitochondrial function, which involve a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis (Warburg effect). Dichloroacetate (DCA) has been shown to reverse this metabolic shift by targeting the enzyme pyruvate dehydrogenase kinase, resulting in normalization of the hyperpolarized state of mitochondria, increased reactive oxygen species production and induction of apoptosis in cancer cells (the work of E.D. Michelakis in Canada). DCA is a small, simple, very cheap molecule, it has been used in humans for rare indications for many years, but it cannot be patented, precluding any interest by pharmaceutical companies, the main sponsors of clinical trials. FEASIBILITY: peripheral neuropathy is the known side effect of DCA but the effect is reversible. A first publication indicated clinical efficacy was present at a dose that did not cause neuropathy. Appropriation of money to test in clinical trials such a promising drug by either the NCI or congress is practical but a political decision and lobbyists from pharmaceutical companies are likely opposed. IMPLICATIONS FOR PUBLIC HEALTH: should DCA prove effective for a substantial proportion of cancers, the public health implications would be huge in terms of live saved and health care cost reduction. (Review or Add Comments)

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Question ID: WS-125
Submitted By Michael Lerman on March 17, 2012 (0 comments)

Sequencing of natural human tumors is teaching us invaluable lessons. It is becoming clear that the new dogmas created in the post genome era are being questioned. The previously suspected genetic heterogeneity of tumors is now proven on the sequence level. The extreme genetic heterogeneity of individual tumors and the existence of multiple tumors (not metastases) pose fundamental doubt on the prevailing dogma of targeted drug(s) and personalized treatments. Besides, the analysis of tumor genomes by Bert Vogelstein (http://www.youtube.com/watch?v=KE8TY0gT--g) has shown that tumors have none, or one, or rarely two targets implying that the targeted drug(s) will not affect most of the heterogeneous CSC (cancer stem cels) residing in different locations within a given tumor. It follows that personalized treatment with targeted drugs will not as a rule halt cancer growth or cure cancer; this is the view of most clinicians facing daily the onslaught of cancer. The question is what should we now do to treat and cure cancers, should we continue looking for illusive tumor targets and targeted drugs (with off-target targets)? Michael Lerman, M.D., Ph.D. (Review or Add Comments)

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Question ID: WS-124
Submitted By Riccardo Illy on March 5, 2012 (0 comments)

Why did the stream of cancer research use the symptomatic approach, i.e. to try to eradicate a cancer already developed, instead of looking for the deep causes of it so to prevent its development? On this issue there is an evident conflict of interest between the pharmaceutical industries and the public institutions. (Review or Add Comments)

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Question ID: WS-123
Submitted By Riccardo Illy on March 5, 2012 (0 comments)

Given that normal cells in an environment with nutrients grow like a cancer, why do they grow in an ordered manner building organs and tissues of an animal body? ref. "Di cancro si vive" a book written by Luigi Oreste Speciani in 1982 (Review or Add Comments)

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Question ID: WS-122
Submitted By Vijayakumar Maleppillil Vavachan on February 13, 2012 (0 comments)

Is GLUT4 activation in normal cells a strategy against cancer? Background: Researchers have conveniently ignored the salvation of normal cells in the relentless war against cancer. Death of a cancer patient occurs mainly due to consumption of nutrients and invasion of important organs by cancer cells leading to nutrient depletion of normal cells and malfunctioning of organ. Caloric restriction has been considered as a pragmatic approach to cancer prevention and therapy. Normal cells depend on mitochondrial oxidative metabolism to produce 36 ATP from a glucose molecule. In contrast cancer cells rely primarily on energetically unfavorable anaerobic metabolism to produce 2 ATP. Cancer cells compensate this disparity by enhanced glucose uptake as compared to normal cells preferably using glucose transporter (GLUT)-1 rather than GLUT-4. This altered metabolism is a hall mark of cancer cells and it plays an important role in cancer development, progression and metastasis. Therefore, contrasting responses in uptake and metabolism of glucose between cancer and normal cells could be a realistic cancer preventive and therapeutic strategy. Feasibility: The role played by GLUT4 in regulating the amount of glucose uptake is not significant in human cancer cells. Wherein, skeletal muscle, adipose tissue, cardiac muscle that constitute majority of the normal cells employs insulin sensitive GLUT4 machinery, preferentially, for glucose uptake. Therefore, activation of GLUT4 in normal cells could be a strategy to equip them against nutritional starvation and death by cancer cells. Implications of success: New classes of GLUT4 modulators that will not cause severe hypoglycemia could be designed to enhance glucose uptake in normal cells. In turn cancer cells will be restricted of calorie and provide a window for cancer treatment and prevention. It also provide a better survival chance for normal cells in case of chemotherapy and hence the enhanced therapeutic index. (Review or Add Comments)

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Question ID: WS-121
Submitted By James Sherley on February 9, 2012 (0 comments)

Are carcinogenic mutation rates equally distributed across all tissue cell types? The immortal DNA strand hypothesis, first proposed by Cairns in 1975, posits that tissue stem cells have a lower mutation rate than other tissue stem cells. Recent advances in high-throughput and high-precision DNA sequencing makes it possible to now consider evaluating this hypothesis directly. Knowledge that such differences in mutation rate existed would inspire investigations to understand their cause; and it would suggest a new basis for understanding human carcinogenic mechanisms and for developing new approaches to reducing cancer risk. (Review or Add Comments)

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Question ID: WS-120
Submitted By James Sherley on February 9, 2012 (0 comments)

What fraction of human cancers arise from initiating events in tissue stem cells? Of the different cell kinetics types in human tissues, stem cells have been proposed as the major target for carcinogenic mechanisms. However, it is a challenging proposition to evaluate this hypothesis. Knowing the distribution of cancer initiation rates across stem, committed progenitors, transiently amplifying cells, arrested cell tissue cell populations would impact many aspects of cancer control and cancer medicine, including the focus of early detection testing, cancer treatment regimens, cancer prevention strategies, and drug design. (Review or Add Comments)

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Question ID: WS-119
Submitted By James Sherley on February 9, 2012 (0 comments)

What is the molecular mechanism by which non-genotoxic carcinogens like benzene cause cancer? There is some research to suggest that interactions with nuclear receptors may be critical for the carcinogenic mechanism of some non-genotoxic agents, but this mechanism does not account for agents like benzene. Many of these agents are environmental toxicants with significant human exposure rates that may contribute to the burden of sporadic cancers. Understanding their mechanism of action may lead to approaches to identify cancers caused by them and prevent their action. (Review or Add Comments)

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Question ID: WS-118
Submitted By Christina Chu on March 27, 2012 (0 comments)

We know that obesity is linked to several cancers, including hormonally driven cancers such as endometrial and breast cancers. But can strategies to treat obesity, affect obesity-associated inflammatory pathways, and change the hormonal milieux actually make substantive modification of cancer risk and prognosis? What strategies for risk modification are appropriate in patients who often have other comorbid illnesses such as type 2 diabetes and heart disease that affect application of traditional approaches to weight loss (diet and exercise)? (Review or Add Comments)

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Question ID: WS-117
Submitted By Richard Peto on January 31, 2012 (0 comments)

Can a new drug be developed that virtually completely inhibits or destroys the breast estrogen receptor (ER) protein without any adverse side-effects on other ERs (eg, in the endometrium or bone)? If so, it would safely reduce the risk of recurrence of ER+ breast cancer by more than half, ie, by somewhat more than tamoxifen does. Background: In countries such as the US or UK, about 80% of breast tumors are ER-positive, and most breast cancer deaths are from ER-positive tumours. For, although most such tumours can be apparently successfully removed, microscopic deposits of cancer cells may remain elsewhere in the body that eventually, not only in the first decade but also in the second decade after surgery, can cause breast cancer recurrence and death; the annual recurrence rate remains approximately constant during years 0-4, 5-9 and 10-14. Endocrine adjuvant therapy greatly reduces these risks. 5 years of adjuvant tamoxifen: Tamoxifen, an old, out-of-patent drug developed 50 years ago, has a half-life of several weeks and (after metabolic activation by liver enzymes), binds to the ER protein, thereby preventing endogenous estrogen from binding to it and stimulating any remaining cancer cells. Trials of about 5 years of adjuvant tamoxifen (with imperfect compliance: the mean treatment duration in these trials was probably only about 4 years) among a total of some 10,000 women with ER+ disease show that allocation to tamoxifen reduces the recurrence rate during years 0-4 by half, reduces the recurrence rate during years 5-9 by a third, and reduces mortality from breast cancer by a third during each of the periods 0-4, 5-9 and 10-14 (P<0.0001 for each of the 3 mortality reductions: see attached figure from the recent EBCTCG meta-analysis of tamoxifen trials [Lancet 2011; 378: 771–84]). 10 years of adjuvant tamoxifen: Unpublished trials of 10 years vs 5 years of tamoxifen show that 10 years of tamoxifen (unlike only 5 years of tamoxifen) substantially reduces the recurrence rate not only during the first decade but also during years 10-14 after surgery, and their preliminary results suggest some further reduction in breast cancer mortality in this period. Endometrial side-effects in post-menopausal women: Unfortunately, tamoxifen is a partial agonist of the breast ER, and a strong agonist of the endometrial ER; although tamoxifen blocks the breast ER it also produces low-level stimulation of it, and tamoxifen strongly stimulates the endometrial ER, causing endometrial hyperplasia and increasing the incidence of endometrial cancer (particularly if tamoxifen treatment is continued for several years) among post-menopausal patients who have not had a hysterectomy. Although this causes few deaths, it is a serious side-effect, and a drug that blocked the breast ER without stimulating it at all, and without stimulating the endometrial ER, would produce a slightly greater reduction in breast cancer recurrence without endometrial side effects. (NB Tamoxifen causes little or no endometrial risk in pre-menopausal women.) 5 years of an aromatase inhibitor in post-menopausal women: The evidence that blocking the breast ER completely would have a somewhat greater effect on recurrence comes from trials among post-menopausal women of aromatase inhibitors (AIs, which can reduce circulating estrogen levels by more than 99% in post-menopausal women only). Trials of 5 years of an AI vs 5 years of tamoxifen found a highly significant further reduction of a fifth in the remaining recurrence risk (so if tamoxifen multiplies the recurrence rate by 0.5, an AI probably multiplies the recurrence rate in untreated women by 0.4). Unfortunately, because AIs eliminate estrogen they remove the protective effects of estrogen against bone deterioration, and cause joint pains, bone thinning and pathological fractures. Chemo-endocrine therapy: Current cytotoxic regimens (eg, with regimens involving taxanes and anthracyclines plus older drugs) reduce breast cancer mortality by about a third in tamoxifen-treated ER-positive disease (see the recent EBCTCG meta-analysis of chemotherapy trials, published online in the Lancet on December 6, 2011 DOI:10.1016/S0140-6736(11)61625-5). Although there are claims that currently available tests on breast tumours will identify subgroups in which the proportional reduction in mortality with chemotherapy is substantially more or less than a third, these claims are not well founded statistically, so no matter whether chemotherapy will or will not be given there will remain a need for effective endocrine therapy. The ideal endocrine drug for ER-positive breast cancer: What is needed is a drug that completely inhibits or destroys the breast ER without affecting the bone or endometrial ER, and that can be taken for at least 5-10 years. The ideal drug would also have a long half-life to protect against imperfect compliance (like tamoxifen, which has a half-life of several weeks) and not require metabolic activation by unpredictable enzymes (unlike tamoxifen, which is a pro-drug that is activated by hepatic enzymes that are inefficient in a minority of patients). (Review or Add Comments)

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Question ID: WS-116
Submitted By Jim Brody on August 22, 2011 (0 comments)

Why does the age-specific incidence of prostate carcinoma increase so rapidly? It is essentially zero below the age of 30, but rises to 1000 per 100k at age 73. In contrast, colon carcinoma is 3 at 30 yrs and rises only to 200 at age 73. (Review or Add Comments)

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Question ID: WS-115
Submitted By Michael Lerman on August 21, 2011 (0 comments)

Sequencing of cancer genomes and/or exoms had established the existence of two types of cancer genes: one show high mutation rates (~100%) while the others show low mutation rates (5-10%); every cancer type/specimen is characterized by a specific assortment of cancer genes with low mutation frequencies ("driver" genes). Does anybody know how to estimate the number of "driver" genes? Michael I. Lerman, M.D.,Ph.D. (Review or Add Comments)

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Question ID: WS-114
Submitted By Charles Congdon on August 22, 2011 (0 comments)

What is the explanation for stopping growth of benign tumors? A mole stops growing and doesn't become a melanoma. Related to this question, I believe, is the 1920s Studies on Tumour Formation by the British pathologist G. W. Nicholson. Nicholson focused on tissue malformations. Do they ever become neoplasms? (Review or Add Comments)

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Question ID: WS-113
Submitted By Steven Smith on August 15, 2011 (0 comments)

Can a Map of the Evolving Frangiome be Produced? Cancer is a form of accelerated evolution. As such alterations in genome structure, gene expression and epigenetic change are all potentiated by the current state of the cell and by its environment as a source of mutagenesis and selective pressure. For example gene rearrangements can be potentiated by chromatin juxtapositions in a given cell type. The TMPRSS2:ERG fusion for example is not likely to occur in a breast cancer because the juxtaposition of the to two portions of chromosome 21 involved in the fusion appears to be a specific response of the differentiated prostate cell to androgen. It follows that, at each stage of tumor progression alterations in chromosome number, regional copy number and chromosome aberration, will potentiate a different set of future alterations, which will be under the influence of the tumor micro and macro-environment. Given these facts it may be possible to develop methods for identifying weak spots in chromosomes elicited by these progression-associated alterations. This is best thought of in terms of what I call genome frangibility: the tendency of a given genome state exhibit a specific set of sites that are easily broken by genomic stresses. This requires not only the mapping of what is best termed the frangiome of normal cells compared to cancer cells, but also comparing the frangiome of circulating tumor cells and dormant cancer cells with that of metastatic cells. By mapping the available weak points and juxtapositions in the genomes of each of these tumor cell types we will begin to be able to stage cancer more accurately and we will be able to more accurately design therapies to fit the different stages of the disease. Applicable methods in this search should include methods like sequence level mapping of chromosome breakpoints, Chromosome Conformation Capture and by emerging methods for detecting cell type specific and cancer specific non-B DNA structure. (Review or Add Comments)

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Question ID: WS-112
Submitted By Sidharth Kerkar on August 9, 2011 (0 comments)

What is the role of inflammation in cancer (friend or foe)? Despite the plethora of data showing that inflammation drives carcinogenesis, acute inflammatory mediators such as IL-12, IFN-gamma, TNF-alpha, and IL-17 have been shown to enhance anti-tumor immunity. The intricacies and mechanisms responsible for this perplexing duality remain largely unexplored. The answers to this question may play a major role in designing the next generation of cancer therapeutics. Sid Kerkar (Review or Add Comments)

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Question ID: WS-111
Submitted By Kazufumi Suzuki on July 16, 2011 (0 comments)

Is cancer is disease of cells or cell-cell interactions? Background Traditionally, it is thought that cancers arise from single cell which has received some damage in its genome. It seems to be true. UV, replication error or other numerous factors which can be cause DNA damage may be initial step of carcinogenesis. But it cannot explain tumor maintenance mechanism. When we study bulk tumor, cancer genome project tell us complicated genetic and epigenetic changes of cancer cells, for example driver mutations and passenger mutations. It is very hard to interpret cause (genetic and epigenetic alternation) and result (bulk tumor behavior, that is growth, metastasis, recurrence and so on). Feasibility We need new concept of cancer. In generally, cancer cannot be exist in single cell. We cannot pursue the nature of cancer in single cancer cell. In human body, like the other organism, any cell’s nature cannot determined by itself. It can only be determined in the context of cell-cell interactions. Cell-cell interaction consists of two way of interaction. One is direct contact, that is signals transmitted directly one cell membrane to the other (junctions). The other type is remote interaction, signals transmitted by cytokines, hormones and other proteins or small molecules. These signaling network end up to make morphogenic field within tissue level. That makes order of tissue. We don’t need to discover morphogen in human. Hypothetical morphogen can be derived from morphogenic fields. Morphogenic fields determine the nature of cells within the field. Genetic alteration of cancer display huge diversity, so we cannot distinguish cause and effect. Cell-cell interaction determines stability of genome, so most of passenger mutations are the effect of aberrant morphogenic field. But there is room that reductionism, that is the assumption of cancer is the disease of cell, explain the phenomenon clearly. For example, cancer metastasis can explain one cancer cell of primary tumor moves to the other organ and expands. Implications for public health We need to establish integrated cancer science which includes traditional methods like genetics which are based on reductionism and systemic approach of cancer which interpret phenomenon by multi-dimensional interactions. That may drive completely new way of research for public health. (Review or Add Comments)

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Question ID: WS-110
Submitted By Michael Tainsky on August 3, 2011 (0 comments)

