PQ - 1
How does obesity contribute to cancer risk?
Background: While many studies have documented an increased risk of cancer incidence and mortality in individuals who are obese, the mechanisms that underlie this risk remain poorly understood. What molecular changes induced by obesity actually promote cancer development? Can we describe these changes in ways that will allow a mechanistic link between risk and cancer cell biology? Are the risks reversible as some data suggest (R) and, if so, by what mechanism?
Feasibility: Recent studies of the endocrinology of eating disorders, the metabolic correlates of fat accumulation, the pathogenic consequences of obesity (such as diabetes mellitus), and the development of powerful molecular profiling methodologies have created opportunities for understanding the relationship of obesity to carcinogenesis at a mechanistic level. Relevant research could include molecular studies to identify metabolic and signaling pathways associated with obesity. Studies on the genetics of obesity may be helpful in identifying key regulatory pathways that may link to cancer development.
Implications of success: A deeper understanding of the mechanisms of the cancer risk posed by obesity could suggest new strategies for countering these risks. Understanding how obesity is mechanistically linked to cancer development would bridge epidemiologic identification of risk factors with the molecular biology of cancer development. This would be a remarkable confluence of two exceptionally important cancer research disciplines and would point the way to many more studies that could make obesity-related cancer pathogenesis much clearer.
PQ - 2
What environmental factors change the risk of various cancers when people move from one geographic region to another?
Background: Numerous studies have identified associations between the incidence of various cancers and local living conditions. There are many well-documented examples of cancer incidence changing as populations migrate from one site to another. These migrating populations will often adopt the cancer incidence profiles of their new host locale. In these instances, it is likely that environmental or cultural influences are contributing to the increased incidence of various cancers. Early studies identified this phenomenon and confirmed these relationships, but continued work on the identification of risk factors in migrating populations has languished in recent years. This question seeks to stimulate more sophisticated studies on epidemiological risk identified through studies of migration.
Feasibility: The methodologies for these studies are well established; however, with more complicated migration patterns seen in our model global economy, it may be necessary to consider more sophisticated metrics of population remodeling.
Implications of success: If new factors that contribute to changes in cancer incidence in migrating populations can be identified, our understanding of environmental carcinogenesis would be significantly enhanced. This information could have important implications for understanding cancer etiology, pathogenesis, and prevention.
PQ - 3
Are there ways to objectively ascertain exposure to cancer risk using modern measurement technologies?
Background: Many methods that measure risk exposure rely on self-reporting or other survey approaches. Such surveys can be accurate in many cases, and they can be designed to increase their accuracy with good survey strategies. However, it would be valuable to develop more quantitative methods to record short-term or long-term exposures with quantitative readouts. With some methods, the techniques could measure biological readouts that might be directly linked to changes associated with cancer development.
Feasibility: This question calls for technological advances that can provide sensitive and accurate methods to measure exposure to agents thought to increase cancer risk. These methods might include devices to detect physical location, physical activity, exposure to carcinogenic agents, or changes in biological readouts that are altered in response to exposure. Detection of various small molecules by improving approaches in mass spectroscopy as well as various other "omic"-style methodologies may be useful in these approaches. New sensors that are tuned to known carcinogens could also be used. The range of measurement goals will include, but not be limited to, detecting exogenous molecules in biological samples, recording imbalances in endogenous metabolites, following changes in epigenetic patterns, or monitoring of time and location compared to potential physical carcinogenic sites through global positioning. In addition, monitors could be tuned to measure immediate short-term exposure or cumulative longer-term exposures.
Implications of success: Increasing the use of exposure measurements promises to give more accurate and quantitative values to factors that predict risk. If biological readouts are possible, the links to changes directly associated with cancer development may help speed the links between epidemiology and cancer biology.
PQ - 4
Why don't more people alter behaviors known to increase the risk of cancers?
Background: A wealth of epidemiological research shows that certain modifiable behaviors are linked to increased cancer risk. These include tobacco use, UV exposure, sexual behaviors, obesity, and lack of cancer screening. However, despite this knowledge, many people struggle with, or are unable to modify, these behaviors. By understanding basic mechanisms of executive control, emotion, and motivation, we might be better able to understand why people fail to alter behavioral patterns, and reduce this resistance to change.
