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2012 RFA Links and Provocative Questions  

RFA Provocative Questions (PQs)

The Provocative Questions (PQ) numbers assigned are completely random and do not reflect any priority or rank order.

PQs can also be searched in three different ways:
  1. By scrolling through the list of PQs below.
  2. By clicking on one of the oval topic buttons below. Note: the categories correspond to the four RFA thematic groupings and do not reflect any priority or grouping of PQs for review or funding purposes.
  3. By keyword searching in the search field provided on the top right.

The full RFA documents can be viewed by clicking on the relevant "NIH Funding Announcement" links at the top.

RFA Questions
PQA - 1
What is the molecular mechanism by which a drug (such as aspirin or metformin) that is chronically used for other indications protects against cancer incidence and mortality?

Background: Numerous observational studies indicate that some drugs commonly used to treat or prevent diseases other than cancer reduce the risk of developing some cancers or produce a better cancer prognosis. For example, a recently published meta-analysis shows that people taking low-dose aspirin to reduce risk of vascular disease have a 20 to 30% lower risk of death due to several types of cancer, including cancers of the esophagus, lung, and pancreas, as well as colon. Other commonly used drugs, such as metformin used for the treatment of Type 2 diabetes, are also associated with a lower risk of cancer. However, the mechanisms by which these agents affect cancer risk and outcome are not well understood, and research needs to move beyond observational studies. Successful applications will determine which changes induced by drugs that are used commonly and chronically for other diseases are key for cancer prevention. The drugs chosen for study should already show good preventative effects in previous studies.

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 to 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 might be possible to establish a causal link to changes in inflammation. For metformin use, the link to cancer prevention has been suggested for patients with Type 2 diabetes. If we can determine why this occurs, we may be able to learn how and why non-diabetics will respond. 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 key molecular mechanisms by which these agents work would be a major breakthrough in cancer prevention. Understanding which cellular events can be regulated to change the risk of cancer development would identify clear biochemical and physiological events whose regulation controls some aspects of 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.

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PQA - 2
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. Successful applications for this question will identify and study molecular mechanisms that are induced by obesity and that are essential for some aspect of tumor development. Key issues for study include: 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 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 potentially lead to many more studies that could elucidate mechanisms of obesity-related cancer pathogenesis.

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PQA - 3
How do cognitive processes such as memory and executive function interact with emotional or habitual processes to influence lifestyle behaviors and decisions, and can we use this knowledge to design strategies to change behaviors that increase cancer risk

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, while others find it easy to modify their behaviors. By understanding basic differences in how individuals differ in their 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 us to understand where in the delivery of the message and in the efforts to change behavior may individuals differ in their ability to avoid risky behavior.

Implications of success: Reductions in behavior that increase cancer risk would have an enormous impact in the incidence of cancer.

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PQA - 4
As modern measurement technologies improve, are there better ways to objectively ascertain exposure to cancer risk?

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. The first steps in development of more quantitative methods to record short-term or long-term exposures with quantitative readouts are beginning. With some methods, the techniques could measure biological readouts that might be directly linked to changes associated with cancer development. This Provocative Question seeks applications that continue the expansion of these methodological developments.

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 strengthen the links between epidemiology and cancer biology.

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PQA - 5
How does the level, type, or duration of physical activity influence cancer risk and prognosis?

Background: Several studies have shown that physical activity has important but poorly understood features that lower cancer risk and positively affect the progression of tumor development. These studies also have suggested that these effects are due to more that just weight loss or caloric restriction. This Provocative Question seeks studies to determine what features of physical activity are most important in achieving these benefits.

Feasibility: Researchers may be able to join with other ongoing studies on the effects of physical activity to learn what components of physical activity affect cancer incidence or progression or it may be possible to initiate new studies to begin to assess aspects of the effects of physical activity. The important features that could be studied include: What types of physical activity, ranging from active life style to aerobic or anaerobic workout programs, lead to these benefits? Is the length of activity or the intensity key to the advantages? Are there good hypotheses that deserve follow-up about what molecular changes induced by physical activity might be linked to the beneficial effects?