Why do many cancer cells and preneoplastic immortal cells abrogate their innate immunity pathway, which is generally considered to be a cytoprotective mechanism? Background: Mammalian cells possess mechanisms to protect themselves from bacteria and viral infections that involve toll-like receptors and signaling leading to induction of DNA-activated protein kinase, RNA-L, and various interferons. However, tumor cells and immortal preneoplastic cells frequently lose a functional innate immunity pathway. It is surprising that cancer cell would lose a defensive pathway. Some intracellular mechanism triggers the innate immunity response pathway. This trigger is upregulated as part of the mechanism of cellular transformation and only cells that abrogate the innate immunity response can tolerate this molecular trigger. Feasibility: The pathways of innate immunity are well characterized involving cell surface and intracellular toll-like receptors. Activation of these molecules results in a series of phosphorylation events on proteins leading changes in programs of gene expression. What is the nature of this intracellular trigger that is a necessary step in the mechanism of cellular transformation resulting in activation innate immunity? Loss of this pathway, a necessary step in cancer cell evolution, can be exploited for the development of cytotoxic treatments to specifically kill innate immunity deficient tumor cells yet spare the normal cells that have retained their innate immunity pathways. Implications of success: The functional differences in innate immunity pathways between normal and tumor cells can be exploited for the development of tumor-specific cytotoxic therapies. The first step in exploiting this difference between normal and tumor cells is a full understanding of mechanisms by which innate immunity is abrogated in tumors. Secondly, we need to identify the intracellular triggers that activate innate immunity as a step in cellular carcinogenesis. Elucidating these mechanisms can lead to the development of therapeutic small molecules or infectious agents that should have minimal side effects against normal cells. (Review or Add Comments)

Average Score: 1.0 1.0 (1 evaluation)
Question ID: WS-109
Submitted By Ian Clements on July 28, 2011 (0 comments)

Can the NCI implement a pilot research project to prove that cancer patients who are provided with regular feedback on their healthiness and how to enhance that, survive longer? Therein, their healthiness would be assessed on five dimensions: 1: Waist measurement, or Waist/Buttocks ratio. Body composition - weight and height, fat%, muscle mass. 2: Vit.D3, homocysteine, and EFA/blood lipid profile (specifically the AA/EPA ratio) 3: Cancer marker related to their particular cancer 4: Exercise levels - average daily times the patient's heart-rate is above 50% maximum. 5: Immune system: absolute levels and ratios of neutrophils/lymphocytes, albumin/globulin. Most of these variables are within the patient's control. All are known to impinge on cancer patient's survival time. Each can be improved at a trivial cost compared with clinical treatments (which often have a far less effect). Each of the aforementioned factors have significant and extensive medical science behind them. The favourable aspects are that patients would be able to be involved much more in their own survival; which would enhance their motivation. Most importantly, there would be quick results, enabling dissemination to all patients. For instance (which is known, actually) when it was found that more of those with optimal Vit.D3 levels were alive at the 1, 5 & 10 year point , then all patients would be advised to take a daily Vit.D3 supplement. My background, to give some credability to this proposal: Electronic Engineer, ex college HoD Technology; MSc & PhD. Diagnosed with terminal metastatic bladder cancer on 'Oct '07 and given a 'dead-by-date' of Oct. '08, I suspect I'm doing something right - not just the chemo (Feb. - July '08), which was thought to be useless/palliative initially. Surprisingly, none of the many specialists or my GP has enquired as to why I've survived so long against all expectations - perhaps because each thinks the other is doing it? But they're not. I practice the above suggested programme. (Review or Add Comments)

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Question ID: WS-108
Submitted By Jim Brody on July 11, 2011 (1 comments)

Why is breast cancer such a different disease in Japan and other Asian countries, as compared to the US? The difference is not just an overall lower rate. Breast cancer occurs more frequently among middle-aged females, as compared to older (60+) women in Japan, unlike the US. Furthermore, Japanese women show a better prognosis than US women, even when controlling for tumor size and lymph node metastasis. (Review or Add Comments)

Average Score: 4.0 4.0 (1 evaluation)
Question ID: WS-107
Submitted By Sheppard Miers on July 8, 2011 (0 comments)

Why does cancer metastasize in humans? How can metastatic cancer in humans be prevented? How can metastatic cancer in humans be cured? Background: The National Cancer Institute (NCI) published Fact Sheet entitled Metastatic Cancer states that most types of metastatic cancer cannot be cured with current treatments and MOST PEOPLE WHO DIE OF CANCER DIE OF METASTATIC DISEASE. The NCI published definition of the term “metastasis” (meh-TAS-tuh-sis) states that it means spread of cancer from one part of the body to another. A tumor formed by cells that have spread is called a “metastatic tumor” or a “metastasis.” (Review or Add Comments)

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Question ID: WS-106
Submitted By Lauren Merlo on July 6, 2011 (1 comments)

How do cancer cells to survive/proliferate despite unstable genomes and high mutational loads? What does this tell us about the difference in distribution of selectively advantageous mutations in cancer compared to other systems and the proportion of cancer cell divisions that can produce viable cells? Finally, what is the relationship between cancer mutation rate and cancer progression, and can this be harnessed as either a biomarker of progression or as a target for cancer therapy? (Review or Add Comments)

Average Score: 4.0 4.0 (1 evaluation)
Question ID: WS-105
Submitted By Kenna Shaw on July 6, 2011 (1 comments)

Cell culture, the propagation of cells in artificial environment conducive to growth, has become one of the major tools in life sciences. Human cells grown in laboratory, subjected to various (single or multiple) perturbations, are serving well in elucidating physico-biochemical mechanisms of response in investigations of physiology and biochemistry. In addition, cell strains and cell lines have extensively been used to identify molecular markers of disease, and recent advances in cell culture have facilitated propagating stem cells for clinical and research purposes. In the laboratory, the cells are usually cultured in a medium containing serum that provides required nutrients for cell growth, 5% CO2 to maintain pH and a temperature of 37oC to mimic the physiological conditions of cells in vivo. However, the cells in culture are mostly subjected to 95% air, i.e., to a high concentration of oxygen (~20%), and high pressure (~152 mmHg). Oxygen status of different regions of an organ is different, and the levels and the requirement of oxygen (~1to10%; physioxia), and pressure (~8-100 mmHg) in each organ are different in the human body. Therefore, in terms of oxygen level, the culture conditions do not mimic the oxygen pressure in vivo. Cells cannot survive without oxygen because of its essential role in generation of ATP during oxidative phosphorylation, but high levels of oxygen (~20%, hyperoxia) are toxic through the production of reactive oxygen species (ROS) and peroxides that damage macromolecules, including proteins, lipids and DNA, and through depletion of active thiols. Reactive oxygen species attack guanine bases in DNA and form 8-hydroxydeoxyguanosine, which can cause transverse mutations. Wide regional variations in tissue oxygenation, low cellular oxygenation (~0.2%, hypoxia) and lack of oxygen (≤0.1%, anoxia) due to abnormal microcirculation in microenvironment are frequently observed in tumors. Although the cells under hypoxic and reoxygenation conditions remain replication competent, the intermittent and continuous oxygen deprivation was shown to deferentially affect cellular processes. Hypoxia and anoxia reduce transcriptional activity, transcription initiation and transcript elongation, while increasing the RNA stability to compensate. Hypoxia induces hypoxia inducible factors (HIF-1α and HIF-2α), and the HIF-1α was identified to play crucial role in carcinogenesis and tumor progression. In addition, hypoxia differentially affects methylation status of several genes, thereby altering the expression of both coding and non-coding RNAs. Thus, the oxygen concentration in the cellular environment could modulate highly dynamic and interconnected but finely regulated biomolecular networks, which drive biological processes, from the gene level to the proteome expression. Most of the tumors are hypoxic, but, currently, the cell lines are cultured in hyperoxic conditions and are used in downstream analysis (in transcriptomics, proteomics, in understanding changes in signal transduction pathways, and in identifying biomarkers). In fact, I feel, the high attrition rate of several drugs during drug development could be due to our current PD/PK assays, and pre-clinical Tox assays involving hyperoxic cultures. Drug absorption, availability, distribution, oxidation, metabolism and elimination are different in hypoxic and hyperoxic environments. Handling of biospecimens in hypoxic conditions, pre-culture processing of tissues in media at atmospheric oxygen levels (hyperoxia), and culturing cells originated from physioxic and hypoxic tissues in a hyperoxic environment may have contributed to generation of data that are spurious, and mislead our understandings of molecular networks, signal transduction pathways and pathophysiology. Most of the studies that identified biomarkers utilized cell lines cultured at hyperoxic conditions, even though the cells in tissues never reach to that level of oxygen. Current culture practices may have permanently altered the molecular profiles in cultured cells and therefore may not represent in vivo conditions. Unfortunately, currently, stem cells for research and regenerative medicine are cultured, and in vitro fertilization is being done at atmospheric oxygen. We may know the consequences from these manipulations, particularly with iPS cells, 15-20 years later. In fact, there are reports that do suggest higher health problems, including retinoblastoma, diabetes and developmental disorders in IVF kids. Therefore, there is a need for new cell strains and cell lines (co-cultures and 3D cultures) that survive and grow in physioxia and hypoxia and are optimized throughout the process (from the time the biospecimen is collected from patient to propagation and analysis) to represent physiological conditions and potentially maintain in vivo genotype and phenotype. A simple titration of oxygen levels in existing cell strain or cell line culture may not serve the purpose, since the oxygen effects are differential and in some cases irreversible. The concept behind this question is whether cell lines and other models, if treated at closer-to physiologic conditions, would be better models/and more apt for discovery and study of cancer biomarkers vs. whether what we study are mostly artifacts- consequences of the culture environment. Development of better tools for discovery using resources that better represent physiology and how to approach the development and testing of these tools is the core of this concept. -From Rao Divi/Kenna Shaw (Review or Add Comments)

Average Score: 5.0 5.0 (3 evaluations)
Question ID: WS-104
Submitted By Antonio Peramo on July 1, 2011 (0 comments)

How are big polysaccharides involved in metastasis?. There is little funding to support investigations in this area (excluding the obvious heparin studies) and macromolecular studies of big linear biopolymers like glycosaminoglycans could provide useful ideas in cancer metastasis. (Review or Add Comments)

Average Score: 4.5 4.5 (1 evaluation)
Question ID: WS-103
Submitted By Aleah Caulin on June 29, 2011 (1 comments)

What mechanisms have evolved in large, long-lived organisms, like elephants and whales, to suppress cancer and how can this be translated into improved cancer prevention in humans? Though this was briefly addressed in the question submitted by Dr. Rui Sousa, we think that this topic is important enough to warrant its own question. Peto’s paradox is the observation that lifetime cancer risk does not increase with body size and lifespan. We would expect that more cells accumulating mutations for a longer period of time would increase the risk of cancer for an organism, but this is not observed. How do large, long-lived organisms suppress cancer more effectively than humans? (Review or Add Comments)

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Question ID: WS-102
Submitted By Rhoda Alani on June 29, 2011 (0 comments)

What are the molecular determinants of tumor metastasis and are those specific to particular metastatic sites? How are the metastasis programs for different tumors determined? Are they fixed from the onset of the malignancy? Are they influenced by the tumor microenvironment? Are they mutable? e.g., does a melanoma that metastasizes to the brain only want to go to this metastatic site? Could a different tumor microenvironment influence a tumor to metastasize to another site? Could this metastatic program be shut off completely? There kinds of questions can now be addressed given recent advances in the development of in vitro tumor model systems. In particular, advances in microfluidics and polymer chemistry allow for the development of highly relevant model systems in which to precisely assess the molecular mediator of tumor metastasis using high-throughput technologies. The combination of novel nanotechnologies, engineering tools, systems biology, and cancer biology research tools can be used to ask these questions in a relevant in vitro model system and test these predictors of metastasis in vivo and through analysis of human tumors. Such questions would allow for the development of novel prognostic tools to determine from a primary tumor its likelihood of metastasis, identify the critical mediators of metastasis for a particular tumor, and delivery of tumor-suppressive agents through a personalized approach to prevent metastasis in patients. This would allow cancer to be more of a manageable chronic disease rather than a ticking time bomb with uncertain outcome. (Review or Add Comments)

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Question ID: WS-101
Submitted By Marie Hanigan on June 28, 2011 (0 comments)

Question: Which concomitant medications taken by cancer patients potentiate, inactivate or alter the toxicity of the therapy? Studies of resistance to chemotherapy invariability assume that the resistance is due to genetic or epigenetic changes within the tumor. Yet, the metabolism and efficacy of many chemotherapy agents can be altered by concomitant medications. In clinical trials, there is a range of responses to the therapy even when all the patients in the treatment arm have the same type of tumor and equivalent stage of disease. Dramatic improvements in response may be possible if the concomitant medications are identified that correlate with enhanced response in clinical trials. Similarly, identifying concomitant medications that correlate with reduced response would also provide important data for improving treatment. Further studies could then be done to identify the mechanistic basis of the interaction. Several studies have shown that medication lists in patient’s charts are incomplete and often inaccurate. The incomplete medication lists in the medical records make it difficult to impossible to retrospectively investigate drug interactions. The clinical experiment is being done everyday across the country, but the data are not being collected. Patients in clincial trials are being treated with chemotherapy while on concomitant medications, but the information about the medications is not being accurately recorded in the medical charts. This is equivalent to doing a basic research study on the effectiveness of a chemotherapy agent in which some of the animals in each group are randomly given unknown doses of unknown drugs. There are several methods for improving the accuracy of medication lists. (Review or Add Comments)

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Question ID: WS-100
Submitted By Ercole Cavalieri on June 28, 2011 (0 comments)

Can endogenous estrogens become chemical carcinogens? BACKGROUND: One of the major pathways in the metabolism of estrogens is their oxidation to catechol estrogens and then to catechol estrogen quinones. When this metabolism becomes unbalanced, an excessive amount of quinones is formed. One of them, the catechol-3,4-quinone, is predominantly responsible for reacting with DNA to form estrogen-DNA adducts that can initiate critical mutations leading to cancer. FEASIBILITY: Studies can be conducted in cultured cells and human subjects to investigate the relationship between formation of estrogen-DNA adducts, cell transformation and human cancer. IMPLICATIONS FOR PUBLIC HEALTH: By understanding the role of endogenous estrogens in the initiation of cancer, strategies for cancer prevention can be devised. (Review or Add Comments)

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Question ID: WS-99
Submitted By Ercole Cavalieri on June 28, 2011 (0 comments)

Can specific antioxidant compounds block estrogen-initiated cancer at the molecular level? BACKGROUND: The antioxidant compounds that can block the initiating step of estrogen-initiated cancer must have the capacity to inhibit the chemical oxidation of catechol estrogens to quinones and/or reaction of the quinones with DNA. In addition, these antioxidants must have the capacity of inducing protective enzymes or modulating activating enzymes in the oxidative metabolism of estrogens. FEASIBILITY: Such studies can be conducted in detail in cell culture systems. In addition, the effects of selected antioxidants can be investigated in human subjects using surrogate endpoint biomarkers. IMPLICATIONS FOR PUBLIC HEALTH: The goal of these studies would be to identify antioxidants that can prevent in humans the formation of estrogen-DNA adducts, the presumed critical step in the initiation of cancer by estrogens. (Review or Add Comments)

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Question ID: WS-98
Submitted By Eleanor Rogan on June 28, 2011 (0 comments)

Can studying cancer etiology guide us to effective cancer prevention? BACKGROUND: The metabolism of estrogens can produce catechol estrogen quinones that react with DNA to form estrogen-DNA adducts and give rise to the series of events that lead to the development of cancer. FEASIBILITY: Determination of estrogen-DNA adducts at the cellular and human levels can provide important information concerning the presumed first step in cancer development. By knowing this step, one can investigate strategies to prevent it. IMPLICATIONS FOR PUBLIC HEALTH: By preventing the first step in the development of cancer, one could develop widely-applicable approaches to reducing the incidence of cancer. (Review or Add Comments)

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Question ID: WS-97
Submitted By Eleanor Rogan on June 28, 2011 (0 comments)

What role does estrogen genotoxicity play in the initiation of breast and other human cancers? BACKGROUND: The reaction of specific metabolites of estrogen with DNA to form adducts is identical to that of the analogous metabolites of the leukemogenic benzene and the human carcinogen diethylstilbestrol. This reaction can lead to specific mutations that may initiate cancer. Elevated levels of estrogen-DNA adducts are found in women at high risk of breast cancer, as well as women diagnosed with the disease. FEASIBILITY: Mechanistic studies of mutations, transformation and carcinogenesis in human cell culture systems and studies of estrogen-DNA adducts in cancer cases and controls can be used to demonstrate the role of estrogen genotoxicity in the initiation of cancer. IMPLICATIONS FOR PUBLIC HEALTH: Demonstrating the role of estrogen genotoxicity in the initiation of breast and other human cancers can lead to biomarkers for risk of developing cancer and to prevention strategies. (Review or Add Comments)

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Question ID: WS-96
Submitted By Mark Pagel on June 27, 2011 (0 comments)

Should enzyme EXPRESSION or enzyme ACTIVITY be used to assess cancer biology and new chemotherapies? These chemotherapies include enzyme inhibitors and also drugs that hit upstream targets that control enzyme expression and/or activity. Enzymes are the "workhorses" of cancer biology and yet <20% of drugs and diagnostics target enzymes, perhaps because this provocative question remains unanswered. (Review or Add Comments)

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Question ID: WS-95
Submitted By Mark Pagel on June 27, 2011 (0 comments)

How can we exploit tumor acidosis for better cancer treatment? Tumor acidosis causes chemresistance against most of our chemotherapies because they are predominantly weak-base drugs. Do we need better diagnostic (imaging) methods that accurately measure tumor pH? Do we need better mouse models for developing weak-acid chemotherapies that work better in acidic conditions? How can we develop alkalinization therapies to potentiate our current weak-base drugs? (Review or Add Comments)

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Question ID: WS-94
Submitted By David Abrams on June 27, 2011 (0 comments)

