For tumors that arise from a pre-malignant field, what properties of cells in this field can be used to design strategies to inhibit the development of future tumors?
Intent: This Provocative Question seeks research that would identify changes in histologically normal cells surrounding or within close proximity of a cancer and that were induced in pre-malignant stages of tumor development. These changes should also be detected in the tumor itself, but not found in truly normal cells of that organ. Such changes might include, but need not be limited to, mutations, epigenetic alterations, or other detectable biochemical events. The identified changes could then be used to design therapeutic or preventive interventions to inhibit the development of future tumors, either at this site or in other pre-malignant fields with similar characteristics. Successful applications could be directed to any of the stages of this characterization–target identification–drug development pipeline as long as they rely on characteristics of the pre-malignant field. In most cases the tissue/cancer type chosen should have a well-documented pre-malignant field (e.g., lung, head & neck, esophageal, colon, or bladder).
Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.
Background: Several studies have shown that cells surrounding solid tumors often have mutations or epigenetic changes characteristic of the tumor itself. These cells appear normal, or at least more similar to normal cells than the tumor, but their genetic or epigenetic alterations suggest that they may be derived from the same precursor cell that led to the tumor. This Provocative Question expands on these observations and asks for experimental approaches that focus on the changes observed in surrounding cells as potential targets to prevent the appearance of future tumors from these fields.
Feasibility: Investigators will need to identify a useful tumor development model to study these types of changes. In general, the organ/tissue/cancer type chosen should have a well-documented pre-malignant field. The studies could utilize animal models or human tissues if the specific tumor and nearby non-tumor samples are available for investigation. Comparisons using -omic style studies would be a good source for the identification of potential similarities between tumors and surrounding cells that are not present in more distant normal cells. These could then be used to build and test hypotheses about new targets for treatment or prevention of future tumor development.
Implications of success: The results from these studies will provide useful tumor development models, define the development patterns of certain genetic and epigenetic changes, and facilitate the identification of early stage lesions. Comparison of responses with drugs targeting early stage lesions versus late stage lesions will help us understand the importance of choosing among various targets based on their stage of appearance. In addition, such studies might inform diagnostic approaches to identify early lesions, stratify individuals at risk, and help prioritize target selection. Finally, it may be possible to design trials to block the development of future tumors based on the identification of the earliest lesions.
What molecular mechanisms influence disease penetrance in individuals who inherit a cancer susceptibility gene?
Intent: Individuals who carry a mutation in a cancer susceptibility gene, for example individuals with Li-Fraumeni, Cowden, or Lynch Syndrome, have a dramatically increased risk over non-carriers of developing cancer. This Provocative Question calls for research to determine how the rate of disease penetrance is influenced by various life experiences such as environmental exposure, patient natural history (e.g., abnormal changes in hormone levels), or interactions with other genes/biological pathways. The intent of this question is to go beyond association studies, which identify factors that change disease penetrance in individuals with an inherited cancer susceptibility gene, and determine the mechanisms that explain how these changes influence disease occurrence. Mechanistic studies of events that either increase or decrease rates of penetrance are suitable for study. Preclinical or computational models may also be used to understand how disease penetrance may be altered.
Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.
Background: The presence of a mutation in a known cancer susceptibility gene (e.g., such as in BRCA1 or BRCA2 for breast or ovarian cancer, PTEN in Cowden Syndrome, TP53 in Li-Fraumeni Syndrome, or MLH1, MSH2, etc., in Lynch Syndrome) raises an individual’s risk of cancer significantly. However, not all mutation carriers will develop cancer, and the risks for developing a specific cancer type can vary within a cancer type/syndrome. It is likely that other genes, environmental exposures, or a person’s own natural history (e.g., abnormal changes in hormone levels) determine cancer susceptibility gene penetrance. Although data on associations among genes and between genes and exposures, environmental and otherwise, exist, determining the underlying molecular mechanisms affecting gene penetrance has been challenging. The intent of this Provocative Question is to support research that deciphers the mechanisms by which these variables influence disease penetrance in the presence of a known cancer susceptibility gene mutation.