Implications of success: Better understanding of how physical activity affects cancer risk will lead to stronger and better recommendations about healthy life style. Eventual understanding of the molecular causes for such benefits could lead to better understanding of what physiological events could serve as models to future prevention research.

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PQA - 6
How does susceptibility of exposure to cancer risk factors change during development?

Background: Cells at various stages of their developmental life cycle will respond differently to risk exposures. A simple well-known example of differential response is seen for cells in early development, which may be more susceptible to exposures that rely on rapid DNA synthesis, than when cells reach mature stages where division is less common. Similarly, exposure risks may be more important when cells are in other stages or under other types of pressures. This Provocative Question seeks experimental approaches that can be used to distinguish when cancer risks are most dangerous and then asks what molecular mechanisms underlie these differences.

Feasibility: Since the measurement of changes induced by cancer risk factor exposure is key to success for this question, it will be essential to identify appropriate systems for study. Longitudinal studies in humans are beyond the scope of this question; therefore, applicants are encouraged to identify other systems where exposure effects can be linked to various outcomes and studied in more detail. Experiments in mice will provide one potential system where both the effect and outcome of exposure can be measured and studied. In addition, some existing human exposure samples may be available to such studies. The goal of these experiments is to move beyond simple observational studies and begin to determine what molecular mechanisms account for the differential responses to risk exposure.

Implications of success: Learning what cellular processes promote and inhibit the effects of exposure will help us understand important variations in the early stages of tumor development. These differences will provide needed insight into how one might identify targets for prevention and early detection. Such information will also help the community prepare better guidance for the management of cancer risk.

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PQB - 1
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 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.

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PQB - 2
As we improve methods to identify epigenetic changes that occur during tumor development, can we develop approaches to discriminate between "driver" and "passenger" epigenetic events?

Background: The continuing improvement in high-throughput analysis of epigenetic regulation is advancing our understanding of the complex nature of tumor development. Several observations argue that epigenetic regulation is key to many stages of tumor development. First, proteins that are important for epigenetic regulation are frequently mutated during tumor development, and these mutations are important for the cancer phenotype. These mutations include point mutations, translocations, amplifications, and loss of miRNA regulation. Second, some chemotherapeutic agents that target DNA methyltransferases or histone deacetylases have shown good efficacy in the clinic, suggesting the changes in these epigenetic regulatory events are key to maintaining the tumorigenic phenotype. Third, the plasticity of tumor cells altering phenotypic states ---for example during epithelial to mesenchymal transition (EMT) or following division of cancer stem or initiating cells---is under epigenetic regulation. Finally, there is growing evidence that at least some forms of drug resistance are due to changes regulated by the epigenetic state. As we are achieving higher resolution of epigenetic events, it will be increasingly important to learn which epigenetic changes are critical for tumor survival. This question sets the challenge to learn which epigenetic events are most important for tumor development and maintenance.

Feasibility: Modern molecular biological methods, including molecular profiling, high throughput ChIP analysis, and functional tests, will be needed to identify and study various epigenetic states. Computational methods to characterize various epigenetic regulatory states could be used to help define potentially important changes. Functional tests, including RNAi knockdown or overexpression of key proteins, may be helpful in changing chromatin structure and linking these changes to cancer phenotypes.

Implications of success: As a field, we anticipate that epigenetic regulation of chromatin states will play important roles in tumor development. These links seem most clear in cases in which mutations that directly alter the epigenetic state have been shown to be important for tumor development. However, many phenotypes of a cancer cell are certainly regulated by epigenetic changes not deregulated by mutation, and the demonstration of this link promises to open the way for the identification of new therapeutic or prevention targets. Similarly, advances in this area will likely provide important advances in the identification of new diagnostic markers.

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PQB - 3
What molecular and cellular events determine whether the immune response to the earliest stages of malignant transformation leads to immune elimination or tumor promotion?