1. What groundbreaking new research initiatives could be prioritized over the next decade to cut tobacco prevalence in half by 2025 in our nation ? 2. What should the next overarching strategic research agenda be now -- to follow and build on the extraordinary success of the last two decades of NCI investment in Tobacco Control Research to Policy initiatives ? 3. How can a new research agenda be developed to take full advantage of the dramatically changed landscape in Tobacco Control and Policy that is afforded by the new 2009 FDA regulation of tobacco products ? Given that tobacco Use Behavior accounts for over a third of all cancer deaths. Given that these cancer deaths are preventable by smoking cessation or prevention of youth uptake. Given that the reduction in lung cancer from 1965 to 1995, primarily in male lung cancer as a result of cutting male smoking prevalence in half, is the greatest public health success of the the 20th century. And Given that it is estimated that this specific reduction in lung cancer is the PRIMARY DRIVER (accounting for at least 40%) of the credit given to the reversal in total cancer deaths in the USA since the war on cancer was declared. It is therefore appropriate, urgent and fitting that NCI continue to lead the way in developing an extraordinary opportunity for the next decade of tobacco control strategic research. Provoking another doubling of the reduction in population prevalence of tobacco use behavior in one generation will not be easy as the rate of decline has stalled at around 20% prevalence. But progress will save more lives and money than any other investment NCI can make in the overall war on cancer in the next ten years. This must be one of NCIs top three provocative challenges. The tobacco industry and the entire landscape of reduced harm products, the new context of FDA regulation of tobacco, and other strong vectors, makes it a new ballgame -- where much of our past research to date no longer applies. A completely new and provocative research agenda in tobacco control is urgently needed. Now more than ever NCI most challenge the nations research community as we watch over 430,000 people die unnecessarily each year from tobacco related diseases. This is the mission of NIH and goes well beyond important biomedical research on nicotine as an addiction. A provocative strategic initiative in tobacco control speaks to a need for research that informs policy and impacts whole population prevalence. NCI has the experience, maturity, and effective infrastructure at NIH to do this task. The environment and behavior are as equally important as biology and genes in improving the nations health in our lifetime and for our children. (Review or Add Comments)

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Question ID: WS-93
Submitted By Desmond Smith on June 24, 2011 (0 comments)

Cancer studies generally focus on sequence changes or copy number changes in single genes. Can we find statistically significant changes genome-wide in pairs of genes? Or triples? etc.? Can we use these changes in gene pairs to map a survival network for the cancer cell? Can we exploit the network for directed therapy? (Review or Add Comments)

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Question ID: WS-92
Submitted By Jim Omel on June 22, 2011 (0 comments)

When cancer is totally absent by every possible evaluation and measure, what is the mechanism by which it returns months, years, or even decades later (same tumor, same cell-type)? (Review or Add Comments)

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Question ID: WS-91
Submitted By Jim Brody on June 15, 2011 (0 comments)

Do cancers originate in utero in a minority of the population? Equivalently, can a particular cancer only occur in a subset of the population? Less than a third of life-long tobacco smokers develop lung cancer. The risk of developing testicular cancer decreases after the age of 30; implying the life time prevalence in an unidentified subpopulation approaches 100%. Answering these questions would lead to a better understanding of how cancers develop and a test identifying those who are not at risk to develop a specific cancer. (Review or Add Comments)

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Question ID: WS-90
Submitted By Patricia Steeg on April 20, 2011 (3 comments)

Can translational data be tested clinically to meaningfully prevent metastatic outgrowth? Background. Tumor metastasis is a major contributor to cancer patient mortality and morbidity. The scientific literature is replete with pathways and drugs validated to prevent experimental metastasis, but few that will shrink established bulky lesions. To prevent metastasis is an adjuvant clinical trial, large, costly trials that are only conducted when a drug shrinks established tumors and promotes existing cytotoxic chemotherapy. Most metastasis preventive drugs will not pass this clinical trial hurdle. Can new clinical trial designs test these drugs in the appropriate settings to validate the scientific data? Feasibility. I propose a series of randomized "secondary metastasis prevention" trials for drugs with preclinical evidence. These would be phase II trials conducted on patients with minimal residual disease, with time to the development of a new metastasis (TTP) as the primary endpoint, not shrinkage of the existing disease. Agents would be delivered in the context of standard of care. Examples include (1) post-resection for solitary liver metastases in colorectal or bladder cancers; (2) post-SRS for patients with one-to few brain metastases; (3)locally advanced breast cancer that fails to develop a pathCR after neoadjuvant therapy; (4) new bone metastases in bone metastatic patients. This should be a new mandate for the cooperative groups. Endpoints also need to include pharmacodynamic markers to identify molecular and other characteristics indicative of a preventive response, for phase III trial enrollment. Implications for public health. We can prevent metastatic disease to a much greater extent than is accomplished today. Once metastatic disease develops, care is essentially palliative only. (Review or Add Comments)

Average Score: 3.5 3.5 (3 evaluations)
Question ID: WS-89
Submitted By Raymond Petryshyn on April 11, 2011 (0 comments)

Should the ability to kill cancer stem cells be a principal characteristic for selection or development of any chemotherapeutic agent? Background: Only infrequently and only in certain disseminated cancers does chemotherapy result in complete cure. Most chemotherapeutics agents are selected because of their ability to shrink tumors and reduce tumor burden. Despite complete responses and longer periods of progression free survival, tumors eventually reoccur and often no longer respond to treatment. There is growing evidence that resistant cancer stem cells are a reservoir for repopulating tumors even after complete destruction by chemotherapy. Feasibility: Identifying and understanding the biology of the cancer stem cell is becoming a focus in cancer biology. There are examples where cancer stem cells have been identified and are being characterized. New research will shed light on the susceptibility of cancer stem cells to various therapies and what this means to the rate of cancer recurrence and overall survival. Such studies could be conducted in real-time during clinical trials of all phases. Implications for success: Testing existing therapies and new anticancer agents for their ability to kill cancer stem cells would be a new concept to treating the most aggressive and non-responsive cancers. The cancer stem cell could be a surrogate biomarker for predicting the most effective treatments and overall survival or as a target for developing new agents. (Review or Add Comments)

Average Score: 5.0 5.0 (1 evaluation)
Question ID: WS-88
Submitted By Raymond Petryshyn on April 11, 2011 (0 comments)

Are antibiotics that inhibit protein synthesis in eukaryotes effective anticancer agents for the treatment of peritoneal cancers and other metastatic cancers? Background: A hallmark of most cancer cells is their ability to rapidly proliferate and spread. Antibiotics that are targeted to bacterial ribosome remain among the most effective arsenal to controlling the proliferation of pathologic bacteria. By analogy, it may be reasonable to expect that a class of antibiotics which has specificity for eukaryotic ribosome may be similarly effective in controlling or eradicating cancer cells. Feasibility: Historically, large numbers of naturally occurring agents have been screened for anti-bacterial properties to combat illness resulting from a spectrum of bacterial infections. In most instances, those agents that preferentially or exclusively targeted bacterial cells were selected for development as antibiotics while those that also targeted eukaryotic cells were set aside for fear of toxicity. However, there are many examples (puromycin, anisomycin, rapamycin, chloramphemicol, sporamycin) of set aside antibiotics that have specificity for the eukaryotic ribosome and exhibit anti-proliferative and antitumor effects. Such agents may be effective against metastatic cancers especially those invading the peritoneum where intra-peritoneal injection (IP) may be particularly effective. Implications for success: Set aside antibiotic agents that are known to inhibit protein synthesis in eukaryotic cells may prove to be as effective in controlling the proliferation of cancer cells as bacterial- specific antibiotics are in controlling bacterial infections. In many cases, the potential of these agents has not been tested or sufficiently tested especially on cancers of the peritoneum where minimal effects on the balance of the GI tract would be expected. These agents may represent effective options for difficult to treat metastatic cancers. (Review or Add Comments)

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Question ID: WS-87
Submitted By John Groopman on April 11, 2011 (1 comments)

What causes cancer? It is axiomatic that genomic instability and mutations are among the core processes in cancer cell development, but the specific agents causing these damages, particularly those of environmental origin,are still poorly understood. The statistical methods employed in epidemiology have probably led to the identification of the small set of highly mutagenic/carcinogenic compounds where human exposures have been high and/or the resultant tumors have been rare e.g. angiosarcoma and vinyl chloride. Thus, it is unlikely that we will discover many more single agents with the requisite potency and exposures and a significant discovery initiative is needed to identify multiplex interactions among these environmental agents that in turn accelerate the cancer process. In particular, special attention needs to be paid to the chemical-biological agent interactions that underlie many of the cancer cases around the world. (Review or Add Comments)

Average Score: 4.0 4.0 (1 evaluation)
Question ID: WS-86
Submitted By David Plas on April 7, 2011 (0 comments)

Question: Does circadian control of metabolism influence tumor cell response to chemotherapeutics? Background: It is well established in night-shift workers that disruption of circadian rhythms increases risk for developing metabolic disorders and cancers. Other work has reported that tolerability and efficacy of some chemotherapeutic drugs varies in a circadian manner according to the time of administration. As multiple investigators have found that oncogenes control cytotoxic responses in cancer cells in part through the regulation of metabolism, it is possible that circadian regulation of metabolism may also regulate cancer cell responsiveness to cytotoxic stimuli. Feasibility: Advancing methods in metabolomics make it feasible to determine metabolic function in tumors as a function of the diurnal cycle in model organisms. Metabolic function during treatment with chemotherapeutics could then be measured and correlated with cytotoxic responses. Implications for public health: Changing the time of administration of a chemotherapeutic could be an effective method for manipulating cancer cell metabolism to maximize chemotherapeutic response. (Review or Add Comments)

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Question ID: WS-85
Submitted By Khandan Keyomarsi on April 6, 2011 (0 comments)

Recent sequencing data has indicated that most cancers have 100s of mutations in 100s of genes and it is not clear which one of these mutations is the driver of the oncogenecity. In some cases, we already know that certain kinases are overexpressed in some cancers and that their overexpression is in fact oncogenic. Under these circumstances the tumor cell is "addicted" to this oncogene. However, in normal cells, the presence or even absence of this kinase poses no adverse affects to its proliferation (i.e. CDK2, CDK4-6, etc have all been knocked out in mice and the normal cell proliferation goes on unabated). So the question which is raised from these observation is that why can't we use these kinase inhibitors at low doses as preventative agents in high risk groups? In the best case scenario, these high risk group will show much lower risk of cancer incidence, and in the worst case scenario they will have the same risk of cancer as their untreated cohorts without any major side affects. (Review or Add Comments)

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Question ID: WS-84
Submitted By Rao Divi on April 6, 2011 (0 comments)

Chronic Exposure-Inflammation-Hypoxia-Cancer: Chronic environmental exposure and progressive macromolecular damage induced inflammation, and increased infiltration of plasma and leukocytes from the blood into the inflamed tissue site may lead to hypoxia. Infiltration of leukocytes into a finite area under a fixed oxygen supply may contribute to hypoxia conditions Hypoxia may further aggravate inflammation leading to further deprivation of oxygen, imbalances in nucleotide pools, DNA replication errors, epigenetic and gene expression changes, and tumor promotion. Even though harboring same pathological genetic variation(s), all cells in a tissue do not get transformed into cancer cells. This could be due to spatiotemporal variations in oxygen gradient and proximity to carcinogens in tissues. It is therefore interesting to study the role of chronic exposure-inflammation-hypoxia in cancer. Despite knowing that tissue hypoxia (pO2 ≤ 2 mmHg) is a hallmark of cancer, and oxygen levels in a tissue (pO2 = 2-40 mmHg) significantly and differentially affect cellular processes, most of the studies that identified cancer biomarkers used tumor cells cultured at atmospheric oxygen (pO2 = 160 mmHg, 21% oxygen; hyperoxia). More than 100,000 biomarkers were identified but very few of them (<100) are clinically useful. Biomarker identification under physioxia conditions and hypoxia conditions may be more relevant. We need a fundamental change in how we conduct biomarker identification. (Review or Add Comments)

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Question ID: WS-83
Submitted By Isis Mikhail on April 6, 2011 (0 comments)

Why are we not studying "outliers" or "rarities" in more depth epidemiologically and else? This may help us understand some of the causes of cancer that we have not paid much attention to in the past. For example, studying heavy long-term smokers who do not develop cancer. Or looking at a cancer rare in one population that is more common in another population. For example breast cancer rate in males is about <1% in the US and higher in Africa as its rate is about 15% among men in Zambia. I believe we have new statistical methods that can help overcome the small sample size and related research challenges. (Review or Add Comments)

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Question ID: WS-82
Submitted By Jean-Yves Bonnefoy on April 5, 2011 (0 comments)

Results of non clinical toxicology studies are generally not available especially for cancer vaccines under development. What about a toxicological database to share such results in order to optimize study design without duplicating unnecessary experiments ? (Review or Add Comments)

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Question ID: WS-81
Submitted By Thomas Mack on March 30, 2011 (0 comments)