Feasibility: Studies suggest that the message of behavior risk may not be conveyed by basic communication approaches. The substance of the message may not be understood or the mode of delivery may be ineffective. Further, even with an effective message and mode of delivery, individuals may be unable to act on the message to alter and maintain their behaviors. Recent advances in behavioral and neurological studies can help to understand where in the delivery of the message and in the efforts to change behavior, an individual loses the ability to avoid risky behavior.
Implications of success: Reductions in behavior that increase risk would have an enormous impact in the incidence of cancer.
PQ - 5
Given the evidence that some drugs commonly and chronically used for other indications, such as an anti-inflammatory drug, can protect against cancer incidence and mortality, can we determine the mechanism by which any of these drugs work?
Background: Given the evidence that some drugs commonly and chronically used for other indications, such as an anti-inflammatory drug, can protect against cancer incidence and mortality, can we determine the mechanism by which any of these drugs work?
Feasibility: Clinical data sets describing the consequences of long-term use of FDA-approved drugs could be mined for the association of drugs with incidence of various cancer types, while ruling out the possibility of a confounding interaction with the disease being treated. For those drugs already identified as being associated with a reduced risk of cancer, the mechanism(s) by which they reduce this risk remain be identified. In the case of aspirin, for example, most speculation on the mechanism of action has centered on changes in its anti-inflammatory activity. Since inflammation associated with cancer development is well studied, it may be possible to establish a causal link to changes in inflammation. Researchers should seek to move beyond correlative studies and establish careful mechanistic studies that link drug action to changes that alter cancer incidence.
Implications of success: Elucidating the mechanisms by which these agents work would be a major breakthrough in cancer prevention. This work could also provide molecular pathways that harbor other targets for prevention and encourage the development of second generation drugs that might diminish toxicities associated with current agents while maintaining efficacy. Success in these studies would provide models for the types of responses that mark good chemoprevention trials. p />
PQ - 6
What are the molecular and cellular mechanisms by which patients with certain chronic diseases have increased or decreased risks for developing cancer, and can these connections be exploited to develop novel preventive or therapeutic strategies?
Background: People with Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as Fragile X Syndrome patients, have a significantly lower risk of most cancers. An exception is melanoma, for which there is an increased risk for Parkinson’s patients. The reverse correlations also hold true. Cancer survivors have a significantly lower risk of developing many of these neurological diseases. It seems likely that if we understood in molecular terms why patients with these diseases or other chronic diseases have altered risk for cancer development, we might find leads for cancer prevention or treatment.
Feasibility: Exploiting this dichotomy may be difficult. Comprehensive databases needed to identify clinical correlations between chronic disease and cancer risk are not commonly annotated for these anti-correlations. However, the technology exists to find these disease/risk relationships. The molecular causes of these diseases or understanding the mechanisms of action for common therapies might be useful places to search for plausible links to cancer development. In some cases, there may be candidate genes or pathways for study. For example, some evidence suggests that suspected anti-cancer targets such as Pin1 are essential for the development of Alzheimer’s disease. Overall, finding the molecular linkage to explain these correlations would be a powerful base for future work.
Implications of success: Understanding the biochemical and genetic bases for these striking disease correlations may reveal novel insights into the mechanisms of cancer development as well as insights into the corresponding diseases. These molecular mechanisms would potentially provide new targets for therapies or prevention.
PQ - 7
How does the lifespan of an organism affect the molecular mechanisms of cancer development, and can we use our deepening knowledge of aging to enhance prevention or treatment of cancer?
Background: The development of most common adult cancers is related to increasing life span and aging; however, the lifespan of animals that get cancer are remarkably different. Mice live only 2 years, dogs perhaps 20, and humans 80. Yet all three suffer cancers that appear to driven by similar mutations in evolutionarily related proteins. Conversely many long-lived animals, such as the sea turtle, appear to have very low rates of cancer incidence. How does the etiology of cancer drive tumor formation in one time frame in some animals and a different one in others? In addition, some types of tumors arise in particular ages. What predisposes some tumors to develop most commonly at these times? A better understanding of these relationships could reveal fundamental regulatory events that control cancer development and progression, offering new means of cancer prevention or early stage detection.