Feasibility: Given the substantial amounts of data that exist on cancer genetic susceptibility along with epidemiologic data on environmental and other exposures, delving more deeply into how these entities interact at the molecular level should be feasible. This work may require interdisciplinary efforts to bring together disparate data types and conduct analyses. Investigators can use in vitro or in vivo models and also preclinical, computational, or mathematical models of germline cancer genetic susceptibility and exposures to study the mechanisms linking these interactions and their impact on penetrance. Exposures may include chemopreventive interventions, in which chemopreventive agents could be used as tools to interrogate the molecular pathways that contribute to (or inhibit) carcinogenesis; such research also would provide insight into the potential such agents have for preventing cancer in individuals with germline mutations in known cancer-promoting genes.
Implications of success: The results of research responsive to this PQ will provide information on mechanisms of interaction between known exposures, environmental or otherwise, and known susceptibility genes that begin to answer the question of penetrance. The results may help define how exposures and genetic factors interact to augment or suppress the action of cancer susceptibility genes, delineate whether specific lifestyle or chemopreventive interventions might be most appropriate for a particular cancer type, or identify networks of molecules to target for chemoprevention or treatment.
How do variations in tumor-associated immune responses contribute to differences in cancer risk, incidence, or progression?
Intent: Tumors vary in the extent and character of immune cell infiltration and other tumor-associated immune responses. These variations may be due to many factors, including differences in heterogeneous variations of the malignant cell phenotype or genotype or in the potential range of immune responses seen when comparing individuals or populations. This Provocative Question asks scientists to propose research into the causes of variable tumor-associated immune responses and/or how these variations relate to cancer risk, incidence, or progression. Successful applications might range from mechanistic studies that attempt to understand how tumor-associated immune responses can contribute to cancer development in an individual to studies of how population-based differences in immune traits (e.g., across such populations as racial/ethnic groups or various age groups) might explain variations in cancer risk, incidence, or progression.
Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.
Background: Although the immune system has the potential to detect and eliminate cancer, considerable variability in immune function exists among individuals and between populations that may help to explain the observed differences in the etiology, risk, and outcomes of a variety of human cancers. Solid tumors are frequently infiltrated by multiple components of the immune system, and individuals or groups may vary in the extent and character of immune cell infiltration and other tumor associated immune responses. These variations may be due to many factors including host genotype, tumor cell heterogeneity, or the range of previous immune responses seen in comparing individuals or populations. Indeed, numerous differentially expressed genes have been reported to cluster around immune response and cytokine signaling pathways among patients from distinct well-defined populations such as various racial/ethnic, age groups, or groups/individuals afflicted with various co-morbid conditions that are associated with unfavorable cancer outcomes. Research is needed to validate these variations in immune response and explore specific mechanisms and pathways that may explain these differences. This Provocative Question asks scientists to propose research into the causes of variable tumor-associated immune responses and/or how these variations relate to cancer risk, incidence, or progression.
Feasibility: Key components of tumor immune surveillance have been shown to have distinct properties in different individuals and vary among some population groups. Responsive applications will include mechanistic or comparative-based studies investigating variations in tumor-associated immune responses, either at an individual level (i.e., susceptible/immunocompromised individuals, unique responders, etc.) or among diverse population groups (i.e., racial/ethnic groups, various age groups, etc.). Demonstrated differences in immune signatures including immune cell infiltration, chemotaxis, and cytokine profiles; studies directed at characterization of immune response markers related to the tumor or with tumor-adjacent stroma as well as consequent cascade of events involving signal transduction; and pathways differentially activated in individuals or among diverse well-defined populations could provide starting points for these studies. The goal of this work should be to explain how these immune variations contribute to the cancer’s aggressiveness or different outcomes.
Implications of success: It is expected that successful applications will lead to studies that increase our understanding of the immunological mechanisms that affect cancer outcomes among individuals and diverse populations. Results from funded projects are expected to serve as a solid foundation for development of tangible strategies to manipulate the immune responses that influence cancer risk, incidence, or progression.
Why do some closely related tissues exhibit dramatically different cancer incidence?