A PROVOCATIVE QUESTION DOES THIS OBSERVATION OUT OF THE BOX WARRANT ATTENTION? An ounce of prevention should still be worth a pound of cure. However, while improvements have been made in the treatment of breast cancer, the number of cases actually prevented is still woefully small, despite the existence of strong predictors of high risk such as age, obesity, family history, and mammographic density. Even the net number of lives saved by secondary prevention, i.e. mammographic screening, is limited[1]. In contrast to the high risk Mendelian genetic predictors evident in linkage studies, responsible for a small minority of heritable cases, the genetic determinants of most heritable cases, as identified to date by GWAS studies, are very diverse, each with limited predictive value [2]. Even the predictive value of family history is diminishing, given the decreasing average American family size and the strong influence of lifestyle. Moreover, those lifestyle factors have proven difficult to manipulate. It seems unlikely that science will enable better means of prevention in the foreseeable future. Additional GWAS studies will probably not enable the screening of individual women, although they may slowly permit a better understanding of pathogenesis. Seven years ago, an observation was published that, if true, gives reason to consider another strategy for the prevention of heritable breast cancer[3]. A subgroup of women was found to be at a level of risk much higher than that of the average American woman. This subgroup is sizeable and growing, and an increasingly large number of women worldwide will become members. The observation is consistent with the body of past literature, withstood the highly skeptical reviewers of a prestigious journal, and was accompanied by a laudatory editorial[4]. Neither the observation, the methodology, nor the interpretation has ever been challenged. Nonetheless, the implications have not been exploited. This may be because the conclusion was (and is) “out of the box”, not in accord with conventional wisdom Specifically, 1811 pairs of female twins affected by breast cancer were identified, divided on the basis of zygosity and discordant/concordant breast cancer, and the differences between co-twins investigated in respect to standard breast cancer risk factors. It had previously been shown that unlike the fraternal co-twin of a breast cancer case, whose risk approximates that of a non-twin sibling, the risk to an identical co-twin of a case is much higher, at a level in excess of four times baseline[5], meaning that concordantly affected North American identical twins represent a genome at very high risk. The comparison of each high risk fraternal twin case to her unaffected co-twin produced a somewhat muted replication of the standard comparison of singleton cases to controls, i.e. a modest increase in risk after early menarche, delayed menopause, nulliparity, and a delayed first full-term delivery, all characteristics consistent with a carcinogenic result of high cumulative exposure to endogenous ovarian hormones, slightly confounded by genome. Because the age-specific incidence of breast cancer increases rapidly with increasing age until about menopause, then adds a relatively constant increment of 2-3% annually, it was reasoned that cumulative protection from breast cancer is, in practice, largely a function of age and competing mortality. Indeed, if the age-specific incidence curve for white California residents in 2008 is projected to older age groups, essentially all women would become affected by the age of about 130, and, aside from the small number of women at risk from Mendelian genes such as BRCA1/2, the phenotype of the more common polygenic forms of breast cancer can be thought of as reflecting a generic downward shift in age-specific incidence ( a fact clearly evident among the siblings and co-twins of breast cancer cases[6]). It therefore seemed reasonable to identify the determinants not only of breast cancer, but also of earlier diagnosis, among women matched on high genetic risk. In each of the 209 identical twin pairs in which both twins had been diagnosed with breast cancer, we compared the twin with the earlier diagnosis to the twin with the later diagnosis, considering the same standard risk factors. We found one very strong predictor of earlier onset of heritable breast cancer, namely age at puberty, whether identified by age at menarche, the age at onset of regular cycles (both long recognized as risk factors among unselected singleton cases), or especially by the age at first breast appearance (thelarche, a reliable comparative[7], especially memorable among twin girls). Puberty coming earlier than that of the co-twin was 5.3 times more likely to be followed by a breast cancer diagnosis diagnosed earlier than that of the co-twin, a highly significant finding, even though most of the breast cancers among these reproductively unexceptional women were post-menopausal. Most dramatically, if the earlier puberty appeared before age 12, the relative risk of having an earlier breast cancer diagnosis shot up to 9.1. These findings were interpreted to suggest that this age-specific increase in incidence resulted not from a cumulative excess in hormonal exposure, but a high heritable susceptibility on the part of immature breast ductal cells to hormone exposure. Almost all (more than chance would predict) of these concordant paired cases were concordant for hormone receptor positivity (5). It was reasoned that the subsequent interim uncontrolled growth of cancer cells occurs very slowly, probably only during the short progestin exposure within the luteal phase of each cycle. The observation is consistent with the available literature, i.e. not only the usual magnitude of early menarche as a standard risk factor among singleton populations[8], and the strong environmentally-driven secular increase in risk among BRCA1 carriers [9] (the latter in tandem with the widespread drop in average age at puberty) [10], but the known susceptibility of the immature breast to the carcinogenic effects of ionizing radiation[11]. Events have given cause for more concern. A secular drop in age at female puberty over recent decades has occurred on all continents[12-23], including Africa[24]. This decrease has recently slowed within developed populations and the affluent members of developing populations [25], but the trend toward younger age, even among women in developed countries, is now clearly stronger for thelarche than for menarche[26-29], and the earlier the breasts appear, the longer the interval between thelarche and menarche[30]. This change cannot be explained fully by changes in socioeconomic or nutritional status, including the emerging obesity epidemic[26], and it is not possible to dismiss the possibility that exposure to endocrine disrupting chemicals is partly responsible. Unfortunately, among this increasingly large proportion of girls with early thelarche, there is sure to be a subgroup with high heritable risk, and among them breast cancer is likely to become much more frequent. If the early breast development in the face of a family history of breast cancer does predict high lifetime risk, intervention is called for, but the means are not obvious. The available means of delaying menarche with GnRH agonists or gonadotropins[31] is crude and not target-organ specific, despite recent progress in understanding the interaction between CNS peptides, the hypothalamus, the pituitary, and the ovary[32]. Targeted support for follow-up research is needed. Others should be encouraged to replicate the original finding, and we plan to do so, although enough affected twin subjects are hard to accumulate. Attempts to reduce the toll of heritable breast cancer should certainly go beyond the narrow goal of identifying additional high risk polymorphic loci. Even if the observation cannot be replicated (and especially if it can), there is abundant reason to assign priority to the following questions: 1. Do the healthy immature breast ductal cells of girls at high heritable risk differ from those of others in the response to ovarian hormones (and endocrine-disrupting chemicals)? 2. As age at thelarche decreases, do healthy breast ductal cells (especially those of girls at high heritable risk) differ in cytology, growth pattern, or the response to ovarian hormones (and endocrine-disrupting chemicals)? 3. Is age at puberty determined only by genetics and stature, but also by particular nutritional, physiological, or toxicological determinants? 4. Are age at thelarche and age at menarche separately determined by cumulative nutritional, physiological, or toxicological determinants? 5. Can interventional strategies be designed to separately delay menarche and thelarche? Breast cancer will more frequently mar the adult lives of girls at heritable risk in all populations as more nascent breasts are exposed to a sudden flood of ovarian hormone. It is not unreasonable to hope that this burden of will someday be substantially reduced by collective or individual interventions, hopefully without the need for detailed reference to the many pertinent genotypes. Thomas Mack M.D., M.P.H. Ann Hamilton Ph.D. 1. USPSTF, Screening for Breast Cancer: USPSTF Recommendation Statement. Ann Int Med, 2009. 151: p. 716-26. 2. Stratton, M. and N. Rahman, The emerging landscape of breast cancer susceptibility. Nat Genet, 2008. 40: p. 17-22. 3. Hamilton, A.S. and T.M. Mack, Puberty and genetic susceptibility to breast cancer in a case-control study in twins.[comment]. New England Journal of Medicine., 2003. 348(23): p. 2313-22. 4. Hartge, P., Genes, hormones, and pathways to breast cancer.[comment]. New England Journal of Medicine., 2003. 348(23): p. 2352-4. 5. Mack, T., et al., Heritable breast cancer in twins. British Journal of Cancer, 2002. 87: p. 294-300. 6. Peto, J. and T. Mack, High constant incidence in twins and other relatives of women with breast cancer. Nature Genetics, 2000. 26: p. 411-4. 7. Berg-Kelly, K. and I. Erdes, Self-assessment of sexual maturity by mid-adolescents based on a global question. Acta paediatr, 1997. 86: p. 10-17. 8. Hsieh, C.-C., et al., Age at menarche, age at menopause, height, and obesity as risk factors for breast cancer: associations and interactions in an international case-control study. Cancer, 1990. 46: p. 796-800. 9. Kotsopoulos, J., et al., Age at menarche and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer Causes and Control, 2005. 16: p. 667-74. 10. Levy-Lahad, E. and S. Plon, A risky business--assessing breast cancer risk. Science, 2003. 302: p. 574. 11. Miller, A., et al., Mortality from breast cancer after irradiation dirung fluoroscopic examinations in patients being treated for tuberculosis. N Engl J Med, 1989. 321: p. 1285-9. 12. Rubin, C., et al., Timing of maturation and predictors of menarche in girls enrolled in a contemporary British cohort. Paed Perinat Epidemiol, 2009. 23: p. 492-504. 13. Chavarro, A., et al., Socio-demographic predictors of age at menarche in a group of Columbian University women. Ann Human Biol, 2004. 31: p. 245-57. 14. Rigon, F., et al., Update on age at menarchein Italy: toward the leveling off of the secular trend. J Adolesc Health, 2010. 46: p. 238-44. 15. Cabanes, A., et al., Decline in age at menarche among Spanish women born from 1925 to 1962. BMC Pub Healrth, 2009. 9: p. 449. 16. Aksglaede, L., et al., Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics, 2009. 123(e932-9). 17. Tomova, A., et al., Menarche in Bulgaria-secular trend in the twentiewth century. Akusherstvo I Ginekologia, 2009. 48: p. 10-4. 18. Kalichman, L., et al., Age at menarche in a Chuvashian rural population. Ann Human Biol, 2008. 33: p. 290-7. 19. Semiz, S., et al., Pubertal development of Turkish children. J Pediat Endocrin, 2008. 21: p. 951-61. 20. Babay, Z., et al., Age at menarche and the reproducive performance of Saudi women. Ann Saudi Med, 2004. 24: p. 354-6. 21. Rah, J., et al., Age of onset, nutritional determinants, and seasonal variation in menarche in rural Bangladesh. J Health, Population and Nutrition, 2009. 7: p. 802-7. 22. Cho, G., et al., Age at menarche in a Korean population: secular trends and influencing factors. Europ J Pediatr, 2010. 169: p. 89-94. 23. Wang, D. and M. Murphy, Trends and differentials in menarcheal age in China. J Biosoc Sci, 2002. 34: p. 349-61. 24. Umeora, O. and V. Egwuatu, Age at menardche and the menstrual pattern of Igbo women of southeast Nigeria. `African J Reproduct Health, 2008. 12(`): p. 90-5. 25. Euling, S., et al., Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics, 2008. 121 S-3: p. S172-S191. 26. Aksglaede, L., et al., Age at puberty and the emerging obesity epidemic. PloS one, 2009. 4: p. e8450. 27. Codner, E., et al., Age of Pubertal events in Chilean school-age girls, and its relationship with socioeconomic status and body mass index. Revista Medica de Chile, 2004. 132: p. 801-808. 28. Ma, H., et al., Onset of breast and pubic hair development and menses in urban Chinese girls. Pediatrics, 2009. 124: p. e269-e277. 29. Herman-Giddens, M.E., et al., Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network [see comments]. Pediatrics, 1997. 99(4): p. 505-12. 30. Marti-Henneberg, C. and B. Vizmanos, The duration of puberty in girls is related to the timing of its onset. Ann Human Biol, 1997. 24: p. 61-4. 31. Boepple, P.A., et al., Use of a potent long-acting agonist of gonadotropin-releasing hormone in the treatment of precocious puberty. Endocrine Reviews, 1986. 16: p. 198-206. 32. Tena-Sempere, M., Kisspepin signaling in the brain: recent developments and future challenges. Molecular and Cellular Endocrinology, 2010. 314: p. 164-9. (Review or Add Comments)

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Question ID: WS-80
Submitted By Society for Immunotherapy of Cancer on March 18, 2011 (0 comments)

Recent data testing new immunotherapy approaches in advanced cancer patients have revealed remarkable clinical responses in subsets of individuals. For example, the anti-PD-1 mAb data presented at ASCO in 2010 showed a ~30 response rate in patients with melanoma, renal cell cancer, and non-small-cell lung cancer. Interestingly, these clinical responses are quite durable, even if they are not complete. As our field optimizes the combinatorial delivery of immunotherapies (e.g., vaccines plus checkpoint blockade), these exciting data raise two inter-related questions: “What predictive biomarkers can be utilized to identify patients likely to derive clinical benefit from immunotherapy? In addition, will these immunotherapies actually become curative in those patients when delivered earlier in the disease course, thus becoming first line therapies?” (Review or Add Comments)

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Question ID: WS-79
Submitted By Society for Immunotherapy of Cancer on March 18, 2011 (0 comments)

Recent work has suggested that standard cancer therapeutics (chemotherapy, radiation therapy, tumor-targeting monoclonal antibodies) all are capable of facilitating a host immune response against the tumor. Mechanistic studies in mice have indicated that the immune response is in fact required for a maximal therapeutic effect of these agents. These data raise the critical question, “Are all effective cancer therapies working, at least in part, through eliciting an anti-tumor immune response?” This is not so far-fetched, as we have known for some time that anti-bacterial antibiotics do not completely cure infections in neutropenic patients until the neutrophil count recovers. (Review or Add Comments)

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Question ID: WS-78
Submitted By Macdonald Pyngrope on March 8, 2011 (0 comments)

Does sugar play a crucial role in cellular growth? Can early detection and proper dietary methods play an important role in mitigating the disease? (Review or Add Comments)

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Question ID: WS-77
Submitted By Dan Zhao on March 7, 2011 (0 comments)

How do the cancer cells balance their phenotype plasticity and genomic stability during tumor development and drug resistance? (Review or Add Comments)

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Question ID: WS-76
Submitted By Christian Kratz on March 7, 2011 (0 comments)

Do risk SNPs in genes that are also somatically mutated in cancer increase the likelihood of acquiring a somatic mutation of this gene? Background: Several GWAS have found robust associations between different types of cancer and risk SNPs at genes that are also somatically mutated in cancer. Examples include SNPs at CDKN2A-CDKN2B (childhood acute lymphoblastic leukemia, glioma, melanoma, basal cell carcinoma), IKZF (childhood acute lymphoblastic leukemia), TACC3-FGFR3 (urinary bladder cancer), and LMO1 (neuroblastoma). It is unknown how the germline SNPs and the somatic lesions are mechanistically connected. Feasibility: Rapidly evolving molecular methods (e.g. next generation sequencing) have created opportunities for studying the relationship of germline and somatic defects. Moreover, biorepositories are now frequently collecting both tumor and unaffected tissue or blood. Implications of success: A deeper understanding of how variations in the genome that are identified through GWAS can promote cancer. (Review or Add Comments)

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Question ID: WS-75
Submitted By Toby Hecht on March 7, 2011 (0 comments)

The survival rate for patients with melanoma where there is no discernible primary tumor is significantly better than for those patients where there is a known primary. The phenomenon of an unknown primary in melanoma is not a rare occurrence and is more commonly found in patients under the age of 60. What is the role of the immune system in this disease process? (Review or Add Comments)

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Question ID: WS-74
Submitted By Neal Freedman on March 7, 2011 (0 comments)

Why are the incidence rates of many cancers higher in men than women? Background: Throughout the world, a large number of different cancer types are more common in men than women. Only a few types of cancer, in contrast, are more common in women than men. For unknown reasons, sex is one of the strongest known risk factors for a number of cancer types. Perhaps the best example is for esophageal adenocarcinoma, where men are seven to ten times more likely to be diagnosed than women. Yet, the prevalence of known esophageal adenocarcinoma risk factors such as obesity and gastroesophageal reflux disease are similar in both sexes. Possible explanations include as yet unknown exposures that preferentially affect men or physiological differences between men and women, such as hormonal or epigenetic differences. Feasibility: Studies exist to examine exposures that may be more common in men or women. Though few studies have so far examined the role of epigenetic mechanisms, such as imprinting or differences between X and Y chromosome genetic content or gene expression, the advent of multiplex genomic tools now allows for the investigation of possible epigenetic sex differences in cancer risk. Multiplex approaches also exist to measure sex hormones; these could be applied to cancers with higher rates in men. Laboratory and non-human animal studies have also observed sex differences in tumor formation, these systems could be exploited in parallel to epidemiologic studies. Implications of success: Understanding the mechanisms responsible for higher cancer rates in men than women will likely provide fundamental etiologic insights into a large number of different cancer types and could also provide new avenues for cancer prevention and public health. (Review or Add Comments)

Average Score: 4.5 4.5 (1 evaluation)
Question ID: WS-73
Submitted By Pier-Luigi Lollini on March 3, 2011 (0 comments)

Why are so few cancer vaccines made against surface tumor antigens? Surface antigens like HER-2 and MUC1 are better targets than the more popular intracellular antigens. Immune recognition of intracellular antigens depends entirely on antigen processing machinery and major histocompatibility complex (MHC) expression, both frequently defective in tumors. In contrast, surface antigens are accessible to antibodies and antibody-mediated cytotoxic activities, even if antigen processing or MHC expression are downregulated in tumor cells. Cancer immunology and immunotherapy could find a wealth of new vaccine targets among tyrosine kinase receptors and other classes of cancer-related surface molecules. (Review or Add Comments)

Average Score: 5.0 5.0 (1 evaluation)
Question ID: WS-72
Submitted By Ward Fleri on March 3, 2011 (0 comments)

In the last few years progress has been made in characterizing epitopes for infectious and autoimmune diseases in the Immune Epitope Database. It would be highly beneficial if extensively curated and annotated epitopes from cancer antigens were also made available to the scientific community. (Review or Add Comments)

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Question ID: WS-71
Submitted By Pier-Luigi Lollini on March 3, 2011 (0 comments)

Why do we treat with interferon so many cancer patients that will not respond? The short answer is because interferon is still used as an empyrical, rather than targeted cancer treatment. Many predictors of response were defined, including the induction of autoimmune responses, tumor expression of interferon receptor, leukocyte infiltration of the primary, and the spectrum of circulating cytokines. Further predictors are related to general patient status and disease extension (time since diagnosis, performance status, circulating tumor cells, LDH, serum hemoglobin and calcium). Now it is the time to validate efficient predictors and to revise eligibility for interferon therapy. (Review or Add Comments)

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Question ID: WS-70
Submitted By Yong Qian on February 28, 2011 (0 comments)

How to study or get tumor cell specific antigens that are true targets for corresponding antibodies? Background: When a cancer cell is treated with Tumorase, a whole-cell giant liposome analog is produced with the cell membrane as the membrane of the giant liposome analog and most, if not all, of antigens outside or inside the cell membrane being preserved. Since the inhibitory molecules including PD-L1 and MHC-I are being removed, the preparation greatly enhances the antigen presentation process to enable none-antigens be eliminated to minimize side-effects and each antigen be identified to maximize the efficacy of a cancer vaccine to be used for the vaccination of the same cancer patient post-surgery. Feasibility: Under the regulation of SFDA (Chinese FDA), it can be used as a medical technology applicable to cancer patients post-surgery. BioMedicure is in the process of collaborating with major hospitals in China. Implication of success: cure of cancer by using cancer cell specific antigens to make cancer cell specific polyclonal antibodies to kill pre-cancer cells and cancer cells through the same cancer patient's immune system or a healthy people's immune system. Yong Qian from BioMedicure (Review or Add Comments)

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Question ID: WS-69
Submitted By Michael Lerman on February 28, 2011 (0 comments)

Gene therapy or better, combined gene therapy holds the potential to cure cancers. The question is: why is this approach not pursued vigorously? Michael I. Lerman, M.D., Ph.D. (Review or Add Comments)

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Question ID: WS-68
Submitted By Sunnie Kim on February 27, 2011 (0 comments)

BACKGROUND: Cancer is a moving target because its progression can bring about new mutations from increasing chromosomal instability and create a diverse population of cells. Yet we know, while some individual cancers carry hundreds of mutations, others seem to have very few genomic changes. Moreover, a relatively small number of mutations are detected significantly higher in frequency than all others including in individual cancers that carry few mutations overall. Does this small number of mutations or its subset at the onset seal the outcome of malignancy? If so, can treatments which target these higher frequency and often identical mutations in genes such as CDKN2A, TP53, and PTEN provide cure in cases of certain early stage cancers? Therapeutics which selectively targets a single biological mechanism or an antigen may miss some “drivers” of the cancer present in a patient today and that may exist tomorrow. So while tackling cancer early when there are few mutations has the best chance of success for a cure, to bring about a cure, eliminating every cancer- driving effects and their sources may be required. This approach seems if not impossible certainly very difficult to achieve. A simpler path, if it can be found, would be to identify a common denominator of all cancer cells that can be used to destroy each and every cancer cells. A common denominator that identifies all cancer cells to be the same yet different from normal healthy cells― whether it may be plasma membrane potential, other electrical property, any other physical, biochemical, or molecular qualities of cancer cells exclusively. FEASIBILITY: From this, for example, smart nanoparticles designed and fabricated to sense and recognize electrical property of different cell membranes and can selectively destroy cancer cells may be investigated. IMPLICATIONS: Ultimately bring about cure for cancer. (Review or Add Comments)

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Question ID: WS-67
Submitted By Masato Mitsuhashi on February 25, 2011 (0 comments)

Background: To fight against cancer, an understanding of cancer cell development and growth as well as an understanding of anti-cancer immunity is beneficial. Although many specific cancers have been well characterized at the cellular, molecular, and genetic levels, an individual’s cancer-fighting immunity has not been well assessed qualitatively and quantitatively due to the lack of appropriate technologies. The key word is “individual” as in personalized medicine. Question: Thus, the provocative question is the assessment of a patient’s immunity against each cancer, which will be a model of personalized onco-immunology. Various immunological methods are available, however, the majority of these technologies are cellular assays, that are applicable as research tools, but they are not suitable for assessing individual’s immunological response. Immunohistochemical staining and flow cytometric analysis are used to identify specific types of immune cells, however, not their functional abilities. Detection and quantification of anti-cancer IgG or antigen-specific cytotoxic T-cells (CTL) are not sufficient. For example, we should know how Fc-receptor-positive leukocytes and CTL behave at an individualized level. Due to polymorphism of receptors, kinases, transcription factors, etc., cellular function may not be common among all cancer patients. Moreover, general and specific immunity may be altered by aging, and by cancer itself, or damaged by chemotherapy. (Review or Add Comments)

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Question ID: WS-66
Submitted By Anil Wali on February 25, 2011 (0 comments)

