Past CSSI Programs

Provocative Questions Initiative

The Provocative Questions (PQ) program was initiated in 2011 and had active funding opportunities from 2011 through 2021, stimulating research in under-explored areas across the cancer research continuum through nearly 400 awards. Approximately 70 understudied, paradoxical, or otherwise difficult-to-address challenges were identified by NCI in collaboration with the cancer research community. The questions spurred not only research through the supported grants, but also inspired new research collaborations and follow-on initiatives at NCI. The PQs represent a unique source of historical challenges in cancer research, some of which are on the path to being solved, while others remain perplexing.

2020 Provocative Questions and Awarded Grants

Funding Opportunities: RFA-CA-20-004 and RFA-CA-20-005
NIH RePORTER link to funded grants

• PQ1: What are the underlying causes of the unexplained rising incidence in early-onset cancers?
• PQ2: How does intermittent fasting affect cancer incidence, treatment response, or outcome?
• PQ3: How do selective pressures affect cell competition and cooperation during cancer initiation and development?
• PQ4: What mechanisms explain sex differences in cancer incidence, lesion location, or response to therapy?
• PQ5: What strategies can block or reverse the emergence of new cell lineage states induced by cancer treatments?
• PQ6: How can cancer cachexia be reversed?
• PQ7: What methods can be developed to integrate patient-generated health data into electronic health records?
• PQ8: What strategies improve and sustain coordination of comprehensive healthcare for underserved cancer patients with comorbidities?
• PQ9: What methods can be developed to effectively study small or rare populations relevant to cancer research?

2017/2018 Provocative Questions and Awarded Grants

Funding Opportunities: RFA-CA-17-017, RFA-CA-17-018, RFA-CA-18-019, RFA-CA-18-020
Revisions: RFA-CA-17-019 through RFA-CA-17-022 and RFA-CA-18-021 through RFA-CA-18-024
NIH RePORTER link to funded grants

• PQ1: What molecular mechanisms influence disease penetrance in individuals who inherit a cancer susceptibility gene?
• PQ2: How do variations in immune function caused by comorbidities or observed among different populations affect response to cancer therapy?
• PQ3: Do genetic interactions between germline variations and somatic mutations contribute to differences in tumor evolution or response to therapy?
• PQ4: Can we develop tools to directly change the expression or function of multiple chosen genes simultaneously and use these tools to study the range of changes important for human cancer?
• PQ5: How does mitochondrial heterogeneity influence tumorigenesis or progression?
• PQ6: How do circadian processes affect tumor development, progression, and response to therapy?
• PQ7: How do cancer-specific subcellular pathognomonic structures develop, what is their function, and can they be a source of novel therapeutic targets?
• PQ8: What are the predictive biomarkers for the onset of immune-related adverse events associated with checkpoint inhibition, and are they related to markers for efficacy?
• PQ9: Can we develop bifunctional small molecules that will couple oncoproteins or other cancer-causing molecules of interest to inactivating processes such as degradation and achieve tissue-specific loss of function?
• PQ10: How do microbiota affect the response to cancer therapies?
• PQ11: Through what mechanisms do diet and nutritional interventions affect the response to cancer treatment?
• PQ12: What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?

2015 Provocative Questions and Awarded Grants

Funding Opportunities: RFA-CA-15-008 and RFA-CA-15-009
Revisions: RFA-CA-16-010 through RFA-CA-16-013
NIH RePORTER link to funded grants

• PQ1: For tumors that arise from a pre-malignant field, what properties of cells in this field can be used to design strategies to inhibit the development of future tumors?
• PQ2: What molecular mechanisms influence disease penetrance in individuals who inherit a cancer susceptibility gene?
• PQ3: How do variations in tumor-associated immune responses contribute to differences in cancer risk, incidence, or progression?
• PQ4: Why do some closely related tissues exhibit dramatically different cancer incidence?
• PQ5: How does mitochondrial heterogeneity influence tumorigenesis or progression?
• PQ6: What are the underlying molecular mechanisms that are responsible for the functional differences between benign proliferative diseases and premalignant states?
• PQ7: What in vivo imaging methods can be developed to determine and record the identity, quantity, and location of each of the different cell types that contribute to the heterogeneity of a tumor and its microenvironment?
• PQ8: What cancer models or other approaches can be developed to study clinically stable disease and the subsequent transition to progressive disease?PQ9: What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?
• PQ10: How do microbiota affect the response to cancer therapies?
• PQ11: What mechanisms of action of standard-of-care cytotoxic, radiologic, or targeted therapies affect the efficacy of immunotherapy?
• PQ12: What methods and approaches induce physicians and health systems to abandon ineffective interventions or discourage adoption of unproven interventions?