Intent: The same organ site can develop different types of cancers (e.g., adeno- versus squamous carcinoma). In contrast, many tissues with closely related developmental histories have wide variations in cancer incidence (e.g., left versus right colon cancers, seminal vesicle versus prostate, etc.). This Provocative Question seeks research applications that will explain the molecular mechanisms that account for different rates of cancer development among closely related tissues.
Background: Many tissues with closely related developmental histories have wide variations in cancer incidence and clinical features. For example, the prostate and seminal vesicle have a closely related developmental history and are under similar hormonal regulation, yet, cancer development is seen primarily in the prostate. Another difference is seen in colorectal cancer (CRC). CRC exhibits differences in incidence, pathogenesis, molecular pathways and outcome depending on the location of the tumor. Approximately 15% of all CRCs arise through a serrated polyp-neoplasia pathway that is highly associated with right-sided CRCs. The right-sided CRCs are more likely to be exophytic, diploid, have mucinous histology, have high microsatellite instability, and CpG island methylation. Left-sided CRCs are frequently infiltrating tumors, present with obstructive symptoms, have chromosomal instability, and are frequently aneuploid. This Provocative Question seeks research applications that will explain the molecular mechanisms that account for different rates of cancer among developmentally closely related tissues.
Feasibility: Investigators will have to apply multidisciplinary approaches, perhaps including -omics-based approaches, and consider potential differences in the tumor microenvironment to understand what accounts for differences in cancer risk between tumors of related tissues. In addition, they may consider the use of appropriate models to induce changes that will mimic the development of such tumors in the appropriate tissues.
Implications of success: Advances in our understanding of the molecular mechanisms that underlie differences in risk for the development and progression of cancer in similar tissues may provide a better understanding of how to manage the risk for each cancer and potentially identify new risk markers, markers for early cancer detection, diagnosis, and prognosis, as well as new targets for prevention and therapy. Furthermore, such knowledge may assist in development of better tissue-specific imaging modalities to detect cancers.
How does mitochondrial heterogeneity influence tumorigenesis or progression?
Intent: Mitochondria within one cell, among closely related cells, or between different individuals can display heterogeneity in mtDNA sequences, dynamic spatial and communication patterns, and functional capacities. This Provocative Question asks researchers to propose mechanistic studies that will characterize how mitochondrial variation within individual tumor cells, among cells within tumor microenvironment(s), or in the same cell types from different individuals influences tumorigenesis or progression. How do these differences vary over time and how do they alter or contribute to tumor development, adaptation, or response to therapy? Successful applications will examine how key aspects of mitochondrial heterogeneity contribute to important steps in tumor development and phenotypic plasticity.
Background: Mitochondria perform an assortment of specialized cellular functions, which vary with cell type, development and physiological cues. Distinct functional tasks rely on cellular coordination of mitochondrial biochemistry, morphology, intracellular position, connectivity and organizational features that are dynamic at both the single mitochondrion and system level. The normal spectrum of mitochondrial complexity becomes enlarged and deregulated in cancers. We currently lack a mechanistic framework to couple mitochondrial variation in cancer cells with certain phenotypic behaviors or how mitochondrial heterogeneity integrates with either common or unique processes of tumorigenesis overall. Aspects of mitochondrial heterogeneity within or among cancer cells may confer selective advantages to environmental or therapeutic stresses, but may also pose targetable vulnerabilities.
Feasibility: Mitochondrial heterogeneity can be seen across numerous scales: cellular, tissue, organism and population level. Applications that consider mitochondrial heterogeneity in any of these scales are welcomed. Successful PQ5 applications should expand our mechanistic understanding of how mitochondrial specializations are realized in cancer cells and integrated into functional or phenotypic states related to stages of cancer development, specific behaviors of cancer cells, or ways to improve cancer prevention and treatment. Projects may draw upon interdisciplinary abilities, such as those from cell biology, cellular anatomy, genetics, engineering, sensors, imaging, and computational biology. Applications focused solely on mitochondrial functions such as apoptosis or metabolism without linking these functions to heterogeneity would not be responsive to this PQ.
