Skip Navigation
National Cancer Institute U.S. National Institutes of Health www.cancer.gov
Sections
You are here: Home Community Dialog Questions from Workshops

Questions from Workshops

"Provocative questions" are inquiries addressed to important problems and paradoxes in cancer research that have received insufficient attention for various reasons.   Some may be built on older, neglected observations that have never been adequately explored; some on more recent findings that are perplexing; and some on problems traditionally thought to be intractable but now might be vulnerable to attack with new methods.  These questions are certainly not intended to represent the full range of important questions that the NCI and its constituencies should be studying -- NCI's greatest efforts are now devoted to major questions that are often quite obviously in need of answers -- but they should draw attention to significant yet under-appreciated opportunities for advancing our understanding of cancer and for developing new means for controlling it.

Here is a set of questions that have emerged from recent workshops on Provocative Questions. The list will expand as more workshops are conducted and web-based discussions occur.

Question ID: Feb 4-1
Submitted By February 4, 2011 Behavioral, Population, Epidemiology, and Prevention Provocative Questions workshop - Submitted to the website on March 27, 2011 (0 comments)

Are there characteristics of cancers, especially early cancers, that can be used to match therapeutic strategies more accurately with clinical risk?

 

Background: Not all cancers that are detected early are worth treating. However, uncertainties about the clinical behavior of a given lesion often lead to more aggressive treatment than may be warranted, which can result in net harm to the patient. For example, such problems can arise with breast ductal carcinoma in situ (DCIS) and some prostate cancers. In addition, the inherent uncertainty in predicting the outcome of a given cancer can result in poor communication of 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, together with a greater awareness of the tumor microenvironment, are resulting in a better understanding of how molecular profiles relate to phenotype, which could allow for better prognostic measurements. Prospective studies could lead to a substantial improvement 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, so that patients could make more informed decisions, thus matching the diagnosis with the most appropriate treatment. These developments would also identify more clearly where therapeutic advances are most needed. These changes could improve the overall benefit from early detection by reducing the risk of harm that arises from overtreatment.

(Review or Add Comments)

Average Score: 5.0 5.0 (1 evaluation)
Question ID: Feb 4-2
Submitted By February 4, 2011 Behavioral, Population, Epidemiology, and Prevention Provocative Questions workshop - Submitted to the website on March 27, 2011 (0 comments)

Why do second, independent cancers occur at high rates in patients who have survived a primary cancer?

 

Background: Second cancers are a major problem in cancer survivorship. Grouped as a single outcome in the 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 patients who have not yet had cancer.

 

Feasibility: It is substantially easier to follow patients who have had one cancer for the development of a second cancer than to observe healthy individuals for the development of a first cancer. These individuals 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 of all types, 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 cancer would 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.

(Review or Add Comments)

This question has not yet been evaluated by users
Question ID: Feb 4-3
Submitted By February 4, 2011 Behavioral, Population, Epidemiology, and Prevention Provocative Questions workshop - Submitted to the website on March 27, 2011 (0 comments)

Do drugs that are commonly and chronically used for other indications prevent cancers and, if so, how?

 

Background: Numerous observational studies indicate that some commonly used drugs used to treat or prevent diseases other than cancer may also be associated with a reduced risk of some cancers or a better cancer prognosis. For example, aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs), which are taken by many healthy people, have been reported to reduce the risk of death from several kinds of cancer, including colorectal cancer. Other commonly used drugs, such as metformin (for the treatment of Type 2 diabetes), may also be associated with a lower risk of cancer. However, the mechanisms by which these agents affect cancer risk and outcome are not well understood, so research needs to move beyond the current observational studies. A more comprehensive approach to pharmacosurveillance may uncover other drugs associated with a reduced (or elevated) risk of cancer.