How can we integrate best practices of eastern traditional medicine, incidence, prevalance and mortality rates seen among global populations with our current standard of care in cancer continuum. Background:There are many instances where prevalance of certain cancers are quite low in East Asian countries due to their dietary intake of spices and supplements that have anti-inflammatory properties. Prostate cancer would be nice example. The prologed use of these dietary practices from early childhood to adult life seem to have profound effect on the well being of majority of the population. It has been well documented fact that migration of these populations to US and acculturation with new dietary practices somehow increase their risk of developing malignancies. It could be partially due to the influence of gene environment interactions, stress and several other biological and non-biological factors. Feasibility:How could this complex problem with complicated disease etiology and pathogenesis be addressed in a simple pragmmatic way. We have made phenominal advances in the field of early detection, stem cells, imaging, targeted therapies based on pharmacogenomics but only incremental advances in prevention of the cancer for last 40 years. Addressing risk behaviors and excercise alone are not enough for "At-Risk" and "High-Risk" populations who are susceptible for developing cancer over their life time. Implications of Success:A global initiative led by NCI that would initiate partnerships with Insitutions of Excellence in Eastern Asain countries that have accumulated myriad of published data and clinical best practices in various types of malignancies. It would be a worthwhile effort to initiate scientific dialogue among scientists from these countries to foster synergy among trans-disciplinary approaches practiced here in USA to combat dreaded insiduous disease like cancer. (Review or Add Comments)

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Question ID: WS-65
Submitted By Rajiv Khanna on February 25, 2011 (0 comments)

Can we design new chemotherapeutic agents which are also immunepotentiating and are not immunosuppressive BACKGROUND: Traditionally most of the cancers are treated with chemotherapy and many of these agents are alos highly immunosuppressive. Recent studies have shown that a successful regression and disease-free response following chemotherapy is critically dependent on the immune status of the patient. Patients who are immunosuppressed are more likely to replase after a successful response to chemotherapy. FEASIBILITY: There are numerous small molecule/natural product libraries which can be used for screening of new compounds which act both as chemotherapeutic agents and immunostimulant. These novel componds should be designed in such a way that rather than killing the cancer cells and normal cells directly, these agents act as chemoattractant to direct the innate and adpative immune system to alter the microarchitecture of tumour which cuts off the nutrient supplies to the tumours. IMPLICATIONS FOR PUBLIC HEALTH: Development of these novel compunds will have significant implications for the clinical management of cancer patients. (Review or Add Comments)

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Question ID: WS-64
Submitted By Esteban Celis on February 22, 2011 (0 comments)

The failure of therapeutic cancer vaccines: Who's at fault? How can we expect to observe relevant anti-tumor effects with vaccination strategies that induce meager immune responses? Have we learned little from infectious disease researchers, on how the immune system successfully deals against infectious pathogens? Most cancer vaccines generate less than 1% antigen-specific T cell responses that usually do not persist. On the other hand, during acute viral infections that resolve and generate protective immunity (e.g., influenza, EBV), the proportion of antigen-specific lymphocytes can reach up to 30-60% of all lymphocytes. We keep blaming immune suppressive agents (T-regs, MDSCs) for the failure of current vaccines to elicit strong immune responses and do not consider that the immunogens we use are simply ignored by both innate and adaptive immune systems because they pose little danger. Thus, a successful vaccine will have to mimic an infectious agent to awaken the innate immune system AND at the same time should focus the adaptive immune response towards relevant tumor associated antigens (TAAs). Unfortunately, infectious recombinant viruses expressing TAAs remain suboptimal anti-cancer vaccines because although they stimulate the innate immune system, the adaptive immune system mainly focuses on the viral antigens. One possible solution is to combine the infectious agent's pathogen-associated molecular patterns (e.g., Toll-like receptor agonists) with optimized TAAs to generate meaningful (intense and long-lasting) immune responses that may translate into clinical benefit. (Review or Add Comments)

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Question ID: WS-63
Submitted By Ignacio Melero on February 12, 2011 (1 comments)

Is surgical tumor debulking a good idea before starting immunotherapy of cancer? In clinical oncology tumor debulking is restricted to a few tumor in which there is proof of significant benefit from the surgeries (i.e ovarian carcinomas) or when local complications are troublesome (i. e: colorrectal or kidney cancer). Otherwise surgery is confined to the cases in which curative erradication is considered feasible. However, the tumor mass is reach in factors and cells that locally and sistemically repress the immune response against cancer. Surgical debulking should help to diminish the amount of target malignant tissue to be destroyed by teh immune response and to reduce the immunosupressive factors while the immnotherapies are launched. The only way to answer this question is the performance of clinical trials in which teh same immunotherapy strategy is tested with and without the surgical operation. (Review or Add Comments)

Average Score: 4.5 4.5 (2 evaluations)
Question ID: WS-62
Submitted By Ignacio Melero on February 12, 2011 (0 comments)

How can we translate preclinical success with combinatorial immunotherapies to patients? Background: Compelling preclinical evidence speaks of synegisitic combination treatments involving various immunostimulatory monoclonal antibodies (CD40, CTLA-4, PD-1, CD137, OX40), adoptive T cell transfer and cancer vacines. Examples of synergistic therapeutic effects are also observed between novel immunotherapies and conventional treatment modalities including chemotherapy. There are Problems (in part real and in part perceived) for development. These include complex and largely undefined regulatory requirements for the combinations, entangled business and intelectual property issues, and very expensive logistics for the trials. (Review or Add Comments)

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Question ID: WS-61
Submitted By Sudha Sivaram on February 11, 2011 (1 comments)

In global health, how can we effectively utilize tools in mHealth and communication technology? Background: The trends in globalization and increasing expertise in information technology in the developing world has resulted in widespread use of telecommunication devices and the internet for a wide range of personal and commercial tasks. Studies to understand feasibility and acceptability of these devices in cancer education and care seeking, in recruitment into clinical trials and in disease surveillance are possible areas of focus. This technology offers an opportunity to engage communities worldwide where there is considerable stigma associated with cancer. Further these tools can also be used to train physicians (RAFT network, Geneva University Hospitals) and health workers, advance treatment practices and serve as an additional reporting conduit for surveillance activities. (Review or Add Comments)

Average Score: 4.5 4.5 (1 evaluation)
Question ID: WS-60
Submitted By Sudha Sivaram on February 11, 2011 (0 comments)

In resource poor countries, can we develop interventions that address both individual level as well as structural level factors influencing behaviors that facilitate risk of cancer? Background. Worldwide modifiable risk factors are a key target for cancer prevention programs. For instance, between 1998 and 2003, individuals reporting heavy smoking in China doubled (25 to 51%) (Qian et al., 2010, Bull WHO); childhood obesity in a study of 14-17 year olds in New Delhi, India showed an increase in obese/overweight children from 16% to 24% in the period from 2002 to 2006(Bharadwaj et al., 2008, Asia Pac J Clin Nutr). While economic changes including globalization have been posited as factors associated with these behavioral trends, there is also discussion about the role of social norms and expectations as well as increasing access to tobacco products and alcohol. Structural factors such as poverty limit contact with the health care system while gender norms and expectations disallow women to become informed and seek care for cancer and other diseases. Feasibility. Behavior change interventions developed and delivered based on an understanding of social norms, perceptions and attitudes of individuals towards disease as well as their interaction with the health care system have been shown to be efficacious in the US and elsewhere. Other behavioral interventions that have been efficacious consider structural influences such as poverty and gender disparities and their interaction with health outcomes (Pronyk et al., 2006, Lancet; Jewkes et al, BMJ 2008 – both HIV/AIDS research examples). Implications for Public Health. Behavior change intervention research offers unique opportunities to gather evidence to explain trends and gaps in advancement of cancer control and prevention. Inequities in health care have been identified by WHO as a key social determinant of health. Designing studies to understand these factors that operate out of the control of the individuals might offer lessons in sustaining the impact of cancer prevention programs. (Review or Add Comments)

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Question ID: WS-59
Submitted By Sudha Sivaram on February 11, 2011 (0 comments)

How can global cancer prevention and control efforts be integrated into existing primary health care services? Background. Cancer is an emerging public health concern in resource poor countries. In 1970, 15% of incident cancers worldwide were reported from developing countries. This number is projected to rise to 70% by 2030 (World Cancer Report, 2008; International Agency for Research on Cancer, 2010). Compared to the developed world, there is evidence that peak prevalence of cancer in developing countries occur at a younger age (Joshi et al. 2006; Int J Epid). Health systems of many resource poor countries, mandated to oversee a broad public health agenda, are often burdened by poor resources and programs are infrequently based on evidence from research (Murray, 2000). Primary health care services designed to provide basic health services to all residents are an integral component of these health systems, and have been critical in the success of programs for other disease outcomes. These lessons can inform global cancer control. Feasibility. Lessons from HIV prevention, tuberculosis control and treatment, and childhood immunization programs suggest that education, treatment and care services might be efficiently delivered through the primary health care system. While these existing systems do have their challenges, this approach holds promise as a way to reach a wider section of the population who do not live in urban and semi-urban areas (where cancer care centers and clinics are typically located). Training community-based health workers in prevention education, symptom identification and referral, education for reducing stigma are some strategies that have been effective in other disease control programs and can be evaluated for cancer control . Implications for public health. Research to understand health systems' features, their interaction with other service delivery systems of the local government, patterns of utilization and public's concerns with quality might help plan, implement and evaluate locally relevant cancer prevention and control programs. (Review or Add Comments)

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Question ID: WS-58
Submitted By Charles Rabkin on February 11, 2011 (0 comments)

Question: What is the prevalence of transformed clones in people without clinical evidence of cancer and what distinguishes such clones from overt malignancies? Background: Pre-malignant changes and microscopic cancers are detectable in many tissues. Examples include circulating lymphocytes with cancer-associated translocations, clonal mutations in dysplastic mucosa of various organs, and undiagnosed prostate and other cancers that are frequent with advanced age. The relationships of these conditions to cancers that cause morbidity and mortality are currently unclear. Feasibility: Advances in understanding the molecular changes in cancer and high throughput technologies for their detection could be profitably applied in cohort studies of cancer etiology to define natural history, risk factors, and prognosis. Implications of success: Molecular or epidemiologic features that pre-sage invasive cancer could be targeted for prevention or early treatment, while benign changes would not require potentially harmful intervention. (Review or Add Comments)

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Question ID: WS-57
Submitted By Masoud Manjili on February 11, 2011 (0 comments)

Do tumor-infiltrating immune cells play a critical role in determining response to chemotherapy? Background: Breast cancer patients who respond to chemotherapy and do not relapse usually have tumor-infiltrating immune cells and the signature of immune function genes in their tumor lesions. It is also known that chemotherapy may not induce complete rejection of the tumors but rather leave undetectable minimal residual tumor cells behind. Immune response is also known to be more efficient in rejecting minimal residual tumors than bulky tumors. Feasibility: Gene array technology as well as IHC and real-time PCR are available to identify signatures of immune function genes in the tumor. Implications of success: If we can identify the signature of immune function genes associated with good prognosis, we will be able to develop neuadjuvant immunotherapy in order to induce tumor-specific immune responses in patients with high risk of relapse. Such immune responses may then take care of minimal residual disease that was generated by chemotherapy. (Review or Add Comments)

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Question ID: WS-56
Submitted By Masoud Manjili on February 11, 2011 (0 comments)

Does inflammatory immune response play any role in determining progression of DCIS to invasive breast cancer? Background: 55-75% of DCIS patients overexpress HER-2/neu in their lesions and are at a greater risk of developing invasive breast cancer. On the other hand, 75% of patients with invasive breast cancer do not overexpress HER-2/neu in their tumors. In addition, several reports suggest that T cell responses, IFN-g in particular, may simultaneously induce apoptosis and HER-2/neu antigen loss in the tumors even in patients with DCIS. Feasibility: Gene array technology as well as IHC are available to determine inflammatory types of the immune response in DCIS lesions. Implications of success: If we can identify distinct types of the immune response signature that can favor patients and those that may induce epigenetic changes in the tumors (tumor antigen loss) and result in tumor escape and recurrence, we may be able to develop a highly tailored immunotherapy for patients with patients with DCIS and breast cancer. (Review or Add Comments)

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Question ID: WS-55
Submitted By Kenneth Brasel on February 10, 2011 (0 comments)

Do liver NKT cells negatively regulate anti-tumor CD8 T cells? Work by Nick Crispe's lab has shown that NKT cells in the liver selectively kill activated CD1d expressing T cells(J Immunol.,2004,172:5222). In addition, several studies using NKT cell deficient mice (CD1d KO) clear tumors faster than WT hosts. NK T cells may naturally keep number of activated CD8 T cells low to suppress autoimmunity, but as consiquence it will also limit the numbers of T cells that could regulate tumor outgrowth. In addition, this mechanism may explain why large numbers of infused CD8 cells, expanded in vitro, do not persist in vivo. (Review or Add Comments)

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Question ID: WS-54
Submitted By David Chia on February 8, 2011 (1 comments)

Question: Why are mRNA expression pattern in blood of cancer patient not being exploited more for early detection and prognosis? Background: Currently tumor can be phenotype by gene expression pattern, and had been useful in the prognoses of diseases. Specific gene expression in blood had been reported, but had not made much progressed since. This may due to the difficulty in isolating RNA from blood. Exosome from tumor had been found in blood. Thus studying mRNA pattern from exosome from cancer patient’s blood, one may be able to phenotype the tumor. Feasibility: Advance in isolation of exosomes from blood will make this task possible. Implication of success: The ability to phenotype tumor using blood will have major implication in early detection, and prognosis of cancer. (Review or Add Comments)

Average Score: 4.5 4.5 (1 evaluation)
Question ID: WS-53
Submitted By Deadly Cancer Coalition on February 8, 2011 (0 comments)

Question: Can we optimize the early translation of available and newly-discovered genetic, molecular, and proteomic information to the individualization of therapy? Background: Molecular classifications are critical to identify targets and enhance drug discovery. Once the pathways that drive and sustain a tumor are identified, then it can be determined whether they are therapeutically targetable. Additionally, genetic analyses can reveal which patients can benefit most from novel or currently available therapies, allowing a strategic and careful selection of personalized treatment regimens and clinical trials. (Review or Add Comments)

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Question ID: WS-52
Submitted By Deadly Cancer Coalition on February 8, 2011 (0 comments)

Question: Can we find better methods to identify and apply more accurate biomarkers that can significantly impact diagnosis, prognosis, and monitoring of individual cancer types? Background: A common feature among many cancers – including the deadliest cancers – is the lack of accurate, specific diagnostic tools, which could facilitate earlier diagnoses and monitor treatment responses. Emphasis on translational research initiatives that take advantage of large-scale genomic projects, such as The Cancer Genome Atlas (TCGA), could potentially facilitate the discovery of biomarkers specific to particular cancer types. By definition, biomarkers would only aid in the diagnostic evaluations of the tumor type in which they were discovered, underlining the desperate need for focused studies on cancers with high mortality rates. Feasibility: Earlier diagnoses and improved disease monitoring may offer clinicians the opportunity to achieve better outcomes in these difficult-to-treat diseases. (Review or Add Comments)

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Question ID: WS-51
Submitted By Deadly Cancer Coalition on February 8, 2011 (1 comments)

Question: How does the microenvironment interact with and influence tumor growth and development? Background: The microenvironment of the tumor plays a pivotal role in nourishing, sustaining, and enabling the spread of all forms of cancer. In pancreatic cancer, for example, the tumor is enclosed by a dense desmoplastic reaction of fibrous tissue, which clearly supports the tumor and likely prevents efficient drug delivery. Feasibility: The tumor-tumor microenvironment relationship and interdependence are critical to the deadliness of these and other cancer types, and must be explored via patient tissue or relevant animal models. (Review or Add Comments)

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Question ID: WS-50
Submitted By Deadly Cancer Coalition on February 8, 2011 (0 comments)

Question: Can we gain greater understanding of the mechanisms of tumor metastasis? Background: Even cancer types that are typically responsive to current treatment modalities tend to be extremely difficult to treat once the cancer starts to metastasize. A commonality of some of the deadliest cancers is a proclivity to metastasize to critical organs, tragically combined with a frequency of late diagnoses. Feasibility: A better understanding of the metastasis-related genes and pathways would benefit all solid tumor types. (Review or Add Comments)

Average Score: 3.5 3.5 (1 evaluation)
Question ID: WS-49
Submitted By Deadly Cancer Coalition on February 8, 2011 (0 comments)

Question: Can we develop a systematic molecular classification of the deadliest cancer types? Background: Understanding the driving molecular pathways (e.g. Bcr/Abl in CML or Her2 in breast cancer) has helped us to develop effective targeted therapeutics. Feasibility: Research that develops a systematic method for molecular definition and classification of all cancers – correlated to historic phenotypic and anatomic origins of the specific cancer types and also to the available genomic information – can stimulate many aspects of fundamental cancer research that may be vital to finding better diagnostic markers and targeted therapeutics. (Review or Add Comments)

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Question ID: WS-48
Submitted By Titia de Lange on February 7, 2011 (0 comments)

Steve Elledge/Titia de Lange: How can we exploit the past and/or ongoing genome instability in cancer? The recent sequencing data and other high resolution genome analyses has revealed that the frequency of mutations and genome rearrangements in solid tumors is much greater than previously appreciated. It seems likely that this rampant genome instability reflect a change in chromosome husbandry (DNA repair, chromosome segregation, telomere protection, etc), allowing the acquisition of a mutator phenotype that is either permanent or episodic. The data also predict that most cancers have undergone adaptive changes that allow them to tolerate the mutator phenotype (e.g. frequent chromosome mis-segregation, deficiency in a repair pathway) and its consequences (e.g. gene dosage alterations, high frequency of deleterious mutations). Such adaptive changes in cell physiology can be exploited as shown by the use of PARP inhibitors in BRCA1/2 breast cancer. Further identification of these adaptations and their associated vulnerabilities provides a fertile ground for new therapeutic interventions. (Review or Add Comments)