2013 Provocative Questions and Awarded Grants

Funding Opportunities: RFA-CA-13-016 through RFA-CA-13-025
NIH RePORTER link to funded grants

• PQA1: How do decision-making processes influence habitual behaviors, and how can that knowledge be used to design strategies that lead to adoption and maintenance of behaviors that reduce cancer risk?
• PQA2: How does the level, type, and/or duration of physical activity influence cancer risk and prognosis?
• PQA3: What biological mechanisms influence susceptibility to cancer risk factors at various stages of life?
• PQA4: For tumors that arise from a pre-malignant field, what properties of cells in this field can be used to design strategies to inhibit the development of future tumors?
• PQB1: Why do second, independent cancers occur at higher rates in patients who have survived a primary cancer than in a cancer-na ve population?
• PQB2: What molecular and cellular events in the tumor microenvironment (for example, the local immune response) determine if a tumor at the earliest stages of malignant transformation is eliminated, stimulated for further development, or made indolent?
• PQB3: What mechanisms initiate or sustain cancer cachexia, and can we target them to extend lifespan and quality of life for cancer patients?
• PQB4: What methods can be devised to characterize the functional state of individual cells within a solid tumor?
• PQC1: What properties of pre-cancerous lesions or their microenvironment predict the likelihood of progression to malignant disease?
• PQC2: What molecular or cellular events establish tumor dormancy after treatment and what leads to recurrence?
• PQC3: How do variations in tumor-associated immune responses among patients from distinct well-defined populations, such as various racial/ethnic or age groups, contribute to differences in cancer outcomes?
• PQC4: What in vivo imaging methods can be developed to portray the "cytotype" of a tumor defined as the identity, quantity, and location of each of the different cell types that make up a tumor and its microenvironment?
• PQD1: What molecular properties make some cancers curable with conventional chemotherapy?
• PQD2: What features of standard-of-care therapies enhance or inhibit the efficacy of immunotherapy?
• PQD3: Do tumors evolve common features that could act as new therapeutic targets when they metastasize to the same secondary site?
• PQD4: What are the mechanistic bases for differences in cancer drug metabolism and toxicity at various stages of life?
• PQE1: What strategies optimize adoption and sustainability of guideline concordant cancer treatments in community settings?
• PQE2: What care delivery models can be developed to transition cancer patients effectively from active therapy to end of life care?
• PQE3: What methods and approaches induce physicians and health systems to abandon ineffective interventions or discourage adoption of unproven interventions?
• PQE4: What are the best methods to identify and stratify subgroups of patients with particular co-morbidities who will benefit from defined cancer therapies?

2012 Provocative Questions and Awarded Grants

Funding Opportunities: RFA-CA-12-015 through RFA-CA-12-022
NIH RePORTER link to funded grants

• PQA1: 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?
• PQA2: How does obesity contribute to cancer risk?
• PQA3: 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?
• PQA4: As modern measurement technologies improve, are there better ways to objectively ascertain exposure to cancer risk?
• PQA5: How does the level, type or duration of physical activity influence cancer risk and prognosis?
• PQA6: How does susceptibility of exposure to cancer risk factors change during development?
• PQB1: Why do second, independent cancers occur at higher rates in patients who have survived a primary cancer than in a cancer-na ve population?
• PQB2: 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?
• PQB3: What molecular and cellular events determine whether the immune response to the earliest stages of malignant transformation leads to immune elimination or tumor promotion?
• PQB4: What mechanisms of aging, beyond the accumulation of mutations, promote or protect against cancer development?
• PQB5: How does the order in which mutations or epigenetic changes occur alter cancer phenotypes or affect the efficacy of targeted therapies?
• PQB6: Given the difficulty of studying metastasis, can we develop new approaches, such as engineered tissue grafts, to investigate the biology of tumor spread?
• PQC1: Can we determine why some tumors evolve to aggressive malignancy after years of indolence?
• PQC2: How can the physical properties of tumors, such as the 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?
• PQC3: Are there definable properties of pre-malignant or other non-invasive lesions that predict the likelihood of progression to metastatic disease?
• PQC4: 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?
• PQC5: Can tumors be detected when they are two to three orders of magnitude smaller than those currently detected with in vivo imaging modalities?
• PQC6: What molecular events establish tumor dormancy after treatment and what leads to recurrence?
• PQD1: How does the selective pressure imposed by the use of different types and doses of targeted therapies modify the evolution of drug resistance?
• PQD2: What molecular properties make some cancers curable with conventional chemotherapy?
• PQD3: 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?
• PQD4: 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?
• PQD5: 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?
• PQD6: What mechanisms initiate cachexia in cancer patients, and can we target them to extend lifespan and quality of life for cancer patients?