 

Feasibility: Clinical data sets describing the consequences of long-term use of FDA-approved drugs could be mined for the association of these drugs with incidence of various cancer types, while ruling out the possibility of a confounding interaction with the disease being treated. Controlled prevention trials could also be considered, using validated surrogate end-points as initial indicators of efficacy. For those drugs already identified as being associated with a reduced risk of cancer, the mechanism(s) by which they reduce this risk could be identified. In the case of aspirin, for example, are these effects attributable to its anti-inflammatory activity or some other mechanism, and are patients who are prevention failures (i.e., they developed colorectal cancer despite aspirin treatment) less responsive to the key anti-carcinogenic pharmacologic effect of the drug? Animal models may help to elucidate these factors.

 

Implications of success: Although the existing observational data may support a cancer prevention hypothesis, clinical trials will be needed to establish definitive evidence for cross-disease benefits. A clearer delineation of the subset of cancers prevented by drugs could lead to more efficient trials. In addition, prevention efforts that capitalize on the effects of comorbid conditions or risk profiles may create important preventive synergies and improve public health. Elucidating the mechanisms by which these agents work could lead to the development of improved or novel agents that might have fewer side effects. (Note that this PQ is similar to a PQ posed by the Clinical and Translational Sciences Workshop on February 2, 2011.)

(Review or Add Comments)

Average Score: 5.0 5.0 (1 evaluation)
Question ID: Feb 4-4
Submitted By February 4, 2011 Behavioral, Population, Epidemiology, and Prevention Provocative Questions workshop - Submitted to the website on March 27, 2011 (0 comments)

What environmental factors change the risk of various cancers when people move from one geographic region to another?

 

Background: Numerous studies have identified geographic differences in the incidence of various cancers. Although genetic differences between populations may account for some of these differences, there are many well-documented examples of migrating populations whose cancer incidence changes substantially, more closely resembling the cancer incidence of the host country. In these instances, it is most likely that environmental or cultural factors are making an important contribution to the incidence of various kinds of cancer. In some instances, such as the effects of ultraviolet light on the incidence of skin cancer at various latitudes, the environmental factors seem clear. In others, however, epidemiologic analysis has failed to identify the key attributable environmental or lifestyle variables and the mechanisms involved.

 

Feasibility: Despite fairly extensive epidemiologic analyses of environmental factors that might account for changes in cancer incidence among migrating populations, these analyses have frequently yielded negative or inconsistent results. These inconclusive efforts may have been limited by failures to consider the full range of hypotheses and environmental, genetic, and behavioral factors. Moreover, the consequences of migration on cancer rates appear to have changed over time, and chronological comparisons of similar migration patterns have not been systematically examined. It was therefore suggested to hold a conference on the topic of changes in cancer incidence in recent and past migrations to discuss and disseminate the available information and consider additional approaches to this important question.

 

Implications of success: If new factors that contribute to changes in cancer incidence in migrated populations can be identified, our understanding of environmental carcinogenesis would be significantly enhanced. This information could have important implications for understanding cancer pathogenesis and prevention.

(Review or Add Comments)

This question has not yet been evaluated by users
Question ID: Feb 4-5
Submitted By February 4, 2011 Behavioral, Population, Epidemiology, and Prevention Provocative Questions workshop - Submitted to the website on March 27, 2011 (0 comments)

How does obesity contribute to cancer risk?

 

Background: Numerous studies have linked obesity with an increased risk of cancer, and some show that weight loss can lower the risk of cancer. However, much less attention has been paid to understanding the underlying mechanisms.

 

Feasibility: Relevant research could include molecular studies to identify metabolic and signaling pathways associated with obesity, imaging studies to determine fat distribution patterns and / or clinical observations of patients who have undergone bariatric surgery or other weight loss strategies, and epidemiologic strategies to disentangle the effects of physical activity and diet. Special populations, such as Native Americans who are genetically predisposed to obesity, may also be useful. A workshop focused on the mechanisms linking obesity to certain types of cancer should also be considered.

 

Implications of success: A deeper understanding of the mechanisms and reversibility of the cancer risk posed by obesity could suggest new strategies for countering those risks and provide greater incentives for control of body weight. Understanding how obesity is mechanistically linked to cancer development also could develop another important field of research which bridges epidemiologically identified risk factors and the molecular biology of cancer development. (Note that this PQ is similar to a PQ posed by the Exploratory Provocative Questions Workshop on October 9, 2010.)