Background: The immune system plays conflicting roles in tumor development, having both the capacity to eliminate transformed cells, as well as the ability to promote their tumorigenic potential. However, the molecular and cellular events that regulate the immunological tipping point between tumor elimination and tumor promotion are not clear. In part, this is due to the difficulty in assessing the earliest time points when newly transformed cells first interact with the surrounding stroma, including the host immune system. Critical events at this stage can determine whether a pre-emergent tumor is either eliminated by the immune response or allowed to progress, in some instances with the support of immune cells. Recent reports have suggested that within hours after an oncogenic event, transformed cells secrete danger signals that attract innate immune cells that support tumor cell expansion. Thus, even before there is a tumor microenvironment (and in particular an immunosuppressive tumor microenvironment) the immune system is alerted to the presence of a potential cancer by tumor-derived danger signals. All along the cancer continuum, from a single transformed cell to a metastatic cancer, it is likely that distinct tumor-derived danger signals are generated and sensed by the immune system. Importantly, the nature of the immune response to these various danger signals could have profound consequences in determining whether tumors are eliminated or allowed to progress. Encouraging studies focused on the earliest time points of carcinogenesis and determining how tumor-derived danger signals influence the anti-tumor immune response could have profound implications for cancer prevention and improving immunotherapeutic approaches to eliminate cancer.

Feasibility: An important prerequisite for studies in response to this question will be the selection of appropriate systems to study the immune response to the very first stages of cells transformation. Genetically engineered mouse models might provide a good system to being such studies or there may be some well understood human tumor development system that could be used. Characterization of well-known immune response mechanisms at these earliest stages may provide a useful starting point for studies. These stages may also lend themselves to high-throughput profiling or other “omic”-style studies to help characterize these events and provide potential new hypotheses for study.

Implications of success: Understanding the earliest types of immune response to the emerging tumor cell promises to be one of the best points to influence the course of malignancy development. The ability to both push the immune response towards elimination or to block any enhancement of tumor development could be used to identify new target for therapy or for prevention.

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PQB - 4
What mechanisms of aging, beyond the accumulation of mutations, promote or protect against cancer development?

Background: The incidence of most common adult cancers increases with age; however, beyond the accumulation of mutations and changes in telomere length in dividing cells, we know little about how aging affects cancer development. While it is generally true that cancer is a disease of aging, this simple statement hides many complicating features. Tumor incidence at most sites shows a peak at particular stages of life; some cancers have highest rates in early adulthood, while others have rates that continue to rise until the seventies or eighties but then decrease with advanced age. The stochastic accumulation of mutations or the shortening of telomeres seems unlikely to account for these differences over time or between tissues. This question seeks thoughtful approaches and new concepts about how changes in aging contribute to increases and decreases in cancer rates at specific sites and over time.

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. To consider causal events that alter cancer incidence rates, it seems likely that mouse or other genetic models that show these changes might provide useful systems to study aging. Similarly, physiological comparisons of tissues undergoing various stages of aging may give clues as to underlying differences in tissues, or the changing microenvironments that support tumor development might be linked to changing rates of cancer incidence. Likewise, 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 alter 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.

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PQB - 5
How does the order in which mutations or epigenetic changes occur alter cancer phenotypes or affect the efficacy of targeted therapies?

Background: It is well understood that some mutations or epigenetic changes are characteristically found at different stages of tumor development. However, we still understand very little of the relationships between the appearance of specific changes and what mutations or epigenetic changes must or frequently follow. These temporal relationships could be due to new physiological states that are induced by the appearance of the earlier changes. Some of these relationships are likely to be between classes of changes in which multiple mutations in a pathway establish the same end results, but other temporal orders may be dictated by individual gene mutations or epigenetic changes. A consequence of the development of a temporal pattern of mutations or epigenetic changes is that early mutations may dictate some aspects of tumor fate and thus may influence what subtypes of tumors may develop or what types of therapeutic approaches may eventually be most effective.

Feasibility: One useful system to look for temporal orders of mutational and epigenetic changes will be provided by mouse tumor models. A large number of different oncogene or tumor suppressor mutations can be activated in well-defined settings and then tumor development followed. Mutations or other changes that occur following the induction of a tumorigenic event could be studied easily here, and the functional relationships then tested in subsequent studies. Similar studies in humans will be more difficult because sequential sampling of the same tumors is difficult or impossible. Some clues might be found by examining the rapidly growing collection of mutations found from genome sequencing projects such as TCGA, in which pairwise associations or lack of association of specific changes could be sought and then tested for any functional relationship. In addition there may be specific human tumor systems that have sufficient similarity in their development that studies of populations of tumors could provide clues for obligatory or preferred orders of changes. One potential type of human system for these studies may be found in virally induced human tumors. Here, it may be possible that some viral tumor systems may provide identical initiating steps that could generate a useful model to identify patterns of subsequent changes. Similar settings may be possible when tumors arise from other common initiating events.