Implications of success: Characterization of how mitochondrial heterogeneity operates in tumors can provide basic mechanistic insights into how cancer cell morphology and organization leads to specific phenotypic behaviors. This PQ5 should expand our knowledge of the intersection between the different roles mitochondria play and strategies that confer cancer cell plasticity and survival advantages.
What are the underlying molecular mechanisms that are responsible for the functional differences between benign proliferative diseases and premalignant states?
Intent: Different populations of cells that continue to proliferate in inappropriate settings or at inappropriate times can pose variable risks to human health. Some cell populations will continue to divide over a lifetime (e.g., ductal hyperplasias, benign lipomas, or papillomas) but pose no or little risk of advancing to malignancy, while other populations will progress to cancer with higher frequency (e.g., adenomas changing to adenocarcinomas). This Provocative Question seeks to stimulate research that will compare the range of these states and determine the underlying molecular and cellular regulatory mechanisms that distinguish these populations. Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.
Background: There has been a long-standing fascination in the differences between benign and malignant tumors, but little modern work to characterize the functional differences between these two tumor types, with very different levels of risk to patients, has been reported. Benign tumors or cysts are being detected with increasing frequency, largely due to advances in cross-sectional imaging using computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS), as well as early detection guidelines for high-risk individuals. Common screen detected neoplasms include pancreatic mucinous cystic lesions, lipomas, breast ductal hyperplasias, and papillomas. A critical unknown question is how to differentiate neoplasms that are likely to remain benign and require only monitoring from those that will progress to malignancy with higher frequency. This Provocative Question seeks research that will compare benign and malignant neoplasms either within one tissue/organ type or across tissue types to determine the underlying molecular mechanisms that account for the variable potential to progress from a benign to malignant disease state.
Feasibility: Advances in genomics, proteomics, and other -omics approaches, as well as imaging modalities, can allow for the identification and molecular profiling of small numbers of cells, their extracellular matrix, and the microenvironment. These new capabilities and knowledge are likely to help characterize various types of benign and malignant tumors. The goal of studies initiated under this PQ is to understand how cell proliferation can occur in benign tumors without the possibility of malignant transformation. Such characterizations may lead to studies that determine whether malignant properties are conferred stochastically, or how neoplasms differ in their likelihood of malignant progression in definable and reproducible ways. Such studies could lead to substantial improvements in the accuracy with which the likelihood for progression of a given neoplasm can be predicted.
Implications of success: Improved prediction of clinical risk may help clinicians better communicate risk/benefit profiles to patients and help patients, together with their doctors, make better-informed treatment decisions. Understanding why certain neoplasms are most likely to progress may also identify where prevention or therapeutic advances are most urgently needed. Insight into the biological basis for this stratification would be an important advance in the field, with broad relevance across tissue/organ sites. These changes have the potential to improve the overall benefit of early detection by reducing the risk of harm from overtreatment.
What in vivo imaging methods can be developed to determine and record the identity, quantity, and location of each of the different cell types that contribute to the heterogeneity of a tumor and its microenvironment?
Intent: The demonstration of the extensive heterogeneity of cell types within a tumor and its microenvironment is one of the most intriguing research surprises of the last decade. This heterogeneity includes variations in the tumor cells within a single cancer, extensive differences among tumor cells from similar cancers that arise from the same tissue of origin, and in the variety of associated cells found in the tumor microenvironment, which range from stromal cells to endothelial cells to infiltrating immune cells of many different types. This heterogeneity contributes to a multitude of tumor behaviors and is thought to be one of the reasons that tumors pose such a complicated therapeutic challenge. This Provocative Question seeks the development of new in vivo imaging methods to allow the rapid identification, quantitation, and location of the different cell types within a tumor and its microenvironment. Work at any stage of technical development of imaging methods in the pursuit of these goals is appropriate. Development and validation of imaging methods for various subsets of cell types for the purpose of building a complete set in future work is also considered responsive.