(Review or Add Comments)

This question has not yet been evaluated by users
Question ID: Feb 4-6
Submitted By February 4, 2011 Behavioral, Population, Epidemiology, and Prevention Provocative Questions workshop - Submitted to the website on March 27, 2011 (0 comments)

Why don't more people alter behaviors known to increase the risk of cancers?

 

Background: A wealth of epidemiological research shows that certain modifiable behaviors are linked to increased cancer risk. These include tobacco use, UV exposure, sexual behaviors, obesity, and lack of cancer screening. However, despite this knowledge, many people struggle with, or are unable to modify, these behaviors. In addition to important external environmental factors, there are at least three classes of explanation that could influence the steps that should be taken to improve the likelihood of behavioral change: (1) the message itself is not designed optimally for impact; (2) the message is not effectively delivered; and (3) the interventions to facilitate behavior change are not optimal.

 

Feasibility: (1) Studies suggest that the nature of messages and how messages about cancer risk are conveyed greatly influences individual’s willingness to adopt behaviors that reduce cancer risk. Educational studies show that making students aware of negative academic stereotypes can acutely depress test performance, while more positive statements have the opposite effect. This approach could be applicable to oncology, if statements about health disparities might negatively influence a patient’s willingness to adopt cancer-preventing behaviors such as cancer screenings. (2) The means by which a message is delivered may also affect a patient’s behavior related to cancer risk, so changing the means and/or sources by which the message is delivered may improve the way a patient receives information about cancer risk. These modifications could include changes in the health system that delivers the message, changes in the role of traditional journalism, and changes in the way we use modern, internet-based communications. (3) Even with an effective message and mode of delivery, individuals may be unable to act on the message to alter their behavior. Advances in the field of neuroscience, coupled with technological advances in brain imaging, offer new opportunities to explore the neural mechanisms of decision-making and behavior change, and to develop novel interventions. For example, emerging evidence suggests it is plausible to enhance cognitive function through focused training in a manner that alters both the brain and the behavior.

 

Implications for success: Reductions in behavior that increase risk of cancer - whether attributable to one, two, or all three approaches - could have an enormous impact in the incidence of cancer. Cognitive training interventions could increase behavioral control among individuals struggling with cancer risk behaviors such as obesity and cigarette smoking. Studying the molecular and neural mechanisms that contribute to cancer-causing behaviors will provide a better understanding of how to change these behaviors and thus reduce cancer risk. How cancer risk is conveyed to patients, especially among minorities, is equally important. By changing the message, we might change the behavior. Lastly, by modifying how different systems communicate information about cancer, we can better understand how various factors influence patients, as well as the organizations and teams that deliver care.

(Review or Add Comments)

Average Score: 5.0 5.0 (2 evaluations)
Question ID: Feb 2-1
Submitted By February 2, 2011 Clinical and Translational Sciences Provocative Questions Workshop - Submitted to the website on March 3, 2011 (0 comments)

What is the clinical significance of finding cells from a primary tumor at another site?

 

Background: Metastatic disease is known to be the major cause of death from cancer. But, 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 growth can occur relatively early in tumor development, and cells at secondary sites may have properties that range from dormancy 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 the main rationale for more intensive therapy, which may or may not be warranted. For example, in some cancers (testicular, bladder), removal of lymph nodes with disseminated cells is helpful, but in others (breast, melanoma) it has no impact on outcomes.

 

Feasibility: New experimental methods, including capture of circulating tumor cells, sensitive techniques for detecting and characterizing small numbers of tumor cells at secondary sites, and the development of 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 establish the points in tumor progression when cells escape from the primary tumor; define the malignant potential of disseminated cells; and identify non-cell autonomous factors and autonomous genomic events that convert dormant cells into aggressively malignant cells.

 

Implications of success: Such analyses could enhance our understanding of the mechanisms that account for a lack of oncogenicity of tumor cells at a secondary site and the mechanisms that contribute to their malignant behavior at those sites, as well as improve our ability to predict the biological behavior tumor cells found at those sites. This information would give clinicians a clearer picture of when intervention is needed to treat such tumor cells and which can safely be left alone or followed for potential later action. A better understanding of the timing of tumor cell dissemination, biological relevance of those cells, and the progressive transformation of disseminated cells, could improve cancer staging, reduce morbidity and associated health care costs from unnecessary cancer treatment, and define drug targets in a variety of disseminated cell types.

