Selection of Appropriate Funding Opportunity under the National Cancer Institute (NCI) Initiative Research Answers to NCI’s Provocative Questions

Notice Number: NOT-CA-12-014

Key Dates
Release Date: September 21, 2012

Related Notices
RFA-CA-12-015, RFA-CA-12-016, RFA-CA-12-017, RFA-CA-12-018, RFA-CA-12-019, RFA-CA-12-020, RFA-CA-12-021, and RFA-CA-12-022

Issued by
National Cancer Institute (NCI)


This Notice is designed to help potential applicants identify appropriate Funding Opportunity Announcements (FOAs) pertaining to the initiative Research Answers to NCI’s Provocative Questions that has been reissued by the National Cancer Institute (NCI). The goal of the Provocative Questions Initiative is to stimulate specific areas of cancer research that are deemed understudied, neglected, paradoxical, or have been difficult to address in the past.

The first round of Research Answers to NCI’s Provocative Questions FOAs published in 2011 (RFA-CA-11-011 and RFA-CA-11-012) were based on a set of 24 Provocative Questions (PQs), which were formulated with a significant input from the extramural scientific community. Over the past year, the NCI has developed an updated set of 24 PQs for the current PQs FOAs. Some of these 24 PQs are new, whereas others are refocused relative to the original list. PQs pertain to a broad range of fields of cancer research, and all are framed to inspire cancer scientists to conceive new approaches and/or feasible solutions.

These 24 questions are not meant to represent the full range of NCI’s priorities in cancer research. Rather, these questions are intended to focus investigators' efforts on specific gaps in current knowledge and inspire creative solutions that may have profound scientific, and ultimately practical, implications.

Each research project proposed in response to this initiative must be focused on solving one particular research problem defined by one specific PQ selected from the current list of PQs. To facilitate the review process, the entire PQ list is divided into four thematic blocks, with each block corresponding to two FOAs (for the R01 and R21 funding mechanisms). Thus, prospective applicants need to consider (and respond to) a specific FOA that lists the particular PQ that they intend to address in the proposed research project.
Note that the group descriptors mentioned below represent merely generalized thematic "labels". Projects proposed to address specific PQs may use strategies that incorporate ideas and approaches from multiple disciplines, as appropriate for a given PQ. Thus, transdisciplinary and/or translational projects are allowed and encouraged as long as they serve the scientific focus of the specific PQ chosen.

Group A covered by RFA-CA-12-015 and RFA-CA-12-016 (using the R01 and R21 funding mechanisms, respectively). PQs in this group seek answers to specific unsolved problems in cancer prevention and risk. The following PQs are included:

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 covered by RFA-CA-12-017 and RFA-CA-12-018 (using the R01 and R21 funding mechanisms, respectively). PQs in this group are focused on perplexing problems in mechanisms of tumor development or recurrence. The following PQs are included:

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?

Group C covered by RFA-CA-12-019 and RFA-CA-12-020 (using the R01 and R21 funding mechanisms, respectively). PQs in this group concentrate on improving tumor detection, diagnosis, and prognosis. The following PQs are included:

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 covered by RFA-CA-12-021 and RFA-CA-12-022 (using the R01 and R21 funding mechanisms, respectively). PQs in this group are focused on problems in cancer therapy and outcomes. The following PQs are included:

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?

Important Notes:

  • The numbering of PQs is essentially arbitrary. This numbering and grouping should not be construed to indicate any particular order of priority. Creative applications proposing research solutions to any of the PQs listed in all four groups (and corresponding eight PQ FOAs) are sought and encouraged.

  • For a series of PQ FOAs using the same funding mechanism (R01 or R21), various FOA parameters (e.g., key dates, set-aside funds, etc.) as well as scientific requirements (including critical aspects of responsiveness) are identical, regardless of the group of PQs covered.

  • Nonetheless, it is essential that every applicant reads the full individual PQ FOA that corresponds to a specific PQ and funding mechanism chosen before preparing and submitting an application.


Please direct all inquiries to:

Emily J. Greenspan, Ph.D.
National Cancer Institute
Office of the Director
Center for Strategic Scientific Initiatives (CSSI)
Phone: 301-496-1045