Background: The heterogeneity of cell types within a tumor and its microenvironment is arguably one of the most important tumor characteristics but remains an understudied imaging research area. Such work would have application to early cancer detection, diagnosis, and assessment of treatment response. Tumor and microenvironment heterogeneity includes variations in the tumor cells within a single cancer, extensive differences among tumor cells from similar cancers that arise from the same tissue of origin, and in the variety of associated cells found in the tumor microenvironment, which range from stromal cells to endothelial cells to infiltrating immune cells. There are many advanced histological methods, microarray and high-throughput sequencing techniques to examine tumor heterogeneity using tissue specimens or body fluid. Although the collected information is static and restricted to the location of the sample, these methods are being used for diagnostic and prognostic purposes in the clinics. In vivo and minimally-invasive imaging methods would be a valuable tool in examining the intact tumors and their microenvironments, various cell types, and their behaviors (in terms of functions). This Provocative Question seeks the development of new in vivo imaging targets and methods to allow the rapid identification, quantitation, function, and location of the different cell types within a tumor, its microenvironment and its behaviors during cancer initiation, progression or in response to treatment.
Feasibility: Image-based instrumentation currently in development can provide significant advances that yield real time, in vivo characterization of tumor phenotypes, the tumor microenvironment and cellular/molecular interactions. In molecular imaging research, methodologies have been recently developed to target specific cell surface markers and specific tumor invasion or proliferation associated signaling and enzymatic activities of both tumor cells and other cell types in the tumor microenvironment. Due to the generally minimally invasive nature of in vivo imaging, quantitative assessment of the genetic evolution of tumor cells and cells in the tumor microenvironment studied longitudinally as a function of time are possible. Imaging methods used as a tool to non-invasively probe cellular interactions can provide the ability to examine a whole tumor in vivo and its associated microenvironment interactions in 3D space. Careful coordination, use of quantitative metrics and technology enhancement to better understand, discover, confirm, or disprove current views of tumor physiology in situ could be used to address this specific Provocative Question.
For proposed research projects, several qualifiers should be addressed with regard to designing imaging and/or multi-functional probes: evidence of targeting specificity, evidence of functional modulations; evidence of favorable physical properties; delivery, biodistribution and minimal toxicity; evidence of improved imaging sensitivity/specificity, signal to noise ratio, and resolution; as well as how the characterization of tumor phenotypes, its environment and behaviors based on in vivo imaging methods will be incorporated into this increasingly sophisticated view of the tumor in situ.
Implications of success: The ultimate goal of this work will be to better understand how identification of different tumor phenotypes and tumor microenvironments could be used to develop improved methods for early cancer detection, diagnosis, and prognosis. If successful, in vivo imaging methods that allow the reliable and quantifiable identification of molecular signatures and architectures of tumors, the evaluation of genetic evolution of tumor cells the other cell types in the tumor microenvironment that contribute to the observed and changing landscapes of tumor heterogeneity, and the real-time assessment of cancer treatment response have the potential to significantly improve cancer detection, diagnoses, treatment response and lead to personalized clinical cancer care
What cancer models or other approaches can be developed to study clinically stable disease and the subsequent transition to progressive disease?
Intent: What biological mechanisms keep some cancers in a stable state and how do we study the transitions from stable to progressive disease? In this Provocative Question we seek the development of new models or approaches to foster the study of both the stable state — including but not necessarily limited to dormant or indolent tumors as well as those meeting the Response Evaluation Criteria in Solid Tumors (RECIST) definition for stable disease — and the progression of such tumors to more aggressive phenotypes. These new approaches might take advantage of advances in various preclinical models or strategies, combinations of biological and computational models, or other approaches that could help us understand the biology of these important stable states. Studies of tumors that are held in stasis by continued drug treatment are not responsive to this request and will not be considered for funding.
Background: Occasionally tumors achieve or reach stable states that persist in the body and do not immediately progress to more dangerous or aggressive stages. Examples of stable disease include indolent tumors, such as chronic lymphocytic leukemia (CCL) that can be remarkably stable, often not progressing until 20 or more year after initial diagnosis, or tumors that reach a state of dormancy after treatment and remain stable for years. The mechanisms that control the maintenance of these stable states are relatively unknown and, if understood, could open a window of opportunity to develop ways to i) prevent metastasis by maintaining stable residual disease or ii) eradicate it. It is thought that both tumor cell intrinsic factors including genetic traits as well as host factors such as niche signals, specific target organ cues, or immune mediated mechanisms could contribute to stabilize disease. This PQ seeks the development of model systems that would faithfully mimic stable disease and/or its eventual progression to advanced stages.