Feasibility: Some of the basic biological processes that control aging have been described, and our knowledge of the molecular drivers of aging continues to improve. For example, the clock gene, PER, is an oncogene is some cancers. As processes implicated in aging are studied in conjunction with animal tumor models, we will be able to understand how key characteristics of tumor development are modified. Similarly, the molecular profiles of related tumors that occur at characteristically different life stages may show distinct patterns that could point to some of the variables that control how tumor incidence can be linked to the properties of aging tissues.
Implications of success: Understanding which features of aging change the rate of tumor incidence promises to identify potential biological processes that could be targets for prevention and therapy. Deeper knowledge of the molecular links between aging and cancer incidence can also identify new markers for early diagnostic tests and risk assessment.
PQ - 13
Can tumors be detected when they are two to three orders of magnitude smaller than those currently detected with in vivo imaging modalities?
Background: Current imaging modalities allow detection of tumors composed of approximately 107 cells or in the range of 1 cubic millimeter. Any increase in imaging sensitivity provides valuable advances in tumor detection; however, a major increase in detection sensitivity would provide a radical change in how we might employ imagining in clinical practice. While new advances are continually being reported and are currently the goal of NCI’s imaging grant portfolio, here we call for methods that might radically change the sensitivity of these imaging methods.
Feasibility: This question calls for a huge jump in imaging sensitivity. How this increase might be achieved is left to the imagination of the community. However, one can recognize that strategies to increase sensitivity might include such approaches as matching imaging probes with biologic targets that provide some enzymatic amplification, developing much more sensitive imaging probes, or greatly improved camera sensitivity.
Implications of success: The ability to detect very small clusters of cells in patients and in experimental cancer models is important from both detection and therapeutic perspectives—to find cancer at its earliest stages, to understand how and when tumors spread, to study how dissemination correlates with malignant progression, to improve strategies for treatment with precisely targeted radiation or drugs, and to monitor therapeutic responses.
PQ - 15
Why do second, independent cancers occur at higher rates in patients who have survived a primary cancer than in a cancer-naïve population?
Background: Second cancers are a major problem for cancer survivors. Grouped as a single outcome in the Surveillance Epidemiology and End Results (SEER) database, second cancers rank fourth in overall cancer incidence and are often associated with poor outcomes. However, researchers have not taken full advantage of this population to study risk factors and mechanisms. The influence of prior therapeutic interventions (including chemo- and radio-therapies) and somatic mutations in this population has been studied to some degree. However, the extent to which underlying genetic predispositions, environmental factors, and life-style behaviors influence risk remain relatively underexplored. It is likely that at least some of the identified risk factors and mechanisms would also be relevant to people who have not had a first cancer.
Feasibility: Given the high risk of these of these patients and their involvement with medical oncology personnel, it should be substantially easier to monitor cancer survivors for the development of a second cancer than to observe healthy individuals for the development of a first cancer. Cancer survivors are often followed prospectively for treatment response and complications, as well as disease progression. Technologies that identify somatic alterations can be integrated with genome-wide annotation of germ-line DNA to investigate the relationship between genetic susceptibility in high-risk individuals and second cancers. With the advent of new, more efficient technologies, it is feasible to broaden these efforts to large-scale clinical trial studies. Efforts to capture clinical, epidemiological, and therapeutic data could also be centered on the development of large-scale cohorts of cancer survivors at risk for second cancers. Because of their heightened risk of cancer, this population of patients may be more motivated, and therefore well suited, for prospective prevention studies, such as chemoprevention or behavioral modifications. Increasing use of electronic medical records could facilitate such studies, including the identification of appropriate patients for particular studies.
Implications of success: Studying patients who have had primary cancers for the development of second cancers could help uncover pathogenic mechanisms of both cancers, including shared etiologic pathways and therapy-related risks. These insights are likely to inform new strategies for preventive interventions.