(Review or Add Comments)

This question has not yet been evaluated by users
Question ID: Feb 2-2
Submitted By February 2, 2011 Clinical and Translational Sciences Provocative Questions Workshop - Submitted to the website on March 3, 2011 (0 comments)

Can carcinogenesis be prevented or slowed by the long-term use of anti-inflammatory drugs and, if so, by what mechanisms?

 

Background: Despite a long history of reports of associations between inflammation and carcinogenesis, especially in the colon, anti-inflammatory drugs are not commonly used to mitigate the risk of cancer (largely because of the risk of bleeding associated with non-steroidal anti-inflammatory drugs (NSAIDS), and the mechanism by which inflammation might promote the development of cancers remains poorly understood. 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 (Lancet, Jan.1, 2011). This study has heightened interest in the relationship of inflammation to carcinogenesis and the potential for use of anti-inflammatory chemoprevention based on a better understanding of the role of inflammation in carcinogenesis.

 

Feasibility: The cellular and molecular determinants of inflammation can be well characterized by cell fractionation and immunological and biochemical methods. Inflammation can also be observed by imaging techniques. Candidate cell types and molecules could be monitored in long-term prospective clinical trials of anti-inflammatory compounds to determine associations between markers of inflammation and the onset of cancer, and companion analyses with animal models are also feasible. Because aspirin and other NSAIDS are widely used, it is possible to exploit patient records and clinical studies to extend the recently reported findings, as well as to design new studies of the short- and long-term effects of such drugs. Insight might also be obtained from analysis of patients who develop tumors at sites associated with protection by NSAIDS, as such treatment “failures” could be attributable to a class of tumors whose development is intrinsically NSAID-insensitive, to patients who have less suppression of inflammation for a given NSAID dose, or to other factors.

 

Implications of success: The identification of specific markers of chronic inflammation associated with the development of various cancers would be a major breakthrough in cancer prevention. Determining that there are distinct classes of tumors whose development is or is not influenced by anti-inflammatory agents would provide important insight into the heterogeneity of cancers. Controlling chronic inflammation as measured by specific cellular and molecular markers may provide an intermediate endpoint for the evaluation of cancer chemoprevention and facilitate new approaches to reducing the risk of cancer death with existing or novel anti-inflammatory agents. Success in this endeavor would also encourage the ancillary evaluation of cancer incidence in the context of intervention studies of other widely used drugs, such as statins and anti-hypertensive agents, which are prescribed for non-cancer indications. (Review or Add Comments)


This question has not yet been evaluated by users
Question ID: Feb 2-3
Submitted By February 2, 2011 Clinical and Translational Sciences Provocative Questions Workshop - Submitted to the website on March 3, 2011 (1 comments)

Is it possible to overcome the resistance of tumors to radiotherapy?

 

Background: Because the area and dose of radiation can be precisely controlled, radiation therapy is an appealing approach for the treatment of diverse types of cancer. However, it is unclear why some cancers respond well and others do not. For example, the local control rate with radiation is nearly 100% for testicular cancer but only 10% for glioblastoma. We do not understand how to explain these differences, whether and how the sensitivities of resistant cells can be modified, or whether there are also mechanisms for acquisition of secondary resistance.

 

Feasibility: Technologies are available to characterize the genetic and epigenetic makeup of radioresistant and radiosensitive cancer cells, to delineate biochemical and physiological pathways involved in radioresistance (e.g. secretion of cytokines or other stress responses), and to test the impact of various radiosensitizers on radioresistance, such as concordant use of traditional chemotherapies or targeted drugs. Improved imaging methods could be used to follow resistance in small lesions, and new animal models might provide opportunities for understanding radioresistance. Several important questions could be addressed: Do common mechanisms mediate targeted drug resistance, chemotherapy resistance, and radioresistance? Is the basis of radioresistance genetic and/or epigenetic? What adaptive responses are unique to resistant cells? Is there a non-cell autonomous component to radioresistance?