Feasibility: An important requirement for studies that address this question will be the development of appropriate models that recapitulate the above-mentioned processes. Genetically engineered models of cancer may be suitable to address some of these processes, including but not limited to: i) mechanistic dissection of stable balance of tumor cell proliferation and survival; and ii) role of the immune system in causing a stable state for cancer. Models such as xenografts might also be suitable and complementary to test the influence of different target organs signals that contribute to stable disease formation. The incorporation of fate-mapping tags to longitudinally track cells during stages of stable cancer might also provide feasibility. Understanding how tumor cells interact with their niches during stable states may be important in some settings. In addition, computational models that provide clues on how cancer might adopt a stable state might be suitable for answering these questions.
A related set of models could be developed to follow stable disease following treatment. These models might include genetically engineered mouse tumors that lead to stable disease after treatment or patient derived tumor samples collected from stable disease following treatment.
Implications of success: Understanding how cancer enters into a stable state will allow for manipulation of these mechanisms to prevent subsequent cancer development. This knowledge could lead to the generation of i) markers as well as imaging and diagnostic tools to determine whether residual cancer is in a stable or progressive state, ii) therapeutics that will maintain cancer in a stable state for extended periods of time and result in a chronic, non-life threatening condition, and iii) therapeutics that may eradicate the stable population of residual cancer cells.
What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?
Intent: While many acute toxicities can be adequately managed during cancer therapy (e.g., febrile neutropenia, acute nausea and vomiting) and will resolve once therapy has been completed (e.g., mucositis), there are other adverse sequelae that persist after completion of therapy and for which there are no effective management strategies. These include, but are not limited to, therapy-induced peripheral neuropathy, neurocognitive impairments, cardiovascular toxicity, pulmonary fibrosis, arthralgias, and immune system-related adverse events. This Provocative Question seeks research that will (1) identify novel mechanisms that induce such chronic sequelae, (2) apply the knowledge gained from understanding these mechanisms to facilitate design of new treatments (or approaches) that may decrease or reverse adverse cancer therapy effects, or (3) facilitate mechanism-based design of new cancer therapies that are expected to show decreased adverse effects when compared with existing therapies. Such studies may be performed in pre-clinical, non-clinical, and/or clinical settings. Successful applications must focus on adverse therapy related sequelae (whether immediate or delayed in onset) for which current management or treatment strategies are limited or ineffective.
Background: Cancer therapy-induced adverse sequelae are a major problem for cancer survivors. Adverse sequelae persisting or developing after cancer therapy are difficult to predict and vary across patients and therapeutic regimens. Without knowing the mechanisms by which cancer therapies lead to adverse sequelae, it is difficult to design clinical management strategies and/or to improve anti-cancer drug development. Thus, understanding the mechanism(s) of adverse sequelae, which therapies cause them, and/or strategies to avoid, minimize, or reverse their occurrence should be principle objectives of research applications responding to this Provocative Question.
Feasibility: One of the challenges in this arena is the ability to explore mechanisms of toxicity and determine whether these mechanisms represent on-target mechanisms that are also responsible for therapeutic efficacy. Preclinical or non-clinical models may be effectively used to obtain mechanistic insights that would be difficult to investigate in detail clinically. Careful evaluation of anti-tumor mechanisms and mechanisms of target organ toxicities are key to understanding whether a given adverse effect can be managed. Preclinical or non-clinical models might also be employed to evaluate initial mitigation strategies, with concurrent evaluation of efficacy of anti-cancer therapies and mitigation of adverse effects. An important prerequisite for preclinical or non-clinical studies in response to this question will be justification of the appropriateness of the systems (i.e., their suitability and validation) chosen to study molecular/cellular mechanisms of toxicity.
Efforts that focus on unique mechanisms are particularly useful. It is also desirable to translate mechanistic understanding of molecular/cellular pathways deemed responsible for adverse effects into testable hypotheses for preventing such adverse effects, or development of new anti-cancer drugs designed to avoid such pathways. The goal of successful applications should be to translate the understanding of the molecular/cellular mechanisms of toxicity into informed drug design, alternate treatment regimens, prevention strategies, or other management modalities.