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Question ID: WS-47
Submitted By Titia de Lange on February 7, 2011 (1 comments)

Steve Elledge/Titia de Lange: How can we exploit the past and/or ongoing genome instability in cancer? The recent sequencing data and other high resolution genome analyses has revealed that the frequency of mutations and genome rearrangements in solid tumors is much greater than previously appreciated. It seems likely that this rampant genome instability reflect a change in chromosome husbandry (DNA repair, chromosome segregation, telomere protection, etc), allowing the acquisition of a mutator phenotype that is either permanent or episodic. The data also predict that most cancers have undergone adaptive changes that allow them to tolerate the mutator phenotype (e.g. frequent chromosome mis-segregation, deficiency in a repair pathway) and its consequences (e.g. gene dosage alterations, high frequency of deleterious mutations). Such adaptive changes in cell physiology can be exploited as shown by the use of PARP inhibitors in BRCA1/2 breast cancer. Further identification of these adaptations and their associated vulnerabilities provides a fertile ground for new therapeutic interventions. (Review or Add Comments)

Average Score: 5.0 5.0 (1 evaluation)
Question ID: WS-46
Submitted By Reza Meyqani on February 7, 2011 (0 comments)

Can Nanochips be programmed so that they can shrink tumors without harming healthy tissues? (Review or Add Comments)

Average Score: 2.0 2.0 (1 evaluation)
Question ID: WS-45
Submitted By Gretchen Gierach on February 7, 2011 (0 comments)

Question: What molecular mechanisms are responsible for the well-established association between mammographic density and breast cancer risk? Background: Epidemiologic studies have consistently demonstrated that high mammographic density is a strong and independent breast cancer risk factor. Emerging data also suggest that increases and decreases in mammographic density relate to corresponding changes in breast cancer risk, suggesting that some inherent characteristic of dense breast tissue is directly related to carcinogenesis. However, the mechanisms that mediate the relation between mammographic density and breast cancer risk are largely unknown. Feasibility: Improvements in molecular analyses of breast tissues, along with rapidly evolving technologies that measure breast density as a standardized, quantitative, and three-dimensional volume using density phantoms, magnetic resonance imaging, or ultrasound tomography, offer opportunities for defining the biology underlying the density-breast cancer relationship, studying temporal changes in breast tissue composition, and identifying stronger risk associations. Implications of success: Understanding the mechanisms underlying the risk associated with high mammographic density could advance our etiological understanding of breast carcinogenesis. Evaluating breast density as a modifiable risk factor may also contribute to the development of improved strategies for early detection and prevention of breast cancer. (Review or Add Comments)

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Question ID: WS-44
Submitted By Lindsay Morton on February 7, 2011 (0 comments)

What is the risk of treatment-related leukemia associated with the many new chemotherapeutic, biologic, and molecularly-targeted agents that have been introduced in recent decades? Which patients are particularly susceptible to developing treatment-related leukemia? Background: Treatment-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is a rare but highly fatal complication of cytotoxic chemotherapy. Certain chemotherapeutic agents are known to be leukemogenic (e.g., melphalan, doxorubicin) and are associated with distinct morphologic and clinical characteristics and cytogenetic abnormalities. However, the dose-response relationship and mechanism are not well established; the leukemogenicity of newer chemotherapeutic, biologic, and molecularly-targeted agents is unknown; and patients who may be particularly susceptible to t-MDS/AML cannot currently be identified. With the increasing use of chemotherapy and improved survival of cancer patients, better understanding the risks and benefits of treatment has important clinical implications. Feasibility: Several large clinical series have provided valuable information about the morphologic, clinical characteristics, and cytogenetic abnormalities typical of t-MDS/AML arising after exposure to different classes of chemotherapeutic agents. The introduction of newer chemotherapeutic, biologic, and molecularly-targeted agents as well as descriptive studies showing changing incidence patterns of t-AML that are consistent with changing treatment practices demonstrate an urgent need for additional study. Newly created registries of patients with t-MDS/AML and follow-up of clinical trials or patients within health maintenance organizations may provide populations in which t-MDS/AML can be studied. Implications of success: Quantification of the risks of t-MDS/AML for newer cancer treatments would provide important information for clinicians assessing treatment risks and benefits. Identifying patients who are particularly susceptible to developing t-MDS/AML would allow for more personalized medicine, with risk/benefit calculations taking into account inherited susceptibility to a highly fatal complication of treatment. Further research in this area should also advance understanding of the mechanisms of t-MDS/AML, which may shed light on the leukemogenic process in primary AML. (Review or Add Comments)

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Question ID: WS-43
Submitted By Patrick Brown on February 6, 2011 (1 comments)

Is there a way to make patient-level data from clinical studies of cancer and other diseases available for re-analysis and meta-analysis without compromising privacy and confidentiality? (eg, by holding it in a public repository that allows identified, credentialed users to carry out re-analyses and meta-analyses without allowing the users to access or glean data on individual patients). Most clinical studies, published and unpublished, do not make the necessary data available in a way that would enable independent re-analysis of the key conclusions, or new analyses or meta-analyses that depend on preserving the linkage of the data relating to each patient. The inability to go beyond the analyses that the original authors of a clinical study choose to carry out and publish, and the inability to pool data from multiple studies for more powerful analyses, represents a huge lost opportunity. The further analyses that would be enabled in this way would substantially increase the payoff from the billions of dollars invested each year in clinical studies. (Review or Add Comments)

Average Score: 5.0 5.0 (1 evaluation)
Question ID: WS-42
Submitted By Jerry Shay on February 5, 2011 (0 comments)

For years we have been studying families with genetic susceptibility to cancer. However, I have not heard about studying individuals with NO history of cancer in their families. This provocative question first poses if there are indeed families with several generations that never seem to get cancer and if so what this may tell us about the genetics and/or epigenetics of cancer? Second, if there are such multi-generation of families without cancer, how can we exploit this knowledge to reduce or delay the incidence of cancer in the general population? One thought is to study families that include centenarians which appear to delay all disease including cancer until very late in life. Everything that affects the general populations appears to be delayed 20-30 years in families that have individuals living into their late 90s or even into their 100's. (Review or Add Comments)

Average Score: 4.0 4.0 (1 evaluation)
Question ID: WS-41
Submitted By Patrick Brown on February 4, 2011 (0 comments)

The seemingly inevitable accumulation of diverse benign, focal changes in skin pigment, texture, microvasculature, hair color and texture, etc., with aging and sun-exposure suggests that numerous mutation-dependent clonal expansions of (presumably) stromal cells accumulate with age, perhaps throughout the body. How common are these locally expanded mutant clones, where in the body are they found, what are the cells, what are the mutations that enable their expansion and how do they accumulate with age? Do they ever play a role in cancer pathogenesis by providing microenvironments favorable for development, survival or self-renewal of cancer cells? Do they play a role in providing “soil” favorable for establishment and growth of metastatic “seeds”? (Review or Add Comments)

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Question ID: WS-40
Submitted By Patrick Brown on February 4, 2011 (1 comments)

Why don’t non-tumor cells metastasize or even get sloppy in their finely-specified localization program through a lifetime of self-renewal and disturbances to their normal environments? What restricts the ability of stem or progenitor cells of any non-malignant tissue from surviving or growing at an ectopic site? For example, are there mechanisms that cause cells to undergo programmed cell death when they fail to detect the precise constellation of molecular signals characteristic of their normal microenvironment, or when they detect signals characteristic of an ectopic site? (Review or Add Comments)

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Question ID: WS-39
Submitted By Patrick Brown on February 4, 2011 (1 comments)

Local intrachromosomal rearrangements escape detection by essentially all standard methods for characterizing cancer genomes, yet there is growing evidence that they may be among the most common and perhaps important genetic lesions in cancer. What is the molecular pathogenesis of these rearrangements? How can we efficiently and systematically identify them? How important are they in cancer pathogenesis and what roles do they play? (Review or Add Comments)

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Question ID: WS-38
Submitted By Patrick Brown on February 4, 2011 (0 comments)

How do cancer cells survive massive gene-dosage imbalances? Extreme gene-dosage imbalances are a common feature of most cancers and almost universal in many cancers. Because this is one of the most extreme and ubiquitous molecular abnormalities in cancer cells, it is remarkable how poorly we understand the mechanisms that enable cancer cells to mitigate its adverse consequences. There appears to be virtually no dosage compensation at the transcriptional level in tumors with these gene-dosage imbalances. There is equivocal evidence for some post-transcriptional regulation and for cellular mechanisms that allow massive protein dosage imbalances to be tolerated, but its extent, how it works or to what extent it might provide a target for therapy are still a mystery. (Review or Add Comments)

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Question ID: WS-37
Submitted By Patrick Brown on February 4, 2011 (0 comments)

Why is it that on the one hand cancers grow too much, die too reluctantly, and live where they don’t belong… and yet we are still incapable of maintaining them and studying them effectively ex vivo? Development of cell and tissue culture systems that support survival and preservation of in vivo phenotypes of cancer and normal cells would hugely improve our ability to carry out controlled experiments and detailed systematic observations of essential developmental and physiological processes. Mouse models and other animal models are a woefully inadequate, expensive and cumbersome alternative. What are the molecular, physical, structural requirements for establishment, survival, proliferation, differentiation, homeostasis of individual cells? What are the requirements for assembly of the complex architecture of tumor or normal tissue in an ex vivo system? Can we replicate them in the laboratory? (Review or Add Comments)

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Question ID: WS-36
Submitted By Barry Graubard on February 4, 2011 (0 comments)

While the causal mechanisms that link excess body weight to increased risk for certain cancers are largely unknown (as noted in other questions), we pose an associated question -- what are the causal mechanisms that link excess body weight to decreased risk of certain other cancers? Background: While many studies have documented an increased risk of incidence of certain cancers in association with increased body weight (renal cancer, cancer of the uterus, and esophageal cancer) many studies have documented a reduced risk of other cancers with increased body weight (e.g., lung, pre-menopausal breast, gastric non-cardia adenocarcinoma, and low grade prostate cancer). Of particular note, studies show that greater body weight increases risk of esophageal adenocarcinoma but decreases risk of esophageal squamous cell carcinoma, which suggests that results are not spurious. The biological mechanisms that underlie these associations remain poorly understood. Since body weight is a result of a complex time varying biological process, it is likely body weight is a mediating factor for various causal pathways for cancer. A non-cancer example of likely mediation of obesity is its relation to diabetes. It has been observed that after bariatric surgery and before there is any substantial loss in body weight, glucose levels in the body drop moving diabetics into nondiabetic status. There are many factors related to the accumulation or reduction of body weight including the aging process, early life development and exposures, genetics, levels of basal metabolism, caloric intake, physical activity and fitness, behavioral and psychological disposition, and cultural and ethnic norms. Understanding how these factors affect body weight will provide insight into identifying exposures that cause or prevent certain cancers that have been previously found to be associated with body weight. Feasibility: Existing cohorts with regular repeated measurements of body weight and factors related to the determination of body weight would allow the application of newly developed statistical methods that use time dependent causal modeling to examine exposures related to cancer and the extent that body weight is a mediator of these associations. These analyses could reveal how changes in body weight over time are associated with some cancers and not others. However, many of these cohorts are limited by small sample sizes or have inadequate measurements or lack measurements of the important factors related to body weight. Therefore, new cohorts need to be established that will provide hard measurements of the factors affecting body weight. Other sources of data are randomized intervention trials that use various means to reduce or maintain body weight. These data sources can be used to examine bio-markers of cancer development, which could provide clues about the mediating pathways of the body weight and specific cancers. Implications of success: A deeper understanding of the mediating relationships of stable or changing body weight with cancer could identify those exposures that increase or reduce the incidence of specific cancers. Identification of these exposures can lead to interventions that prevent cancer. (Review or Add Comments)

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Question ID: WS-35
Submitted By Eric Engels on February 4, 2011 (2 comments)

Question: To what extent is the increase in cancer risk with aging due to immune senescence? Background: The incidence of many cancers rises with age, and the aging of the U.S. population will lead to an increasing cancer burden. To some extent, the increase in cancer incidence with age is attributable to the cumulative exposure to carcinogens, and the attendant accumulation of somatic mutations. Nonetheless, older adults also manifest progressive declines in host immune function with aging (i.e., immune senescence), which leads, for example, to decreased responses to vaccines and increased frequency of clinical infections. The contribution of immune senescence to the development of cancer in adults is unknown. Feasibility: Recent technological developments in characterizing the immune system allow investigators to address this question. It is possible to assess immune function in multiple dimensions, including quantification of recent thymic emigrant lymphocyte populations, lymphocyte immunophenotyping and gene expression profiling, and multiplex measurement of circulating cytokines. Cross-sectional and longitudinal assessments in older adults would allow characterization of changes in the immune system with aging. Concurrent measurement of these markers in cancer cases and controls, ideally in pre-diagnostic samples, would provide an assessment of the contribution of these immune changes to the development of cancer. Implications of success: Demonstration of an association between immune senescence and cancer risk would expand our understanding of the role of normal immunity in preventing cancer. Identification of an immune profile associated with elevated cancer risk may point towards novel prevention strategies or identify individuals who would most benefit from enhanced cancer screening. (Review or Add Comments)

Average Score: 3.0 3.0 (1 evaluation)
Question ID: WS-34
Submitted By James Goedert on February 4, 2011 (0 comments)

Question: What and how are digestive tract microbes associated with subsequent risk of colorectal and other digestive tract cancers? (James Goedert; Mahboobeh Safaeian; Ann Hsing) Background: Commensal microbes that inhabit the human digestive tract, the microbiota, are required for good health and are postulated to affect cancer risk through several mechanisms, including detoxification, synthesis of micronutrients or digestion their precursors, local and systemic inflammation, disruption of balance in immune response and tolerance, and maintenance of hormonal homeostasis. Understanding which microbial communities, or which microbial functions, are associated with cancer precursors (e.g., colorectal polyps, gastric dysplasia, oral leukoplakia) and digestive tract cancers could provide new approaches to early diagnosis and ultimately to prevention. Feasibility: Next-generation sequencing and chip technologies are starting to be applied effectively to define the diversity of the proximal and distal digestive tract microbiota, as well as expression of microbial genes, in healthy humans and alterations of this diversity associated with major phenotypes, including obesity and inflammatory bowel disease. Establishment of a biobank with routinely collected oral, fecal and perhaps other materials, in a large network of pre-paid health plans will provide the essential pre-cancer specimens that are necessary to attribute causality. Specimen collection, storage, and processing methods have been proven effective. Implications of success: As with the addition of human papillomavirus (HPV) DNA testing to cervical cytologic screening, a fecal test for “high risk” microbiota, integrated with colonscopy and other screening tests, would help to reduce colorectal cancer mortality through early detection. Similar approaches can be envisioned for other digestive tract cancers. (Review or Add Comments)

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Question ID: WS-33
Submitted By Sanford Dawsey on February 4, 2011 (0 comments)

Are there additional common malignancies that are caused by oncogenic viruses? Background: 50 years ago, no malignancies were thought to be caused by viruses. Since then, oncogenic viruses have been shown to cause about 20% of human cancer cases, including cervical cancers, hepatocellular carcinomas, Kaposi’s Sarcomas, nasopharyngeal carcinomas, and several lymphomas. Whenever a viral etiology is found, the possibility exists that a prophylactic or therapeutic vaccine can be developed that can significantly reduce the mortality of the virus-induced cancer. Feasibility: With the advent of high-throughput sequencing and computational subtraction bioinformatics, it is now possible to efficiently identify viral mRNA transcripts in tumor tissues, and promising viruses (including novel ones) can be evaluated in population studies for their association with tumor development. Such an approach has not yet been initiated in a systematic way for the major human cancers, but this could be done if the NCI leadership made this a priority and encouraged appropriate collaborations. Implications of Success: Finding a new viral cause and developing a successful vaccine for even one major human cancer could make a tremendous impact on cancer mortality worldwide, and could be one of the most significant contributions of our generation to reducing the burden of cancer in the world. (Review or Add Comments)

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Question ID: WS-32
Submitted By Jill Koshiol on February 4, 2011 (0 comments)

Question: What failures in immune surveillance lead to cancer development and to poorer prognosis given cancer? (Jill Koshiol; Eric Engels) Background: HIV-infected individuals are at increased risk for some cancers, in large part due to immunosuppression and the frequent presence of viral co-infections. Although use of highly active antiretroviral therapy (HAART) has led to declines in Kaposi sarcoma and non-Hodgkin lymphoma (NHL), other cancers that occur more often in HIV-infected populations have not decreased (e.g., cervical, anal, and lung cancers), and some (e.g., Hodgkin lymphoma) have increased. Perhaps surprisingly, HIV-infected persons do not have markedly high risk for other cancers that appear to be influenced by the immune system (e.g., melanoma). Finally, cancers occurring in HIV-infected individuals appear to be more aggressive than similar cancers arising in uninfected individuals. These differences in outcome may reflect interactions in the tumor microenvironment involving tumor cells and the host immune system. Feasibility: Detailed evaluation of tumor tissues from those cancers arising in HIV-infected persons compared to HIV-uninfected persons can yield important information on the etiology of cancers in the HIV-infected population, and by extension, the role of an intact immune system in preventing and controlling cancer in healthy individuals. Examination of these tissues can identify histologic characteristics (e.g., tumor infiltration by immune cell subsets) or molecular markers that could have etiologic or prognostic importance. Implications of success: By identifying differences in immune response between HIV-infected and HIV-uninfected persons, it may be possible to identify normal immune surveillance mechanisms that must be overcome in HIV-uninfected persons for the development of cancer but do not need to be circumvented in HIV-infected persons given the extensive immunosuppression due to HIV itself. Identification of these underlying molecular mechanisms may allow development of interventions to prevent progression to cancer in HIV-uninfected individuals and improvement of prognosis in HIV-infected individuals. (Review or Add Comments)