Implications of success: Obligatory or preferred orders of mutational or epigenetic changes suggest specific responses to either earlier changes or other environmental selective pressures. Deciphering these patterns will increase our understanding of how to predict the developmental patterns of these tumors and types of therapies that will be most effective.

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PQB - 6
Given the difficulty of studying metastasis, can we develop new approaches, such as engineered tissue grafts, to investigate the biology of tumor spread?

Background: Metastasis continues to be difficult to study. We have almost no reproducible systems to study this deadly process. Mouse tail vein injections of tumor cells often leads to tumor growth at various sites in a process that mimics metastasis to some degree. Some tumors in genetically engineered mouse models will metastasize, but the process is hard to stage or follow in any rigorous detail. This Provocative Question calls for the development of new approaches to study metastasis.

Feasibility: While the range of potential approaches to develop methods to study metastasis is left to the imagination and creativity of the community, one potential exciting approach is the construction of engineered tissue beds that could serve as sites for invasion of metastasizing tumor cells. Such sites could be modified to determine which physical or biological properties promote more successful invasive and subsequent tumor proliferation. Many parameters of metastasis could be measured if it were known when and where to follow this process, and such sites could allow more careful analysis of what events guide the development of metastasis. These types of suggestions also raise a large number of other potential approaches that might make the study of metastasis more controllable and thus more readily compared among tumor types and more readily modifiable.

Implications of success: In many ways, metastasis is the most important stage of tumor development. Developing new methods to allow its careful study would provide important new avenues to learning about this stage of tumor development.

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PQC - 1
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 proliferative 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.

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PQC - 2
How can the physical properties of tumors, such as a cell’s electrical, optical or mechanical properties, be used to provide earlier or more reliable cancer detection, diagnosis, prognosis, or monitoring of drug response or tumor recurrence?

Background: There continue to be major advances in method development for the characterization of the physical properties of tumors. These physical features include, but are not limited to, the optical, electrical, and mechanical properties of tumor cells. Some studies have suggested that these properties may be easier to detect than other properties such as histological staining or other commonly used diagnostic methods. This Provocative Question seeks studies that expand on the physical characterization of tumors in different stages of development and asks that these physical features be correlated with appropriate diagnostic tests.

Feasibility: Applications for this question will link advances in measurement of the physical properties of tumors with important clinical properties of tumors. Useful applications could include such subjects as advances in diagnostic techniques or the ability to distinguish specific stages of tumor development. Studies could be done in mouse models or on well-annotated human tumor samples.

Implications of success: Advances in tumor diagnostics continue to be a major need in our characterization of tumors.

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PQC - 3
Are there definable properties of pre-malignant or other non-invasive lesions that predict the likelihood of progression to metastatic disease?

Background: Not all cancers detected early are worth treating. However, uncertainties about the clinical behavior of a non-malignant lesion often leads to more aggressive treatment than may be warranted, which can result in net harm to the patient. Currently, the detection of non-malignant (presumptive pre-malignant) lesions, such as so-called “in situ carcinomas” of the prostate gland or breast, are often treated vigorously because of the possibility that they are likely to adopt aggressive behaviors with time. In addition, the inherent uncertainty in predicting the outcome of a given cancer can result in poor communication of the actual risk to the patient, promoting decisions that may not be appropriate for the given benefit/risk profile.

Feasibility: Major advances in genomic and proteomic technologies that can genotype and phenotype small collections of cells, together with a greater awareness of the tumor microenvironment, are resulting in a better understanding of how molecular profiles relate to phenotype. New knowledge will help determine whether malignant properties are conferred stochastically, or whether early lesions differ in their likelihood of malignant progression in definable and reproducible ways, thus allowing for more accurate prognostic determinants. Prospective studies could lead to substantial improvements in the accuracy with which the clinical behavior of a given lesion can be predicted.