Implications of success: Better understanding of the molecular and/or cellular mechanisms leading to adverse sequelae may guide selection and development of therapies for individual patients and may lead to better adverse sequelae management and remediation strategies. Further, it is hoped that new mechanistic insights will lead to effective prevention strategies and treatments by minimizing or reversing adverse sequelae entirely.
How do microbiota affect the response to cancer therapies?
Intent: This Provocative Question seeks grant applications that use our increasing knowledge of the normal human microbiota to understand how these organisms or their secreted products affect cancer therapies. Approaches may include studies that focus on effects of the changing microbiota within an individual patient undergoing treatment or among different patients undergoing identical therapy but with different outcomes. Analogous studies in pre-clinical models are also invited. Key aspects of study might include either how the microbiota alter the composition, concentration, stability, or effectiveness of standard or experimental classes of therapies, or the identification and study of microbial regulatory mechanisms that mediate these changes.
Background: Recent studies demonstrate altered microbiota in many cancer patients. For example, these changes include gastrointestinal (GI) microbiome in patients with colorectal cancer (CRC) and inflammatory bowel diseases (IBD). In addition, changes in the microbial communities of the lung and oral cavity have been associated with tumor development in both local and distal tissues. Additional studies have shown when bacterial communities are compromised, for example by immunodeficiency or antibiotics, standard chemotherapy regimens may lose efficacy either through direct bacterial biotransformation or by inhibition of therapy-induced anti-tumor immune responses. Since microbial regulatory mechanisms are involved in establishing and maintaining tissue homeostasis and altering drug metabolism, understanding how a patient’s microbiota may enhance or inhibit cancer therapies will help to optimize anti-tumor therapies.
Feasibility: Drug metabolism and microbiome-related studies in humans and preclinical models suggest a number of approaches that can be used to study how anti-tumor therapies are affected by microbial metabolic capacity. New information from metagenomic and metabolomic analyses provide a rich resource of technical approaches to characterize and test if changes in the microbiota during tumor development or anti-tumor therapy affect response to therapy. Drug metabolism approaches can be used to determine how drugs are modified by various microbial populations. Since microbial genetics and function can be readily manipulated either in vivo or ex vivo using standard molecular biology techniques or by drug and dietary interventions, alterations in the microbiota can be easily achieved and used to study changes in drug metabolism or in markers of drug effectiveness. A fundamental understanding of microbial physiological regulation, metabolism, and composition in the context of a cancer therapy will provide insights into an individual’s response to the therapy (including initial efficacy and development of resistance) and guide potential intervention strategies.
Implications of success: Research findings resulting from successful completion of work under this PQ are expected to lay the foundation for adjuvant targeting of microbiota functions, offering many potentially attractive strategies for therapeutic manipulation and engineering optimized anti-tumor chemo, targeted, and immunotherapies. A detailed knowledge of each cancer patient’s unique microbial drug metabolizing capacity and activity has high translational value to clinical practice, since this new information could be exploited to optimize individual therapeutic responses. This knowledge could also be used in the future to develop approaches that include: the direct manipulation of a patient’s microbiota, alteration of microbial signals to change host metabolic regulation, or development of new metrics for patient stratification, based upon matching therapeutic agents with an individual’s microbial drug metabolism profile.
What mechanisms of action of standard-of-care cytotoxic, radiologic, or targeted therapies affect the efficacy of immunotherapy?
Intent: With the increasing and successful use of immunotherapy in cancer treatment, many investigators have begun to consider approaches that combine standard of care treatments, such as chemotherapy, radiotherapy, or targeted therapy for a particular tumor, with immunotherapy. Standard of care is defined as a treatment that is accepted by medical experts as a proper treatment for a certain type of disease and that is widely used by healthcare professionals. There may be more than one standard of care for any individual cancer type. Cancer immunotherapy encompasses a wide range of treatment modalities that harness the anti-tumor effects of the immune system, and the factors that influence the efficacy of immunotherapy alone are becoming understood. However, there is a lack of information on their effects when used in combination with standard of care interventions. This Provocative Question seeks new investigations that will define molecular or cellular mechanisms for enhancements, antagonisms, or toxicities that occur when cancer immunotherapy and standard of care treatments are used in combination (either sequentially or concomitantly) as compared to when cancer immunotherapy is used alone.