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Question ID: WS-31
Submitted By Jill Koshiol on February 4, 2011 (0 comments)

Question: How can we better understand the role of immune response in cancer etiology and prognosis? (Jill Koshiol; Ligia Pinto; Ann Hsing; Nat Rothman; Qing Lan; Mark Purdue) Background: A number of studies have found that chronic inflammation is associated with tumor development and progression, as demonstrated by infectious conditions, such as Helicobacter pylori infection increasing risk of gastric cancer; and autoimmune diseases, such as inflammatory bowel diseases and Sjögren's syndrome increasing risk of colon cancer and non-Hodgkin lymphoma. The association between inflammation and cancer is complex, however, with some immune responses contributing to tumorigenesis, while others inhibit tumor growth. Feasibility: The availability of large, carefully collected biological specimens combined with high-quality clinical data in a large number of high quality prospective cohort studies and the availability of validated high throughput multiplex technologies and robust immunohistochemistry markers will contribute to clarifying the role of immune response in cancer etiology and tumor prognosis, especially for tumor models with known precursors (e.g., gastric cancer, cervical cancer, multiple myeloma, chronic lymphcytic leukemia). For example, several studies have already identified serum cytokine and related biomarkers that are associated with increased risk of lymphoma for 6-10 years before disease occurs. Implications of success: A better understanding of the pro- and anti-tumorigenic patterns of immune cell infiltration and cytokine expression involved in cancer development and progression in the general, immunocompetent population may help identify biomarkers important for early steps in cancer etiology and progression from pre-cancerous conditions, as well as identifying potential targets for cancer treatment and sub-populations of patients who may need more aggressive therapy. (Review or Add Comments)

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Question ID: WS-30
Submitted By Maria Teresa Landi on February 4, 2011 (1 comments)

What molecular mechanism(s) are responsible for the association between inflammation and cancer risk or progression? Maria Teresa Landi, DCEG, GEB Background. A growing body of evidences supports the contribution of chronic inflammation to the development of malignancies. The association between the use of non-steroidal anti-inflammatory agents (NSAIDs) and protection against cancer further emphasizes the role of inflammation in carcinogenesis. Recently, inflammation has also been linked to the acquired capacity to metastasize during tumor progression. Basic research has shown that organ-specific carcinogenesis is linked to the development of a chronic local inflammatory micro-environment and obesity may play a role in this process. Although inflammatory signaling molecules in the tumor micro-environment have been identified, the molecular basis of the association between inflammation and cancer and why the inflammatory response to the same triggering agents varies across individuals remain largely unknown. Feasibility. Genome-wide association studies (GWAS) have identified genomic loci associated with different cancer types. Circulating inflammatory markers have been tested in inflammatory diseases. To investigate genetic susceptibility to inflammation, GWAS-derived genetic variants in the inflammatory pathway(s) can be tested in healthy controls in relation to circulating inflammatory markers. The genetic variants associated with markers of inflammation can be analyzed in relation to cancer risk in the presence of factors that may trigger inflammation, such as previous diseases (e.g., pancreatitis), obesity, infections (e.g., Helicobacter pylori), tobacco smoking, intermittent sun exposure, alteration of sex steroid hormones, or occupational exposures (e.g., asbestos). In outcome studies, the association between cancer treatment and disease-free survival or development of toxicities in relation to inflammation-related genetic variants can also be studied. If tissue specimens are available, presence of inflammatory elements in the tumor micro-environment in subjects exposed to triggering agents can be conducted in relation to cancer outcome. Experimental studies before and after administration of NSAIDs can be used to verify the role of these factors and the reversibility of the inflammatory environment. Implications of success. A deeper understanding of the mechanism(s) associated with inflammation-related carcinogenesis and individual susceptibility to inflammation-related cancer could suggest new prevention strategies particularly for at-risk subjects. Understanding the mechanistic link between treatment-associated inflammation and cancer outcome can improve cancer treatment strategies. Epidemiological, genetic, clinical and biological investigations can be integrated to reach these goals. (Review or Add Comments)

Average Score: 4.0 4.0 (2 evaluations)
Question ID: WS-29
Submitted By Allan Hildesheim on February 3, 2011 (0 comments)

Question: What are the specific mechanisms of antigen processing and presentation whose variation impact risk of development of infection-related cancers? Background: Results from multiple genome-wide association studies (GWAS) of 1) cancers that are proven to be caused by infections and 2) chronic carriage of infections that have been definitively linked to cancer have repeatedly found that polymorphisms in the Major Histocompatibility Complex (MHC) region of chromosome 6 show the strongest evidence for association. These findings reinforce previous candidate gene studies that have shown clear associations between HLA genes located within the MHC and these same infection and cancer outcomes. It is plausible that genetic predisposition based on HLA genes is among the most consistent genetic factors known to predispose to human cancers. HLA genes are complex, highly variable, have different biological functions, and are in strong linkage disequilibrium with each other. As a result, despite our knowledge that HLAs (and possibly other immune-related genes in the MHC) are important for the development of infection-related cancers, the specific genes/alleles involved and their precise biological role in cancer development remains unproven. Feasibility: GWAS studies have paved the way for large, targeted studies that could for the first time elucidate the specific HLA (or other) genes within the MHC involved in cancer development. HLA-specific and SNP/sequencing-based genotyping approaches exist that can be combined to allow for the evaluation of this question within well-characterized and sufficiently powered epidemiological studies, combined with functional biological studies of resultant associations. Implications of success: If this question can be answered, it will be the first time that a specific immunological mechanism is shown to be involved in the development of multiple cancer types caused by infectious agents and that together account for approximately 20% of all cancers worldwide. (Review or Add Comments)

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Question ID: WS-28
Submitted By Allan Hildesheim on February 3, 2011 (0 comments)

Question: Why does EBV cause different types of cancer in different populations? Background: It has long been known that Epstein-Barr virus (EBV), a ubiquitous virus that establishes lifelong infection in its host, is linked to the development of various cancers, including Burkitts lymphoma (BL), other subtypes of non-Hodgkins lymphomas (NHL), nasopharyngeal carcinoma (NPC) and a subset of gastric cancers. However, the distribution of EBV-associated tumors varies considerably in different regions. The reasons why EBV tends to cause BL in some regions and NPC in others is poorly understood. Geographical differences in the virus, the host, or other environmental exposures likely explain differences and deserve further study. Feasibility: The maturing of well-characterized population studies of EBV-associated tumors in various geographical regions, combined with new high-throughput technologies capable to exploring viral and host genetics, and viral and host gene/protein expression patterns make it feasible to explore this question in ways that were not possible in the past. Implications of success: Understanding why a ubiquitous virus causes cancer in some individuals and not others, and why individuals who acquire viral-associated cancers do so at different sites would shed light into important pathogen and host mechanisms of cancer development. The practical applications of such new-gained knowledge are hard to predict prospectively, but are likely to exist. (Review or Add Comments)

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Question ID: WS-27
Submitted By Allan Hildesheim on February 3, 2011 (1 comments)

Question: Do events in early life affect risk of cancer development in later life? Background: It has long been hypothesized that early life events are important predictors of adult-onset diseases including cancer. In-utero endocrine exposures, early life exposures and responses to viruses and other pathogens, and early life exposures to environmental/chemical toxins have all been suggested to be associated with cancer development. Most studies to date, however, have been retrospective and/or small, and have therefore been limited in their ability to fully elucidate the link between early life exposures and cancer. Feasibility: Advances in our ability to 1) measure early life exposures postulated to affect health, 2) collect the necessary biological specimens required to measure these exposures, and 3) evaluate proximal intermediate cancer precursors and their outcomes make thoughtful study of this area feasible should the political will to embark in such an effort be present. Implications of success: Understanding important early life predictors of adult-onset diseases could make currently unmodifiable risk factors amenable to modulation through early life public health interventions. (Review or Add Comments)

Average Score: 2.5 2.5 (3 evaluations)
Question ID: WS-26
Submitted By Olivera Finn on February 3, 2011 (6 comments)

Why are cancer vaccines not considered a priority area to develop for cancer prevention? For reasons that after 30 years in tumor immunology research I still do not understand, tumor immunologists have been saddled with a challenge to develop a therapeutic cancer vaccine. While doomed to failure in this ultimate goal, we have learned a lot about the immune system of a cancer patient and the immune targets on the cancer cell. From numerous small individual efforts we have derived consensus observations. The most important: many targets of therapeutic vaccines are present on premalignant lesions and could be targeted with prophylactic vaccines to prevent progression of these lesions to cancer; if the right prophylactic setting is selected, contrary to naysayers, it would not take 25 years to know that the vaccine was effective – many settings would give this answer in 3-5 years; the best animal models have shown high immunogenicity and complete safety of prophylactic cancer vaccines; the high safety profile supports future vaccination of people at risk. (Review or Add Comments)

Average Score: 5.0 5.0 (6 evaluations)
Question ID: WS-25
Submitted By Olivera Finn on February 3, 2011 (0 comments)

ProtectOME? We have paid a lot of attention to the importance of the cancer genOME, cancer proteOME, cancer metabolOME and will probably invent other cancer OMES without acknowledging the most important fact that cancer grows in the host and its chance to express all its various OMES is fully dependent on whether the host immune system will allow it or not. There is accumulating evidence that the immune system recognizes abnormal expression of various cellular proteins that occur during viral infections, bacterial infections, chronic inflammations and malignant transformation. By building immune memory for “abnormal self” through exposure to pathogens early in life the immune system is better prepared to eliminate abnormal cells before they become a threat. By gaining access to large well-annotated cohorts of individuals whose sera can be interrogated in a high throughput fashion for specific antibody signatures (many of which are expected to correspond to antibodies against well known tumor associated antigens), we will gain better insight into cancer risk, cancer prognosis and targets for cancer therapy. Specific molecules or their synthetic mimics recognized by antibodies and correlated with good health, low cancer risk, better cancer prognosis after diagnosis, longer survival, better response to immunotherapy, or any other outcome, would become the protectome to be interrogated for other diseases and used in designing therapies. (Review or Add Comments)

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Question ID: WS-24
Submitted By Jorge Gomez on February 2, 2011 (0 comments)

Why some patients respond to treatment (chemotherapy or targeted therapy) and some others do not? (Review or Add Comments)

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Question ID: WS-23
Submitted By Pawel Kalinski on February 2, 2011 (0 comments)

Background: Accumulating data indicate that clinical benefit of immmunotherapies of cancer, including cancer vaccines, may take place in the absence of objective clinical responses (as measured by RECIST rriteria). Recent FDA guidance discusses the differences in the mode of anticancer effects of vaccination (indirect and delayed in time )versus the killing of tumor cells by cytostatic drugs (direct adn immediate) (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm182443.htm), reflecting the observations that vaccines and potentially other immunotherapeutic drugs may prolong overall survival even in the presence of early progression of the disease. In this situation, the classical design of early phase clinical trials, and the emphasis on RECIST criteria of response developed to evaluate the effectiveness of chemotherapeutic agents (that directly target tumor cells), may limit our ability to identify new immunotherapeutic drugs, and potentially other cancer drugs that target cancer only indirectly (for example, targeting tumor stroma). The same time, the use of Overall Survival as the primary endpoint in the currently-used clinical trial designs translates into large size of study cohorts, long follow-up times, and the resulting high costs of trials, making it difficult to use in early-phase clinical testing. In this situation, addressing the folllowing questions would help to accelerate the development of new cancer treatments, especially these treatments that aim to change the pattern of interactions of cancer cells with the the host (immunotherapies and stroma-targeting approaches): 1) Can alternative endpoints and novel trial designs be developed to reduce the size of study cohorts in early-phase clinical trials and accelerate the development of biologic therapies of cancer? 2) Can selection of particular inclusion criteria be used to reduce the variation in a) natural course of disease and b) response to therapies, allowing to reduce the study cohorts in early phase clinical trials using overall survival as the primary endpoint of efficacy? 3) Why only a fraction of patients treated with individual biologic agents fulfils the RECIST criteria of response? Can the response to this question facilitate the development of improved therapies? Can it be used to stratify the patients on prospective clinical trials? (Review or Add Comments)

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Question ID: WS-22
Submitted By Irving Weinberg on January 31, 2011 (0 comments)

Can we make sense of various measurable factors relating to breast tissue activity (i.e., breast density, insulin-like growth factor, PET-measurements of glucose uptake in the breast) to predict the likelihood of future malignancy? Background: Separate groups have determined strong relationships between each of the above factors and the risk of breast cancer. Because of silo-ing within the biomedical community, no group has put it all together. Feasibility: A longitudinal clinical trial that included the collection of serum and breast tissue for local IGF measurements, combined with quantitative measurements of x-ray density and FDG uptake, might shed light on the biology of carcinogenesis. (Review or Add Comments)

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Question ID: WS-21
Submitted By C. Anthony Blau on January 31, 2011 (0 comments)

How can we convert the experiences of individual cancer patients into scientifically valid experiments? Background: We know that every cancer is unique, yet our clinical trials assume that patients can be clustered into groups that are more or less similar. Feasibility: It would be feasible to intensively study a small number of cancer patients who are beyond "standard of care." These patients would be highly selected based on their interest and the clinical and scientific appropriateness for their participation in a "Manhattan Project" in which the patient and their tumor would be the subject of investigation. In a "no-holds-barred" effort, any scientifically defensible technology that might provide insight into the patient and/or their tumor should be considered. The goal of this effort would be to generate hypotheses regarding tumor drivers and potential susceptibilities, and then to directly test these hypotheses by treating the patient with the corresponding drug (or drugs) that are predicted to be effective. Repeated biopsies of the tumor following drug treatment would allow one to monitor the molecular responses to the treatment and to correlate these with clinical responses. Additional biopsies after disease relapse might uncover tumor strategies for escape, and the treatment could be modified accordingly. While this approach may be premature for some types of advanced cancer, it seems especially well suited for cancers where a lot is already known, for example GIST. An obvious difficulty of this approach rests in a lack of controls, however innovative strategies could be envisioned, for example comparisons of stable versus progressive disease within an individual patient. Implications of success: Efforts to deeply understand a few cancer patients may uncover important findings for cancer patients generally. (Review or Add Comments)

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Question ID: WS-20
Submitted By Peter Scardino on January 31, 2011 (0 comments)

Do regional lymph nodal metastases from solid tumors differ biologically from metastases to distant sites? Background: Metastases from solid tumors to regional lymph nodes (LN) are relatively common, their frequency varies markedly among tumor types but within type is associated with the aggressiveness of the primary tumor, their presence and extent are usually poor prognostic factors, they are difficult to detect by imaging, and the therapeutic benefit of lymph node dissection remains uncertain. Since the days of Halstead, regional lymph node dissection (LND) – more or less extensive - has generally accompanied surgical (and often radiotherapeutic) treatment of the primary tumor. A sizable minority of patients with regional LN metastases survive long term without recurrence after locoregional therapy alone (no systemic therapy). The few randomized trials performed have left unsettled the therapeutic value of regional LND, yet enthusiasm for more trials is muted by the uncertainty about the biological and clinical significance of nodal metastases. Recent studies suggest tumor induced lymphangiogenesis is an important mechanism that promotes nodal metastases. Feasibility: Modern cancer biology has the tools to discover whether nodal metastases differ in biologically important ways from the primary tumor and distant metastases in the same patient, and to identify the features that distinguish classes of tumors with frequent (e.g., melanoma) versus rare (e.g., sarcoma) nodal metastases. As the TCGA completes comprehensive genomic analyses of large sets of primary tumors, it could focus on matched pair analyses of primary tumors, LN metastases and distant metastases from the same patient. Randomized clinical trials of patients at high risk for LN metastases could assess the therapeutic benefits, if any, of regional LND (none v. any, limited v. extensive) in a variety of tumor types (e.g., bladder, kidney, prostate cancer). Implications of success: hundreds of thousands of surgical resections and radiation treatments of primary tumors are performed each year in the U.S. without clear indications whether therapy should also be directed specifically at the regional lymph nodes. If LND has no therapeutic benefit, the cost and morbidity of these procedures could be eliminated, and focus could be placed on the development of better noninvasive imaging to detect nodal metastases and optimal use of systemic rather than regional therapy for patients likely to have nodal metastases. Novel targeted therapeutics, which reduce the risk of LN mets, or block their ability to metastasize further, could greatly increase disease free survival rates for the common cancers. (Review or Add Comments)

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Question ID: WS-19
Submitted By Peter Scardino on January 31, 2011 (0 comments)