Implications of success: Improved prediction of clinical risk could help clinicians in communicating risk/benefit profiles for treatment options. Patients could make better-informed decisions, thus matching the diagnosis with the most appropriate treatment. These developments could also identify where therapeutic advances are most needed. Insight into the biological basis for this stratification would be an important advance, with likely relevance to analogous lesions of several tissues. These changes could improve the overall benefit of early detection by reducing the risk of harm from overtreatment.

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PQC - 4
How do we determine the significance of finding cells from a primary tumor at another site and what methods can be developed to make this diagnosis clinically useful?

Background: Metastatic disease is the major cause of death from cancer. However, just as not all primary cancers are prone to metastasize, not all tumor cells found at secondary sites are life threatening. Dissemination from a primary tumor site can occur relatively early in tumor development, and cells at secondary sites may have properties that range from indolence to aggressive malignancy. Furthermore, relatively quiescent tumor cells may require additional genetic and/or epigenetic alterations, perhaps in conjunction with non-cell autonomous alterations, to achieve a fully malignant phenotype at the secondary site. Yet, because the spread of tumor cells is usually viewed as an unfavorable prognostic indicator, detection of such cells commonly represents a rationale for more intensive therapy, which may or may not be warranted.

Feasibility: New experimental methods allow sensitive techniques for detecting and characterizing small numbers of tumor cells at secondary sites, and improved animal models of cancer have created opportunities for expanding our knowledge of disseminated cells and refining our lexicon for classifying them. For instance, recent advances in DNA sequencing enable the generation of phylogenetic trees of tumor cell populations to determine their clonal relationships and evolutionary distance from each other, and from portions of the primary tumor that are at different stages of progression. With these new tools, it may now be possible to define the malignant potential of disseminated cells.

Implications of success: Such analyses could enhance our understanding of the mechanisms that account for either a lack of oncogenicity or malignant behavior of tumor cells at a secondary site, as well as improve our ability to predict the biological behavior of tumor cells found at those sites. This information would give clinicians a clearer picture of when intervention is needed and when such tumor cells can be safely left alone or followed for potential later action.

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PQC - 5
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. The goal would be to detect tumors when they contain approximately 104 cells.

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. This increase in sensitivity comes with some concerns about over-diagnosis, but dramatic increases in imaging sensitivity opens a range of possibilities that are not available to the community at present.

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PQC - 6
What molecular events establish tumor dormancy after treatment and what leads to recurrence?

Background: Even apparently successful cancer therapy may leave dormant tumors or other types of minimal residual disease. These dormant tumors may remain stable for decades and in the best cases will not present further danger to the patient. However, frequently these tumors may undergo poorly understood changes and become aggressive and dangerous lesions. This Provocative Question seeks molecular explanations to both how these dormant tumors are generated and what might lead to their re-emergence as malignant tumors.

Feasibility: Perhaps the most difficult aspect of this question will be to identify a system where these dormant tumors can be studied in a reproducible manner. One can imagine that the use of mouse models may be possible or there may be types of human tumors treated under specific regimens that lead frequently to the appearance of dormant tumors. In these cases, it presumably will be the recurrent tumors arising from dormancy that will be available for careful study. These tumors could be profiled using modern biological methodologies to look for potential similarities or differences.

Implications of success: This is a stage of tumor development that has been difficult to study to date, and we, therefore, know very little about how these tumors arise or why malignant variants eventually arise. Advances in methods to characterize these unusual stages of tumors and the increasing knowledge of the primary tumors for comparison promise to allow the field to determine how these dormant tumors arise, how to look for these types of tumors after treatment, and which ones will be most important to follow.

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PQD - 1
How does the selective pressure imposed by the use of different types and doses of targeted therapies modify the evolution of drug resistance?

Background: One of the most disappointing features of the development of targeted therapeutics is how routinely drug resistance emerges. Evolutionary theory suggests that strong selection will always result in the emergence of resistant populations as long as some portion of the stressed population can adjust to the selective pressure. Similar theories also suggest that varying the selective pressure will change the kinds of tumor cells that will emerge. Since this is a central issue for modern day cancer biology, it is important to learn how selective pressure from drugs with different mechanisms of action for the same target, agents with a wide range of target inhibition and PK/PD properties, and therapies given at different doses affect the emergence of resistant tumor cells.

