Table 1.

List of current 24 provocative questions by group and thematic focus

Provocative questions (PQ) groupFocusQuestions
Group A (RFA-CA-12-015 and RFA-CA-12-016)*Cancer prevention and risk
  • 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?

Group B (RFA-CA-12-017 and RFA-CA-12-018)*Mechanisms of tumor development or recurrence
  • PQB1: Why do second, independent cancers occur at higher rates in patients who have survived a primary cancer than in a cancer-naïve 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?

Group C (RFA-CA-12-019 and RFA-CA-12-020)*Tumor detection, diagnosis, and prognosis
  • 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?

Group D (RFA-CA-12-021 and RFA-CA-12-022)*Cancer therapy and outcomes
  • 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?

NOTE: This grouping does not reflect any priority of PQs for review or funding purposes. Supporting information relating to the 24 PQs can be found at: *Letter of Intent in response to PQ's RFAs due on May 20, 2013.