 

Implications of success: Understanding radioresistance could substantially improve patient outcome for multiple types of cancer, especially if the results led to the identification of well tolerated potentially effective radiosensitizers that could be tested in prospective clinical trials.

(Review or Add Comments)

Average Score: 5.0 5.0 (1 evaluation)
Question ID: Feb 2-4
Submitted By February 2, 2011 Clinical and Translational Sciences Provocative Questions Workshop - Submitted to the website on March 3, 2011 (0 comments)

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 growths composed of 107-109 cells (in the range of 1 to several hundred cubic millimeters). But there is room for enhanced sensitivity, since PET scanners collect less than 1% of the radioactivity that comes from the PET agent. Since early detection of primary or metastatic lesions is likely to provide a greater opportunity for effective treatment and since clinical decisions on patient management are often based on microscopic lesions, more sensitive imaging could change clinical practice and cancer outcomes.

 

Feasibility: Although there is a trade-off between sensitivity and resolution of imaging methods, it should be possible to detect smaller tumors, if imaging probes can be more precisely matched to biologic targets on tumor cells (which might be achieved through partnerships between the pharmaceutical industry and academia in which agents disqualified as drugs might be “repurposed” as imaging agents), if new and more sensitive imaging probes can be developed, and if the sensitivity of cameras can be improved.

 

Implications of success: Being able to detect very small clusters of cells in patients and in experimental cancer models is important from therapeutic and investigative perspectives—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.

(Review or Add Comments)

This question has not yet been evaluated by users
Question ID: Feb 2-5
Submitted By February 2, 2011 Clinical and Translational Sciences Provocative Questions Workshop - Submitted to the website on March 3, 2011 (0 comments)

How do we modify our clinical trials system to determine the optimal criteria for rapidly evaluating new cancer therapies?

 

Background: There are many new agents in the development pipeline. However, the testing of agents is constrained by limited resources and patients for conducting clinical trials. Moreover, traditional clinical trial designs may not be useful for some targeted agents, and unsuccessful trials have rarely been studied further to gather the benefits of failure.

 

Feasibility: It may be useful to select for clinical development only those agents that demonstrate proof-of-mechanism and preclinical efficacy in cell culture or in animal models. Further, a method that could be used in a clinical trial to determine if the putative target or its pathway is being inhibited could help accelerate drug evaluation. Other biomarkers (when available), intermediate endpoints, and stopping rules could be incorporated in clinical trial design.

 

Implications of success: Focusing on drugs that have shown proof-of-mechanism and have clinical assays to monitor target or pathway inhibition may hasten the availability and development of agents with greater potential among those in the pipeline, result in better patient selection and fewer failures in late stage development, and provide insight into those tumors or trials in which the treatment is not successful.

(Review or Add Comments)

This question has not yet been evaluated by users
Question ID: Feb 2-6
Submitted By February 2, 2011 Clinical and Translational Sciences Provocative Questions Workshop - Submitted to the website on March 3, 2011 (1 comments)

What are appropriate criteria for determining and testing combination cancer therapies?

 

Background: Multi-modality and multi-drug therapies are commonly used in oncology, and the potential utility of multi-agent treatments is well-recognized as a basis to increase cancer cell death and to diminish the likelihood of drug resistance. However, until recently, the FDA has been reluctant to test the combined efficacy of two or more agents that have not been individually vetted, and the scientific community has been reluctant to consider strategies for multi-drug cancer therapies based on known mechanisms of resistance, activation of signaling pathways, mutational combinations, or synthetic lethalities.

 

Feasibility: Characterization of tumor cells for mutations, changes in cell signaling, and responses to single drugs and combinations can provide useful information about potential combination therapies, in conjunction with modeling of cell and tumor behavior. Such studies can be expanded to screen thousands of drug combinations using high-throughput robotic methods, with further testing of promising combinations in animal models. The underlying principles that would drive selection of multiple agents are poorly understood, but appear to be learnable with modern molecular biology methodologies. Combinations with radiotherapy and traditional chemotherapy could also be tested. Efforts to design trials of such combinations in patients would need to include consideration of patterns of drug bioavailability and toxicity that may be influenced by administering drugs together.