 2011 Provocative Questions and Awarded Grants

Funding Opportunities: RFA-CA-11-011 and RFA-CA-11-012
NIH RePORTER link to funded grants

• PQ1: How does obesity contribute to cancer risk?
• PQ2: What environmental factors change the risk of various cancers when people move from one geographic region to another?
• PQ3: Are there ways to objectively ascertain exposure to cancer risk using modern measurement technologies?
• PQ4: Why don't more people alter behaviors known to increase the risk of cancers?
• PQ5: Given the evidence that some drugs commonly and chronically used for other indications, such as an anti-inflammatory drug, can protect against cancer incidence and mortality, can we determine the mechanism by which any of these drugs work?
• PQ6: What are the molecular and cellular mechanisms by which patients with certain chronic diseases have increased or decreased risks for developing cancer, and can these connections be exploited to develop novel preventive or therapeutic strategies?
• PQ7: How does the lifespan of an organism affect the molecular mechanisms of cancer development, and can we use our deepening knowledge of aging to enhance prevention or treatment of cancer?
• PQ8: Why do certain mutational events promote cancer phenotypes in some tissues and not in others?
• PQ9: As genomic sequencing methods continue to identify large numbers of novel cancer mutations, how can we identify the mutations in a given tumor that are most critical to the maintenance of its oncogenic phenotype?
• PQ10: 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?
• PQ11: How do changes in RNA processing contribute to tumor development?
• PQ12: Given the recent discovery of the link between a polyomavirus and Merkel cell cancer, what other cancers are caused by novel infectious agents and what are the mechanisms of tumor induction?
• PQ13: Can tumors be detected when they are two to three orders of magnitude smaller than those currently detected with in vivo imaging modalities?
• PQ14: Are there definable properties of a non-malignant lesion that predict the likelihood of progression to invasive or metastatic disease?
• PQ15: Why do second, independent cancers occur at higher rates in patients who have survived a primary cancer than in a cancer-naïve population?
• PQ16: How do we determine the clinical significance of finding cells from a primary tumor at another site?
• PQ17: Since current methods to assess potential cancer treatments are cumbersome, expensive, and often inaccurate, can we develop other methods to rapidly test interventions for cancer treatment or prevention?
• PQ18: Are there new technologies to inhibit traditionally "undruggable" target molecules, such as transcription factors, that are required for the oncogenic phenotype?
• PQ19: Why are some disseminated cancers cured by chemotherapy alone?
• PQ20: Given the recent successes in cancer immunotherapy, can biomarkers or signatures be identified that can serve as predictors or surrogates of therapeutic efficacy?
• PQ21: Given the appearance of resistance in response to cell killing therapies, can we extend survival by using approaches that keep tumors static?
• PQ22: Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene?
• PQ23: Can we determine why some tumors evolve to aggressive malignancy after years of indolence?
• PQ24: Given the difficulty of studying metastasis, can we develop new approaches, such as engineered tissue grafts, to investigate the biology of tumor spread?

Thrombosis in Cancer: Standardization of Biomarker Measurements

Thrombosis is a major source of morbidity and mortality for people with cancer. To support the need for improved, actionable biomarkers of thrombosis, a pilot study was conducted to advance standardization and provide guidance for the measurement of thrombosis biomarkers. The project reproduced variable blood sample handling conditions experienced in the clinic and assessed their effects on sample integrity. Specimens were exposed to preanalytical variables including delay to centrifugation, delay to assay, and freeze/thaw cycles, and were analyzed for markers of coagulation, fibrinolysis, cellular injury, and inflammation. Blood samples, accompanying clinical and biomarker data, and Standard Operating Procedures (SOPs) for collection, handling, and analysis are available to researchers. Samples were donated pre-treatment from individuals with suspected cancer and include prostate, kidney, pancreas, colon, lung, head/neck, breast, lymphoma cases. Please contact michelle.berny-lang@nih.gov to request blood plasma or cell pellets for research use.