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Information regarding background, feasibility and implications for success for each PQ will be posted soon


PQ - 1

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?


Intent: This Provocative Question seeks research that would identify changes in histologically normal cells surrounding or within close proximity of a cancer and that were induced in pre-malignant stages of tumor development. These changes should also be detected in the tumor itself, but not found in truly normal cells of that organ. Such changes might include, but need not be limited to, mutations, epigenetic alterations, or other detectable biochemical events. The identified changes could then be used to design therapeutic or preventive interventions to inhibit the development of future tumors, either at this site or in other pre-malignant fields with similar characteristics. Successful applications could be directed to any of the stages of this characterization–target identification–drug development pipeline as long as they rely on characteristics of the pre-malignant field. In most cases the tissue/cancer type chosen should have a well-documented pre-malignant field (e.g., lung, head & neck, esophageal, colon, or bladder).

Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.


  
PQ - 2

What molecular mechanisms influence disease penetrance in individuals who inherit a cancer susceptibility gene?


Intent: Individuals who carry a mutation in a cancer susceptibility gene, for example individuals with Li-Fraumeni, Cowden, or Lynch Syndrome, have a dramatically increased risk over non-carriers of developing cancer. This Provocative Question calls for research to determine how the rate of disease penetrance is influenced by various life experiences such as environmental exposure, patient natural history (e.g., abnormal changes in hormone levels), or interactions with other genes/biological pathways. The intent of this question is to go beyond association studies, which identify factors that change disease penetrance in individuals with an inherited cancer susceptibility gene, and determine the mechanisms that explain how these changes influence disease occurrence. Mechanistic studies of events that either increase or decrease rates of penetrance are suitable for study. Preclinical or computational models may also be used to understand how disease penetrance may be altered.

Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.


  
PQ - 3

How do variations in tumor-associated immune responses contribute to differences in cancer risk, incidence, or progression?


Intent: Tumors vary in the extent and character of immune cell infiltration and other tumor-associated immune responses. These variations may be due to many factors, including differences in heterogeneous variations of the malignant cell phenotype or genotype or in the potential range of immune responses seen when comparing individuals or populations. This Provocative Question asks scientists to propose research into the causes of variable tumor-associated immune responses and/or how these variations relate to cancer risk, incidence, or progression. Successful applications might range from mechanistic studies that attempt to understand how tumor-associated immune responses can contribute to cancer development in an individual to studies of how population-based differences in immune traits (e.g., across such populations as racial/ethnic groups or various age groups) might explain variations in cancer risk, incidence, or progression.

Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.


  
PQ - 4

Why do some closely related tissues exhibit dramatically different cancer incidence?


Intent: The same organ site can develop different types of cancers (e.g., adeno- versus squamous carcinoma). In contrast, many tissues with closely related developmental histories have wide variations in cancer incidence (e.g., left versus right colon cancers, seminal vesicle versus prostate, etc.). This Provocative Question seeks research applications that will explain the molecular mechanisms that account for different rates of cancer development among closely related tissues.

Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.


  
PQ - 5

How does mitochondrial heterogeneity influence tumorigenesis or progression?


Intent: Mitochondria within one cell, among closely related cells, or between different individuals can display heterogeneity in mtDNA sequences, dynamic spatial and communication patterns, and functional capacities. This Provocative Question asks researchers to propose mechanistic studies that will characterize how mitochondrial variation within individual tumor cells, among cells within tumor microenvironment(s), or in the same cell types from different individuals influences tumorigenesis or progression. How do these differences vary over time and how do they alter or contribute to tumor development, adaptation, or response to therapy? Successful applications will examine how key aspects of mitochondrial heterogeneity contribute to important steps in tumor development and phenotypic plasticity.

Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.


  
PQ - 6

What are the underlying molecular mechanisms that are responsible for the functional differences between benign proliferative diseases and premalignant states?


Intent: Different populations of cells that continue to proliferate in inappropriate settings or at inappropriate times can pose variable risks to human health. Some cell populations will continue to divide over a lifetime (e.g., ductal hyperplasias, benign lipomas, or papillomas) but pose no or little risk of advancing to malignancy, while other populations will progress to cancer with higher frequency (e.g., adenomas changing to adenocarcinomas). This Provocative Question seeks to stimulate research that will compare the range of these states and determine the underlying molecular and cellular regulatory mechanisms that distinguish these populations. Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.


  
PQ - 7

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?