Evolutionary theory also suggests that lessening the selective pressure to a level that seeks to hold the population in check may succeed at least for extended periods of time. Evolutionary fitness studies show that most mutations that arise after selection are slightly deleterious in nature. Thus, mutant cells typically proliferate slower than the parental population. While strong selection will easily let the mutated cells emerge, if the selection is balanced correctly, evolutionary biology principles suggest that populations may emerge that contain a combination of sensitive parental cells and populations of the drug-resistant cells whose fitness is impaired. This Provocative Question seeks to understand how selective pressure imparted by drug treatment drives tumor evolution. Potentially interesting questions include: Do weaker selective pressures modify the timing and characteristics of emerging resistant clones? Do the relative IC50s or other characteristics of various drugs for targeted oncoproteins change the characteristics of tumor evolution? How does the fitness of resistant clones compare to parental populations? Can an evolutionary stable population of parental tumor cells and resistant clones be established by adjusting the selective pressure imposed by the drug? How do cytostatic and cytotoxic drugs compare when measuring tumor evolution and the emergence of resistant cells? How do combinations of agents affect the dynamics of tumor evolution?

Feasibility: Testing these issues is best done in animal models. Existing agents with various properties can be compared and provide good test cases. Even agents that induce outcomes other than cell killing also could be considered, perhaps used in combination.

Implications of success: These approaches present novel and challenging ideas for cancer therapy, but they highlight the importance of making sure we know what outcome for cancer patients is ultimately most useful. Living for some time with a debilitating tumor may be preferable to a rapid tumor regression with an almost certain drug resistant relapse.

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PQD - 2
What molecular properties make some cancers curable with conventional chemotherapy?

Background: Although chemotherapy is often effective, it is only rarely curative. However, it is well established that certain childhood cancers, some adult disseminated cancers, and rarely some adult solid tumors can be completely cured with chemotherapy, even with drugs that are often of much less value in other settings. While these responses are wonderful when they occur, there is little understanding of the underlying mechanisms that might explain why these cancers can be completely cured with chemotherapy. This Provocative Question seeks to understand what molecular properties of tumors make them curable by conventional chemotherapy.

Feasibility: This question has largely been ignored since it was recognized, often decades ago, that such tumors could be cured by standard chemotherapeutic strategies. New methods are available for studying the biology of these "curable" cancers and for exploring the mechanisms by which the effective drugs work.

Implications of success: If we could identify the properties of cancers that render them susceptible to eradication by chemotherapy, we might better understand how certain therapies work, contemplate converting relatively insensitive tumors to highly sensitive ones, or develop new approaches to the treatment of intransigent malignancies.

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PQD - 3
What underlying causal events—e.g., genetic, epigenetic, biologic, behavioral, or environmental—allow certain individuals to survive beyond the expected limits of otherwise highly lethal cancers?

Background: In biological research, the study of an unusual or rare event sometimes allows the identification of key features of more common forms. This has been true in cancer research where the careful characterization of rare tumors has identified disease events that are common in other tumors. A good example of this has been the cloning and characterization of tumor suppressor genes in rare childhood cancers. The study of the genes and their protein products has greatly expanded our knowledge of similar events seen in many common tumors. Studying extreme variants in tumor development promises to provide a similarly powerful avenue to learn about key events in cancer. This Provocative Question focuses on the unusual cases of individuals who have survived well beyond the expected limits of otherwise lethal cancers. Understanding what features of the tumor or of the patient allow individuals to survive may identify biological mechanisms that will be useful in treating patients at earlier stages.

Feasibility: The types of disease and the clinical features that would form the basis for these studies are best left to the creativity and rigor of applicants. There may be many approaches to study these phenomena, but one general strategy that may be effective would be to compare various features either of the tumors or of the patients who survive with those who suffer normal tumor development patterns. Comparisons could be made using a number of strategies, but unless potentially interesting features are known from other work, large –"omic" scale comparisons may be useful experimental approaches to generate new hypotheses.