Do regional lymph nodal metastases from solid tumors differ biologically from metastases to distant sites? Background: Metastases from solid tumors to regional lymph nodes (LN) are relatively common, their frequency varies markedly among tumor types but within type is associated with the aggressiveness of the primary tumor, their presence and extent are usually poor prognostic factors, they are difficult to detect by imaging, and the therapeutic benefit of lymph node dissection remains uncertain. Since the days of Halstead, regional lymph node dissection (LND) – more or less extensive - has generally accompanied surgical (and often radiotherapeutic) treatment of the primary tumor. A sizable minority of patients with regional LN metastases survive long term without recurrence after locoregional therapy alone (no systemic therapy). The few randomized trials performed have left unsettled the therapeutic value of regional LND, yet enthusiasm for more trials is muted by the uncertainty about the biological and clinical significance of nodal metastases. Recent studies suggest tumor induced lymphangiogenesis is an important mechanism that promotes nodal metastases. Feasibility: Modern cancer biology has the tools to discover whether nodal metastases differ in biologically important ways from the primary tumor and distant metastases in the same patient, and to identify the features that distinguish classes of tumors with frequent (e.g., melanoma) versus rare (e.g., sarcoma) nodal metastases. As the TCGA completes comprehensive genomic analyses of large sets of primary tumors, it could focus on matched pair analyses of primary tumors, LN metastases and distant metastases from the same patient. Randomized clinical trials of patients at high risk for LN metastases could assess the therapeutic benefits, if any, of regional LND (none v. any, limited v. extensive) in a variety of tumor types (e.g., bladder, kidney, prostate cancer). Implications of success: hundreds of thousands of surgical resections and radiation treatments of primary tumors are performed each year in the U.S. without clear indications whether therapy should also be directed specifically at the regional lymph nodes. If LND has no therapeutic benefit, the cost and morbidity of these procedures could be eliminated, and focus could be placed on the development of better noninvasive imaging to detect nodal metastases and optimal use of systemic rather than regional therapy for patients likely to have nodal metastases. Novel targeted therapeutics, which reduce the risk of LN mets, or block their ability to metastasize further, could greatly increase disease free survival rates for the common cancers. (Review or Add Comments)

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Question ID: WS-18
Submitted By Al Musella on January 30, 2011 (0 comments)

Why isn’t there a national database of cancer patients [perhaps only include those cancers with poor outcomes] which includes their treatments and outcomes. Perhaps include all any genetic testing done. We have no idea how treatments work in the real world. Clinical trials have strict criteria, and exclude a huge segment of the cancer population. They also do not allow the addition of off protocol medications. In the real world, treatments are combined in unique ways and adjusted as needed instead of following a protocol explicitly. They are also used on older patients, sicker patients and patients who do not have access to major centers. We have no idea how alternative treatments and homeopathic treatments work. We hear of individual case reports of amazing success, but out of how many? IF there are 10 complete remissions out of 20 patients, we should look further into it. If there are 10 out of 10,000 – we can safely ignore it. But we have no idea how many users there are. There are many brilliant oncologists out there who are practicing the art of medicine by trying different combinations. Nobody is tracking this. The few who track them rarely publish them. We need a way to spot promising trends and then follow up on them. I set up such a registry for brain tumors – I call it the brain tumor virtual trial. See virtualtrials.com. It is patient reported treatment and outcome data, but it gives us a feel for what is working the best, and what is being tried. My experiences are that it is a worthwhile project and should be expanded to all poor outcome cancers, and combine patient reported with physician reported data. There is a unique opportunity now as the government is pushing doctors into using Electronic Health Records. We could easily add a meaningful use metric of submitting the data to a national database. A simple button that would take the data from the HER and submit it to the national database. (Review or Add Comments)

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Question ID: WS-17
Submitted By John Baron on January 27, 2011 (0 comments)

Does DFMO really seriously impede colorectal carcinogenesis, as suggested in a recent clinical trial with an adenoma endpoint? Does this imply that polyamines are central to the development of neoplasia in the large bowel? Meysekens et al reported that DFMO + sulindac reduced the risk of all adenomas by about 70%, and reduced the risk of advanced adenomas by more than 90%. These findings are substantially more marked than those of any other chemopreventive agent. Since DFMO is a designer drug that inhibits ornithine decarboxylase, the first step in the synthesis of polyamines, these results imply that polyamines may be central to colorectal carcinogenesis. (Review or Add Comments)

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Question ID: WS-16
Submitted By Ellen Provost on January 27, 2011 (0 comments)

Are women with BRCA positive breast cancer at increased risk for serious side effects/complications from radiation therapy? Are women with the BRCA gene mutation at increased risk for cancer by undergoing mammograms? (Review or Add Comments)

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Question ID: WS-15
Submitted By Ellen Provost on January 27, 2011 (0 comments)

What are the most appropriate cancer screening modalities for women with fibrodense breast tissue with or without fibrocystic changes in order to catch cancer as early as possible? Do women with fibrodense breast tissue get diagnosed at later stages? What about the role of MBI (gamma radiation) technologies in helping to find cancer early in these women? (Review or Add Comments)

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Question ID: WS-14
Submitted By Caryn Lerman on January 27, 2011 (0 comments)

How can we harness advances in neuroscience to promote changes in cancer-related behaviors and cancer prevention? Advances in our understanding of neurobiology, coupled with technological advances in brain imaging, offer unprecedented opportunities to explore the neural substrates of decision-making and behavior. With the proper foundational research, this work could potentially be translated into cognitive training interventions to increase behavioral control among individuals struggling with cancer risk behaviors, such as obesity and tobacco use. (Review or Add Comments)

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Question ID: WS-13
Submitted By David Mankoff on January 26, 2011 (0 comments)

Question: How can we use molecular imaging to accelerate the process of drug development and testing? Background: Molecular imaging can quantify the in vivo biology of cancer, and monitor its response to treatment, and can provide a useful tool for accelerating translation of new therapeutics into clinical trials and clinical practice. Imaging may be particularly helpful for targeted drug therapy, by verifying that the target is present in all disease sites and by measuring the effect of the drug on the target and on the cancer. While the ability of molecular imaging to facilitate cancer drug testing and clinical trials has been recognized for some time (Kelloff,2005), there has been slow progress in harnessing the full power of molecular imaging for clinical cancer trials. Feasibility: The limited access of investigators to novel molecular imaging probes has hampered widespread use. However, over the past few years, work by individual centers, the NCI Cancer Imaging Program, and NCI research grants has resulted in a readily available commercial supply of many probes. NCI-held INDs for PET probes have contributed to their wider use in clinical trials, and provided standardized imaging protocols and data analysis. Early studies have demonstrated the ability to implement molecular imaging and obtain consistent and reproducible results in multi-center trials. The remaining hurdle is providing an incentive to use molecular imaging in early drug trials, mostly likely by encouraging private-public partnerships between pharma (sponsors of early drug trials) and academia and cooperative groups (experts in molecular imaging). At the same time, it is important to continue development and phase I validation of new imaging probes. Implications of Success: The use of molecular imaging to guide drug testing should increase the efficiency of drug development and accelerate the clinical implementation of treatments destined to be useful. In many cases, these same imaging tests can be used to guide the selection of targeted cancer therapy in the clinic, directing clinicians towards the drug most likely to be effective, and avoiding drugs unlikely to have an impact on the tumor and the patient’s survival. 1. Kelloff GJ, Krohn KA, Larson SM, et al. The progress and promise of molecular imaging probes in oncologic drug development. Clin Cancer Res. Nov 15 2005;11(22):7967-7985. (Review or Add Comments)

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Question ID: WS-12
Submitted By Stephen Lippard on January 26, 2011 (1 comments)

Cisplatin is one of the most widely used anticancer drugs, being used in the clinic for over 30 years. Its efficacy against testicular cancers is extremely high compared to all other tumors. My question is: WHY? The answer to this question would have profound implications in the design of newer generation platinum compounds to treat cancer. (Review or Add Comments)

Average Score: 5.0 5.0 (1 evaluation)
Question ID: WS-11
Submitted By Liewei Wang on January 26, 2011 (0 comments)

With the advancement of technology, genome wide association studies have been performed with regard to risk and treatment outcomes of cancer. Although the whole genome scan can expand our knowldege to the areas that are not known currently, we have not gained insights on the biology assoicated with these association studies. How can we move beyond biomarkers and use these information to help identify and understand novel biology and novel mechanisms? How to best use the technology to advance our understanding of cancer development and treatment? More studies need to be focused on the function and mechanisms in the post genomic era. (Review or Add Comments)

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Question ID: WS-10
Submitted By Gerald Denis on January 26, 2011 (0 comments)

Cancer, obesity and inflammation Background. ‘Metabolically healthy obese’ (MHO) individuals comprise about 25% of the adult obese population in the US. This population enjoys a significantly reduced risk of complications arising from obesity, such as cardiovascular disease and Type 2 diabetes. Interestingly, they also display a reduced inflammatory profile, including relatively less severe elevation of TNF, CRP, TGFb and other proinflammatory cytokines in the context of their obesity, as well as relatively less severe ablation of protective factors such as adiponectin. Given the well established links between obesity and inflammation, and between inflammation and cancer, it is reasonable to hypothesize that MHO individuals show a reduced incidence of certain obesity-associated cancers, such as colorectal cancer and breast cancer. (Cf. Denis (2010) Discov Med 10: 489-99. PMID: 21189220) Feasibility. Unhealthy obese individuals should be compared to MHO, with regard to SNPs in the genes that encode pro-inflammatory cytokines, or loci implicated in the HLA-associated diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, lupus and Type 1 diabetes). Serum markers of inflammation could be correlated with cancer risk. Biomarkers that define protection from cancer could be deduced from such populations. Implications. For the sake of argument, if human inflammatory responses exhibit a Gaussian distribution, and the MHO population anchors the left hand end, then a symmetric distribution of inflammation implies a right hand end of the population that is more ’pro-inflammatory’ than the mean. Obese individuals at this end of the distribution, accounting for perhaps as many as 10 million Americans, would be predicted to have much greater risk of obesity-associated Type 2 diabetes and cardiovascular disease than the mean, and also to have elevated risk for obesity-associated cancers. At present, biomarkers that identify this at-risk group are unknown, nor are therapeutic options or behavioral interventions identified. NCI should consider developing an RFA to address this question. (Review or Add Comments)

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Question ID: WS-9
Submitted By Amy Zhang on January 26, 2011 (0 comments)

How can we refocus biobehavioral research on promoting patient's self care and community-center(clinic) based care to manage chronicle diseases? How can we learn from other countries (such as China) that use less resources but more patient's own self-care and community supports to maintain societal health? (Review or Add Comments)

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Question ID: WS-8
Submitted By Rui Sousa on January 25, 2011 (4 comments)

Why are different tissues so dramatically different in their tendencies to develop cancer? This question seems rarely to have been addressed in the literature and yet it needs an answer. The prostate gland, for example, weighs 10-20 grams, but accounts for 220,000 new cancer cases every year in US males. In contrast, soft tissues (fat, muscle, sinew, and cartilage) make up the largest part of the human body (by weight or cell number), but soft tissue cancers account for only 8,000-9,000 new cases in the US each year. We can estimate that a prostate cell is 10,000-100,000 times more likely to become cancerous than is a cell of the soft tissues! Stated differently: if all the cells in our body were as likely to become cancerous as a prostate cell is, we would all be developing about 2-3 new cancers every year. The extraordinary differences in the oncogenic potential of different human tissues is a less easily dismissed question than is Peto’s paradox, which observes that, since whales have about 1000 times as many cells as humans, they should have vastly more cancers if their cells had similar oncogenic potential as ours(Bredberg, 2009, Cancer resistance and Peto's paradox. PNAS 106:E51). But in the latter case, a reasonable adaptive explanation is that whales have necessarily evolved better cancer resistance mechanisms (more active DNA repair or immune surveillance mechanisms) than humans, since they would otherwise be nonviable as a species. I am unaware of any evidence, however, that the repair mechanisms of human tissues showing high cancer incidence are poorer than those in tissues where cancer is rare; nor is there any obvious adaptive explanation for such a difference. The molecular mechanisms and expression patterns of genes known to predispose to cancer (the BRCA or RB genes, for example) are little help in illuminating this since they are usually ubiquitously expressed and perform functions required in all cells (BRCA1: the enigma of tissue-specific tumor development, Monteiro, Trends in Genetics 19, 2003, 312). To be sure, hypotheses can be advanced to explain this. Perhaps secretory tissues (breast, prostate, pancreas, etc…) are more prone to become cancerous (buy, why)? Perhaps tissues that are developmentally responsive to sexual hormones (breast, uterus, prostate, testes) are more plastic and thus more likely to transform? But this is all pure speculation and it seems a scandal that we do not have a more substantive answer for why different tissues can vary by up to 100,000-fold in their probability of originating a cancer (Review or Add Comments)

Average Score: 4.5 4.5 (2 evaluations)
Question ID: WS-7
Submitted By Lewis Kuller on January 21, 2011 (1 comments)

Does substantial weight loss reduce the incidence and mortality due to cancer? Probably about 200,000 individuals now have various types of surgeries in the United States for obesity. Several studies suggest that weight loss reduces the incidence of some cancers, both endocrine- and nonendocrine-related. The Swedish Obesity Study (pseudo trial) reported a substantial decrease in cancer incidence and mortality. More moderately obese individuals in the BMI range of 35-50 kg/m2 are now having surgery. They usually can maintain substantial weight loss for a long period of time. it may be feasible to do a clinical trial to compare, for example, LAP-BAND® surgery for weight loss with behavioral weight loss and other surgical procedures with cancer outcomes as one of the events. We also can raise the question whether it is possible from observational follow up studies to determine the risk of cancer. It is possible that substantial weight loss may be one of the most effective ways to reduce cancer incidence in the population. (Review or Add Comments)

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Question ID: WS-6
Submitted By Lewis Kuller on January 21, 2011 (0 comments)

Insulin resistance and hyperinsulinemia may stimulate cell growth and angiogenesis. Hyperinsulinemia syndrome, such as the metabolic syndrome, has been associated with a substantial increased risk of many cancers, including most recently pancreatic cancer. Metformin is a safe and very effective drug widely being used in the treatment of type 2 diabetes and has been show to have effects in decreasing insulin levels and insulin resistance and also effecting changes in cells which has been associated with longevity. There are a variety of studies suggesting that metformin is associated with a decrease in incidence of cancer and potentially increased longevity. A clinical trial in nondiabetic individuals would be useful to determine whether metformin reduces the risk of cancer, especially pancreas and colon cancer, decreasing CVD and increasing longevity. This drug is safe, very cheap and has minimal side effects. (Review or Add Comments)

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Question ID: WS-5
Submitted By Lewis Kuller on January 21, 2011 (0 comments)

Hypertension and kidney cancer – Hypertension is a major risk factor for kidney cancer independent of obesity, race, cigarette smoking and renal disease. There is also a substantial increased risk of kidney cancer among patients with chronic kidney disease, i.e. on dialysis. Clear cell renal carcinoma is often associated with mutations in the von Hippel Landau tumor suppressor gene, an important regulator of hypoxia inducible genes. Hypertension may cause renal cell hypoxia and increased hypoxia inducible factors, which could be related to hyperplasia and renal cell carcinoma. Hypertension is also associated with increased angiotensin-1, an important cell proliferator. There are very few studies that determine whether specific antihypertensive drugs increase or decrease the risk of renal cell carcinoma. We would hypothesize that antihypertensive drugs, which are direct renin inhibitors would reduce the risk of renal cell carcinoma. A well done case-control study could perhaps determine the relationship of specific drug therapy for hypertension and renal cell carcinoma, the characteristics, i.e. presence or absence of specific Von Hippel Landau mutations, somatic mutations. Similarly, the massive national dialysis data base may be queried to determine the risk and characteristics of patients who develop renal cell carcinoma. (Review or Add Comments)

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Question ID: WS-4
Submitted By Sara Barton on January 20, 2011 (1 comments)

I've met a number of Stage IV patients over the years who have survived at that level well past the expected norm, many for more than four years beyond, and these specific patients seem to have life survival skills that they brought to the cancer situation. They also often had spouses with similar survival skills learned through catastrophic events they endured. These patients have learned to identify subtle physical changes that allow them to get immediate treatment for metasticized cancers. Do people who have these existing survival skills fare better during cancer treatment as a result of previous (often unrelated)catastrophic experience, and are their experienced spouses a significant factor in their survival? If so, can these same survival skills be taught to other cancer patients? (Review or Add Comments)

Average Score: 4.5 4.5 (3 evaluations)
Question ID: WS-3
Submitted By Gregory Petsko on January 19, 2011 (2 comments)

People afflicted with Alzheimer's, Parkinson's, and Huntington's diseases, as well as Fragile X Syndrome patients, have a significantly lower risk of most cancers (the exception is melanoma, for which there is an increased risk for Parkinson's patients). The converse is also true: cancer survivors are at lower risk for several neurodegenerative diseases. What is the biochemical/cell biology basis for this striking inverse correlation, and can it be exploited for new therapeutic approaches? (Review or Add Comments)

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Question ID: WS-2
Submitted By Steven Pavletic on January 19, 2011 (0 comments)

Why there has not been a more formal tracking and studying of spontaneous regressions of advanced cancers? Background: Each year over last couple decades several case reports of spontaneous regressions of wide variety of cancers appear in the peer reviewed literature. Feasibility: It should not take huge resources to establish a formal tracking system - registry of all such cases at the NCI using the standardized set of questions and describing clinical circumstances around such regressions and rank the levels of credibility of such cases. This could be preceeded by a comprehensive review - meta analysis of all available literature. A system for obtaining blood samples for studying such patients and or being seen at the intramural NCI could be also fairly easily established and well suited for the NCI intramural program. Implications: If proven true the fact that cancer can regress "spontaneously" or after some identifiable triggers could harbour the clue for the cure of cancer. (Review or Add Comments)

Average Score: 4.5 4.5 (1 evaluation)
Question ID: WS-1
Submitted By Jingwu Xie on January 14, 2011 (2 comments)

Are cancer stem cells responsible for cancer recurrence after treatment? Cancer stem cell theory has been proposed to explain tumor recurrence after cancer chemotherapy. Although there are some disagreements about the markers and even the existence of cancer stem cells. This theory is still the best to explain a lot of biology in cancer treatment. The question is to provide evidence for the cancer stem cell hypothesis. (Review or Add Comments)

Average Score: 3.5 3.5 (1 evaluation)