 

Implications for success: Combination therapy will certainly be more effective than single-drug approaches by eliminating larger proportions of cancer cells or by overcoming primary or secondary mechanisms of drug resistance and the possibilities of gaining large synergistic effects could greatly enhance effective and less toxic cancer treatments.

(Review or Add Comments)

Average Score: 5.0 5.0 (1 evaluation)
Question ID: Feb 2-7
Submitted By February 2, 2011 Clinical and Translational Sciences Provocative Questions Workshop - Submitted to the website on March 3, 2011 (0 comments)

What are the principles for design of health information systems that will allow efficient and prospective collection of patient data?

 

Background: Health information systems are necessary to deal with the overwhelming amount of information being generated in basic, translational, and clinical research, especially in oncology. It is widely recognized that such systems could markedly improve medical decision-making and delivery of health care in the future, and provide a wealth of outcome information, but detailed designs of these systems has not been worked out or tested conclusively.

 

Feasibility: The US government is encouraging development of information systems that can support rapid-learning, knowledge-based health care systems. Greater use of electronic medical records, new computing principles, and availability of virtual learning technology are helping to design new systems, but the precise methods by which patient data can be appropriately incorporated into such systems, with suitable consent and privacy protections while also permitting appropriate access for research purposes, have not yet been defined. However, the oncology community could help develop such systems, using (for example) patient data originating from cooperative clinical trials groups.

 

Implications for success: Prospective collection of health information from all patients could enhance medical practice and research in many ways, especially if “information warehouses” were able to offer health care providers with relevant information expeditiously. In optimal systems, patients would be monitored over time and would have access to their own data. In addition, the information system could be used to identify candidates for clinical trials, substantially increasing accrual rates.

(Review or Add Comments)

This question has not yet been evaluated by users
Question ID: Oct 9-1
Submitted By October 9, 2010 Provocative Questions Workshop - Submitted to the website on January 9, 2011 (3 comments)

Why are some disseminated cancers cured by chemotherapy alone?

 

Background:   Although chemotherapy is very effective only very occasionally and turning cancer into a chronic, asymptomatic condition is often stated to be a desired outcome, it is well established that certain disseminated cancers can be completely cured with chemotherapy.   These include solid tumors (testicular carcinoma, choriocarcinoma, and Wilms’ tumor) and hematological malignancies (ALL, Burkitt’s lymphoma, and diffuse large B-cell lymphoma).   

 

Feasibility:   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.

 

(Review or Add Comments)

Average Score: 5.0 5.0 (1 evaluation)
Question ID: Oct 9-2
Submitted By October 9, 2010 Provocative Questions Workshop - Submitted to the website on December 17, 2010 (3 comments)

How can we harness new technologies to inhibit traditionally “undruggable” target proteins, such as transcription factors, that are required for cancer cell viability?

 

Background:   Many tumor cells are known to be dependent on the expression of transcription factors---mutant or inappropriately expressed wild-type factors---based on experiments with artificially regulated transgenes or inhibitory RNAs.  Yet in the vast majority of cases, we don’t know how to interfere with these factors or their activities in clinical settings because, in general, we lack the means to inhibit proteins that are not enzymes.

 

Feasibility:   Several approaches---hormone-like ligands, structural modeling of proteins and protein-protein interactions, interference with protein modification or protein stability, and inhibitory RNAs---have the potential to form the basis for novel therapeutic strategies against traditionally “undruggable” targets of this type.

 

Implications of success:  A wide range of malignancies could be candidates for clinical trials with these new classes of drugs designed to block the actions of formerly refractory targets.

 

(Review or Add Comments)

Average Score: 4.5 4.5 (4 evaluations)
Question ID: Oct 9-3
Submitted By October 9, 2010 Provocative Questions Workshop - Submitted to the website on December 17, 2010 (2 comments)

Are there definable properties of non-malignant lesions that predict the likelihood of progression to invasive disease?