Intent: The demonstration of the extensive heterogeneity of cell types within a tumor and its microenvironment is one of the most intriguing research surprises of the last decade. This heterogeneity includes variations in the tumor cells within a single cancer, extensive differences among tumor cells from similar cancers that arise from the same tissue of origin, and in the variety of associated cells found in the tumor microenvironment, which range from stromal cells to endothelial cells to infiltrating immune cells of many different types. This heterogeneity contributes to a multitude of tumor behaviors and is thought to be one of the reasons that tumors pose such a complicated therapeutic challenge. This Provocative Question seeks the development of new in vivo imaging methods to allow the rapid identification, quantitation, and location of the different cell types within a tumor and its microenvironment. Work at any stage of technical development of imaging methods in the pursuit of these goals is appropriate. Development and validation of imaging methods for various subsets of cell types for the purpose of building a complete set in future work is also considered responsive.

Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.


  
PQ - 8

What cancer models or other approaches can be developed to study clinically stable disease and the subsequent transition to progressive disease?


Intent: What biological mechanisms keep some cancers in a stable state and how do we study the transitions from stable to progressive disease? In this Provocative Question we seek the development of new models or approaches to foster the study of both the stable state — including but not necessarily limited to dormant or indolent tumors as well as those meeting the Response Evaluation Criteria in Solid Tumors (RECIST) definition for stable disease — and the progression of such tumors to more aggressive phenotypes. These new approaches might take advantage of advances in various preclinical models or strategies, combinations of biological and computational models, or other approaches that could help us understand the biology of these important stable states. Studies of tumors that are held in stasis by continued drug treatment are not responsive to this request and will not be considered for funding.

Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.


  
PQ - 9

What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?


Intent: While many acute toxicities can be adequately managed during cancer therapy (e.g., febrile neutropenia, acute nausea and vomiting) and will resolve once therapy has been completed (e.g., mucositis), there are other adverse sequelae that persist after completion of therapy and for which there are no effective management strategies. These include, but are not limited to, therapy-induced peripheral neuropathy, neurocognitive impairments, cardiovascular toxicity, pulmonary fibrosis, arthralgias, and immune system-related adverse events. This Provocative Question seeks research that will (1) identify novel mechanisms that induce such chronic sequelae, (2) apply the knowledge gained from understanding these mechanisms to facilitate design of new treatments (or approaches) that may decrease or reverse adverse cancer therapy effects, or (3) facilitate mechanism-based design of new cancer therapies that are expected to show decreased adverse effects when compared with existing therapies. Such studies may be performed in pre-clinical, non-clinical, and/or clinical settings. Successful applications must focus on adverse therapy related sequelae (whether immediate or delayed in onset) for which current management or treatment strategies are limited or ineffective.

Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.


  
PQ - 10

How do microbiota affect the response to cancer therapies?


Intent: This Provocative Question seeks grant applications that use our increasing knowledge of the normal human microbiota to understand how these organisms or their secreted products affect cancer therapies. Approaches may include studies that focus on effects of the changing microbiota within an individual patient undergoing treatment or among different patients undergoing identical therapy but with different outcomes. Analogous studies in pre-clinical models are also invited. Key aspects of study might include either how the microbiota alter the composition, concentration, stability, or effectiveness of standard or experimental classes of therapies, or the identification and study of microbial regulatory mechanisms that mediate these changes.

Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.


  
PQ - 11

What mechanisms of action of standard-of-care cytotoxic, radiologic, or targeted therapies affect the efficacy of immunotherapy?


Intent: With the increasing and successful use of immunotherapy in cancer treatment, many investigators have begun to consider approaches that combine standard of care treatments, such as chemotherapy, radiotherapy, or targeted therapy for a particular tumor, with immunotherapy. Standard of care is defined as a treatment that is accepted by medical experts as a proper treatment for a certain type of disease and that is widely used by healthcare professionals. There may be more than one standard of care for any individual cancer type. Cancer immunotherapy encompasses a wide range of treatment modalities that harness the anti-tumor effects of the immune system, and the factors that influence the efficacy of immunotherapy alone are becoming understood. However, there is a lack of information on their effects when used in combination with standard of care interventions. This Provocative Question seeks new investigations that will define molecular or cellular mechanisms for enhancements, antagonisms, or toxicities that occur when cancer immunotherapy and standard of care treatments are used in combination (either sequentially or concomitantly) as compared to when cancer immunotherapy is used alone.

Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.


  
PQ - 12

What methods and approaches induce physicians and health systems to abandon ineffective interventions or discourage adoption of unproven interventions?


Intent: Well-intentioned efforts to speed diffusion of research results into practice may result in the adoption of new treatments and approaches to care before their effectiveness has been documented. Multiple studies have documented the continued use of some medical treatments and approaches to cancer care known to be ineffective. This Provocative Question seeks hypothesis-driven studies that explicitly examine how physicians and/or health systems can be induced to diminish delivery of ineffective or unproven cancer care. Responsive applications may, for example, involve the study of natural experiments, such as changes in reimbursement or institutional policy, or the development and testing of interventions targeted at providers or delivery systems. Studies focused on patient factors or including interventions involving only patients are not responsive to this question.

Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.