Background: Combining two or more therapies is one of the most common and effective methods to increase the effectiveness of cancer treatments. Looking for new combination therapies has become increasingly important, as new targeted therapies have led to the generation of resistant tumors after initial efficacy. Most approaches to test new combinations have relied on empirical assays that combine various small molecule inhibitors with one another or with chemotherapies. These approaches are being augmented by others that rely more deeply on rational strategies and use detailed knowledge of how different therapeutic outcomes can be best combined. Given the recent advances in the use of immunotherapy, i.e., approaches that rely on augmenting the ability of the host immune system to mount an immune response against the tumor, such as stimulatory cytokines, activators of co-stimulatory molecules, immune checkpoint inhibitors, immune maturation agents, and therapeutic vaccines, the concept of combining these approaches with targeted therapy, radiotherapy, or chemotherapy has begun to be considered and tested. However, we have little knowledge of how the results of current standard-of-care treatments for various malignancies will enhance or inhibit the addition of immunotherapeutic agents. This Provocative Question seeks to understand how best to combine these therapeutic approaches.
Feasibility: Any tumor model that shows a favorable response to an immunotherapeutic agent could be used to study how this response might be altered by other cancer therapeutic agents. We leave it to the ingenuity of applicants to choose how such agents might be selected for comparison. Any molecular events that are altered by potential agents could provide useful intermediate markers to measure collaborative effects that could predict changes in tumor response.
Implications of success: Extending the range of tumors that might respond to immunotherapeutic agents or the strength or duration of the anti-tumor response induced may signal useful approaches that could be studied in subsequent clinical trials. More information about how any standard-of-care therapy enhances or inhibits immunotherapy will expand our understanding of the principles behind effective combination therapy.
What methods and approaches induce physicians and health systems to abandon ineffective interventions or discourage adoption of unproven interventions?
Intent:Well-intentioned efforts to speed diffusion of research results into practice may result in the adoption of new treatments and approaches to care before their effectiveness has been documented. Multiple studies have documented the continued use of some medical treatments and approaches to cancer care known to be ineffective. This Provocative Question seeks hypothesis-driven studies that explicitly examine how physicians and/or health systems can be induced to diminish delivery of ineffective or unproven cancer care. Responsive applications may, for example, involve the study of natural experiments, such as changes in reimbursement or institutional policy, or the development and testing of interventions targeted at providers or delivery systems. Studies focused on patient factors or including interventions involving only patients are not responsive to this question.
Background: Efforts to improve the quality of cancer care have traditionally focused on the dissemination of new discoveries into community practice. The central question has been how to ensure access to the latest evidence-based care, be it screening, diagnostic procedures, treatments, symptom management, processes of care, or other approaches aimed at improving cancer outcomes. Once innovations are adopted, they are rarely abandoned when new evidence calls their effectiveness into question. In addition, there are historical practices that continue despite a lack of evidence of their effectiveness. Some innovations and historical practice have actually proven to be harmful to patients and often increase the cost of cancer care without an accompanying improvement in outcomes. Thus, improving care also involves ceasing to offer care that lacks an evidence base, increasingly described as “de-innovation” or “de-adoption.” There are many potential explanations for why practitioners and administrators may continue to offer unproven care, such as patient demand, practitioner knowledge, system inertia, and economic pressures. These factors may act as facilitators or barriers.
Feasibility: The expanding understanding of practitioner, delivery system, and community factors in adopting innovations has had limited application to the opposite challenge of “de-innovation” or “de-adoption.” Emerging multi-level methods, as well as increases in the research interests and capabilities of health care delivery organizations, provide an opportunity to address this scientific gap.
Implications of success: Proven strategies to minimize the delivery of cancer care not based in evidence will enable practitioners and administrators to address quality and cost issues arising from unnecessary care.