PQ - 17
Since current methods to assess potential cancer treatments are cumbersome, expensive, and often inaccurate, can we develop other methods to rapidly test interventions for cancer treatment or prevention?
Background: There are no reliable models that predict drug response in human tumors. Tumor cells in culture are widely used to help identify and characterize potential drug targets, and they can serve as useful models to check initial drug penetration of cell membranes and target engagement. Mouse xenograft or genetically engineered mouse models often provide good settings to test drug pharmacodynamics, but seldom yield reliable measures of drug efficacy. Other animal models are used extensively for drug pharmacokinetic tests, but none of these models are useful mimics of drug activity in humans. This Provocative Question calls for the development and testing of new systems that accurately predict how drugs will act in humans.
Feasibility: Advances in 3-dimensional cell culture suggest that multiple cell types can be assembled in vitro and that engineered tissues often mimic many of the features of human organs. If systems can be developed that mimic the natural environment of tumors, perhaps these models will recapitulate drug action. It also seems possible that complex cell-free systems could be developed that would recapitulate at least some features of drug responses. Since it seems unlikely that any one new system will serve as an accurate model for all tumors, each may need to be tuned to the particular features of a particular tumor type or subtype.
Implications of success: If systems can be developed that accurately predict drug responses in human, advances in drug treatment or prevention would be dramatically streamlined, and the time frame for drug development shortened considerably. These new systems might also allow strategies for combination therapies to advance from empirical tests to approaches that are based on the biology of the tumor and its environment. The ultimate benefit for patients would be immense.
PQ - 18
Are there new technologies to inhibit traditionally "undruggable" target molecules, such as transcription factors, that are required for the oncogenic phenotype?
Background: Many tumor cells are known to be dependent on the expression and function of transcription factors or other proteins that are not easily targeted by standard drug development strategies. Typically, these proteins do not have enzymatic activities that can be inhibited by small molecule organic drugs. Nevertheless, cancer cells are often fully dependent on the continued expression and biological activity of these proteins, as shown by RNAi experiments or other functional tests. Many groups have tried to identify small molecule inhibitors that would interfere with the function of these proteins by blocking their interaction with other essential proteins. However, except for rare cases, these approaches have not led to drug candidates for clinical trials. Still other groups have looked for allosteric inhibitors that might change protein function through binding to targeted proteins and altering an essential function. Here, also, little success has been reported. Currently NCI is funding a small number of investigators to look for inhibitors of protein/protein interaction using a series of approaches. Because solving this problem would have such a large impact in the development of new cancer therapies, this question is included to continue driving the field’s quest for new and unusually creative approaches to inhibit these traditionally “undruggable” targets.
Feasibility: This question seeks new ideas to develop approaches for drug development for protein/protein interactions or other non-enzymatic inhibition of oncoprotein function.
Implications of success: New classes of drugs designed to block the actions of these refractory targets would provide a wide range of opportunities for cancer treatment and prevention.
PQ - 23
Can we determine why some tumors evolve to aggressive malignancy after years of indolence?
Background: Indolent tumors have been detected in a wide range of tumor sites. Very little is known about why these tumors persist for extended periods of time and then evolve to malignancy. Some are recognized as indolent after treatment, while others appear as a stage of natural tumor development before treatment. Still others are seen only at autopsy. Research to characterize these various tumors could help to understand what controls this state. Is it a true proliferatively dormant state or an active state that just balances cell division and death? How is this state maintained? Do tumors of the same site undergo similar transitions as they move from dormancy to malignancy? Can we predict which tumors will remain dormant and which one will progress?
Feasibility: Many of the tools for tumor profiling will be useful to help characterize these tumors. Modern molecular and cellular techniques can be used to help understand which pathways are active and essential in indolent states.
Implications of success: Expanded insight into the mechanisms that control tumor development promises to enrich our understanding of the cancer process. Characterization of indolent tumors will help us understand the mechanisms that hold tumor progression in check. Indolent tumors seldom pose any inherent risk to patients, so approaches that would hold other tumors in this state or that would extend the time that indolence persists could provide important therapeutic benefits.