Implications of success: Identification of features that allow patients to survive with an otherwise devastating disease open two major avenues for future research. Such studies could be used to identify those who may be more likely to respond well to treatment or to live longer with cancer. In addition, these features could provide starting places to look for new treatment or prevention strategies for other patients.

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PQD - 4
What properties of cells in a pre-malignant or pre-invasive field—sometimes described as the result of a cancer field effect—can be used to design treatments for a tumor that has emerged from this field or to block the appearance of future tumors?

Background: Several lines of experimentation have shown that the cells that surround solid tumors often carry mutations or epigenetic changes characteristic of the tumor itself. These cells appear either normal or at least more like normal cells than the tumor, but their genetic changes suggest that they may be derived from the same precursor cell that led to the tumor. Early carcinogenesis studies developed the concept of the cancer field, essentially arguing that early carcinogenic events initiated a pre-malignant event that led to the expansion of a precursor lesion. An individual cell within this field later would suffer other tumorigenic events that led to full carcinogenesis. More recent sequencing and other –“omic” work has shown that seemingly normal cells adjacent to the tumor often carry a subset of alterations that are found in the tumor. These findings also have led to the hypothesis that the surrounding cells in the cancer field may be derived from a precursor to the tumor. In both these examples, it is suggested that the changes found in the surrounding cells may harbor early changes that are essential for the tumor precursor and thus for the derived tumor itself. This Provocative Question expands on these models and asks for experimental approaches that might use the changes seen in surrounding cells as potential targets to treat the tumor or to prevent the appearance of secondary tumors from these fields.

Feasibility: Investigators will need to identify a useful tumor development model to study these types of changes. These could be in the mouse or there may be specific tumor and nearby non-tumor samples available for some human tissues. Comparison of –“omic” style studies would be the most likely source for the identification of potential differences in tumor and surrounding cells. These then could be used to build and test hypotheses about new targets for treatment or prevention of secondary tumor development.

Implications of success: The results from these studies will provide a useful tumor development model for 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 suggest diagnostic steps that could identify early lesions and thus might help prioritize target selection. Similarly it may be possible to design trials to block the future development of secondary tumors based on the identification of the earliest lesions. Finally, the classification of lesions as either early or late stage promises to help us understand the development pattern of certain tumor mutations.

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PQD - 5
Since current methods to predict the efficacy or toxicity of new drug candidates in humans are often inaccurate, can we develop new methods to test potential therapeutic agents that yield better predictions of response?

Background: Depending on your viewpoint there are few or 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 models or 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. Patient-derived xenographs (PDXs) when transplanted into immune-deficient mice show promise in some settings to predict tumor response to therapies, but are often hard to establish, maintain, and do not reproduce many of the features of the human tumor microenvironment. If systems like these can be modified and can be developed that better 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 response in humans, 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.

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PQD - 6
What mechanisms initiate cachexia in cancer patients, and can we target them to extend lifespan and quality of life for cancer patients?

Background: Cachexia or wasting syndrome is a common, devastating condition seen in many patients who are suffering from the late stages of cancer. When present, cachexia will almost certainly be a component of the actual events that lead to death. Although there have been several previous periods of intense work on cachexia, we still know little about what signals the initiation or maintenance of cachexia. This Provocative Question calls for new studies on the biology of cachexia, the signals that are important for its regulation, and the reasons why it resists reversal.

Feasibility: Modern methods of biological characterization promise to generate new information about the process and control of cachexia. “Omic” studies of affected tissues and of tumors themselves may provide new clues to its origins and the inability to reverse its course. All approaches open to modern in vivo biological studies should be available to characterize and study cachexia. New animal models may be possible to generate and would provide reproducible systems to study this process, and it may be possible to establish genetic, RNAi, TALEN, or chemical biology studies to look for essential features of wasting and its regulation.

Implications of success: Advances in our knowledge about the causes and biology of cachexia will lead to better understanding of this devastating cancer associated event. Whether any of the causes or consequences of cachexia will be treatable is unknown, but any advances will depend on intense study of its biology.

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National Cancer Institute Department of Health and Human Services National Institutes of Health