 

Background:   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 represent pathologies that are likely to adopt aggressive behaviors with time.   It is difficult to reverse this pattern of care without knowing whether it is possible to judge its malignant potential from the genetic, biochemical, or cellular features of the lesion.

 

Feasibility:   The advent of technologies that permit determination of genotypes and phenotypes of very small collections of cells may now reveal whether the malignant properties are conferred stochastically or whether early lesions differ in definable and reproducible ways with respect to the likelihood of malignant conversion.

 

Implications of success:   Knowing whether early lesions can be categorized with high levels of confidence into groups with low, intermediate, or high predictive value for progression to invasive cancer would strongly influence both the search for early lesions in various cancer-prone tissues and the therapeutic decisions that are already being made.  Insight into the biological basis for this stratification would be an important advance with possible relevance to analogous lesions of several tissues. 

 

(Review or Add Comments)

Average Score: 5.0 5.0 (1 evaluation)
Question ID: Oct 9-4
Submitted By October 9, 2010 Provocative Questions Workshop - Submitted to the website on December 17, 2010 (0 comments)

Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene?

 

Background:   The viability of cancer cells is often dependent on the continued production and activity of oncogenic proteins that the cell’s normal progenitor or an equivalent cell did not require.   This forms the basis for swift regression of several tumor types with targeted therapies or other means of inhibiting expression of an oncogene.

 

Feasibility:   Many examples of oncogene-dependence (or “oncogene addiction” as it is commonly called), both in human cancers and mouse models of cancer, are now subjects of great interest because the “addicting” oncogene products are promising targets for modern cancer therapy.  The signaling networks in which they are active are also being studied to identify other therapeutic targets.   However, little is known about the purported “imbalances” in cells that render them hypersensitive to loss of oncogene products that their healthy progenitors lacked.

 

Implications of success:   Knowledge of how a cell develops vulnerability to the loss or inactivation of an oncogenic protein, and undergoes programmed cell death in consequence, would very likely suggest additional novel targets for therapy.   In addition, it might offer insight into the question of which tumors are susceptible to targeted therapies and the problem of eliminating all cells in a tumor with such therapies.

 

(Review or Add Comments)

Average Score: 3.5 3.5 (1 evaluation)
Question ID: Oct 9-5
Submitted By October 9, 2010 Provocative Questions Workshop - Submitted to the website on December 17, 2010 (3 comments)

What molecular mechanism(s) are responsible for the well-documented association of obesity with certain types of cancer?

 

Background:  While many studies have documented an increased risk of cancer in association with obesity, the mechanisms that underlie this risk are poorly understood. Furthermore, the extent to which the risk can be reduced by weight loss (by dieting or bariatric surgery) has not been established. Understanding of the mechanisms for the association and strong evidence for significant reversal of risk would have important effects on cancer prevention efforts, in the manner illustrated by the successes of smoking cessation programs. 

 

Feasibility:   Recent studies of the endocrinology of eating disorders, the metabolic correlates of fat accumulation, and the pathogenic consequences of obesity, such as diabetes mellitus, have created opportunities for understanding the relationship of obesity to carcinogenesis at a mechanistic level.   In addition, bariatric surgery and other means to control body mass may provide patient populations in which the reversibility of obesity-associated cancer risks can be studied.

 

Implications of success:  A deeper understanding of the mechanisms and reversibility of the cancer risk posed by obesity could suggest new strategies for countering those risks and provide greater incentives for control of body weight.  Understanding how obesity is mechanistically linked to cancer development also could develop another important field of research which bridges epidemiologically identified risk factors and the molecular biology of cancer development.   

 

(Review or Add Comments)

This question has not yet been evaluated by users

Download Plugins: Download Plugin Adobe Acrobat Reader   Download Plugin Adobe Flash Player   Download Plugin Microsoft Word Viewer   Download Plugin Microsoft Excel Viewer   Download Plugin Microsoft PowerPoint Viewer   Download Plugin Real Player   Download Plugin Windows Media Player   Download Plugin Quicktime Player   Download Plugin WinZip
National Cancer Institute Department of Health and Human Services National Institutes of Health USA.gov