Remaining receipt dates for the 2017 Provocative Questions are June 29 and October 30, 2018
The collective scientific scope of the PQ RFAs is defined by the list of PQs. These PQs define research areas appropriate for the RFAs. They should NOT be construed as examples of specific topics. The scientific scope of each individual application must clearly and distinctly correspond to one (and only one) of the PQs listed below. Within an area defined by a given PQ, applicants may propose and pursue any topic they deem relevant as a "research answer" to that PQ. It is important, however, that applicants carefully read the Intent Statement for each PQ. Additional information for each PQ is contained in the Background, Feasibility and Implications of Success statements below.
PQ1: 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 considered nonresponsive to this Provocative Question.
Background: The presence of a mutation in a known cancer susceptibility gene (e.g., such as in BRCA1 or BRCA2 for breast or ovarian cancer, PTEN in Cowden Syndrome, TP53 in Li-Fraumeni Syndrome, or MLH1, MSH2, etc., in Lynch Syndrome) raises an individual’s risk of cancer significantly. However, not all mutation carriers will develop cancer, and the risks for developing a specific cancer type can vary within a cancer type/syndrome. It is likely that other genes, environmental exposures, or a person’s own natural history (e.g., abnormal changes in hormone levels) determine cancer susceptibility gene penetrance. Although data on associations among genes and between genes and exposures, environmental and otherwise, exist, determining the underlying molecular mechanisms affecting gene penetrance has been challenging. The intent of this Provocative Question is to support research that deciphers the mechanisms by which these variables influence disease penetrance in the presence of a known cancer susceptibility gene mutation.
Feasibility: Given the substantial amounts of data that exist on cancer genetic susceptibility along with epidemiologic data on environmental and other exposures, delving more deeply into how these entities interact at the molecular level should be feasible. This work may require interdisciplinary efforts to bring together disparate data types and conduct analyses. Investigators can use in vitro or in vivo models and also preclinical, computational, or mathematical models of germline cancer genetic susceptibility and exposures to study the mechanisms linking these interactions and their impact on penetrance. Exposures may include chemopreventive interventions, in which chemopreventive agents could be used as tools to interrogate the molecular pathways that contribute to (or inhibit) carcinogenesis; such research also would provide insight into the potential such agents have for preventing cancer in individuals with germline mutations in known cancer-promoting genes.
Implications of Success: The results of research responsive to this PQ will provide information on mechanisms of interaction between known exposures, environmental or otherwise, and known susceptibility genes that begin to answer the question of penetrance. The results may help define how exposures and genetic factors interact to augment or suppress the action of cancer susceptibility genes, delineate whether specific lifestyle or chemopreventive interventions might be most appropriate for a particular cancer type, or identify networks of molecules to target for chemoprevention or treatment.
PQ2: How do variations in immune function caused by comorbidities or observed among different populations affect response to cancer therapy?
Intent: Although the immune system has the potential to detect and eliminate cancer, considerable variability in immune function exists among populations and in response to comorbidities. These variations may help to explain observed differences in response to cancer therapies among patients and different populations. This Provocative Question seeks applications that will identify and/or validate immune response variations among cancer patients (including tumor-associated immune responses and/or host immune responses) and investigate how these variations may positively or negatively affect response to cancer therapy. Successful applications might include mechanistic or epidemiological studies to investigate how population-based differences in immune traits (e.g., across such populations as racial/ethnic groups, age groups, and/or gender) can influence therapeutic outcomes. Furthermore, applications may seek to determine how comorbid conditions (e.g obesity, heart disease, diabetes, etc.) may influence immune function and elucidate mechanism(s) by which this influence may affect therapeutic responses.
Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.
Background: Comorbid conditions (e.g. autoimmune diseases, cognitive impairment, heart disease, diabetes, obesity, etc.) are frequent among cancer patients and may influence the progression of disease, treatment options, response to cancer therapies, and overall outcomes. The effects of these various comorbid conditions on the host immune functions remain to be fully elucidated. Furthermore, systemic and tumor-associated immunological variations have additionally been identified between different patient populations including across racial/ethnic, age, and gender groups. Notably, the increasing use of cancer immunotherapy approaches, often combined with conventional therapies such as chemotherapy and/or radiation, has induced unprecedented efficacy against a range of tumors while redefining cancer therapy. However, despite these recent advancements in cancer therapeutic options, there remain significant gaps in investigations involving patients with comorbidities and in racial/ethnically diverse patient populations, due to their underrepresentation in clinical trials. Research is needed to better understand variations in immune function amongst patients and explore specific mechanisms that may contribute to favorable therapeutic responses. This Provocative Question asks scientists to propose research into the causes of variable immune functions in subsets of cancer patients and/or how these variations may influence therapeutic responses.
Feasibility: Key components of immune responses have been shown to vary among population groups (e.g., across such populations as racial/ethnic groups, age groups, and/or gender) and have distinct properties in individuals with comorbidities. Responsive applications may include mechanistic, epidemiological, or comparative-based studies investigating variations in immune responses, either in response to chronic comorbid conditions or among well-defined population groups. Demonstrated differences in immune signatures including immune cell infiltration, chemotaxis, and cytokine profiles; studies directed at characterization of immune response markers related to therapeutic targets; and pathways differentially activated or inhibited in individuals or among diverse well-defined populations could provide starting points for these studies. The goal of this work should be to explain how these immune variations contribute to positive, negative, or no response to cancer therapy.
Implications of Success: Successful applications should propose studies to increase understanding of immunological mechanisms that affect response to cancer therapy among patients suffering from comorbidities and/or among diverse populations. Results from funded projects are expected to serve as a solid foundation for developing tangible strategies to manipulate the immune responses that influence favorable response to cancer therapy.
PQ3: Do genetic interactions between germline variations and somatic mutations contribute to differences in tumor evolution or response to therapy?
Intent: Cancer is characterized by numerous genetic and epigenetic alterations occurring in both the germline and somatic (i.e., tumor) genomes. Independently, projects focused on characterizing the germline and tumor genomes have led to improved understanding of cancer etiology and biology that will be exceedingly valuable as starting points for the identification of prognostic, diagnostic and therapeutic markers as well as therapeutic targets for the development of new treatments. This Provocative Question seeks research that would integrate germline and somatic genetic data in a systematic manner to gain a comprehensive picture of how the genetics of both the person and the tumor interact to affect tumor evolution, progression, or response to therapy.
Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.
Background: Cancer initiation, progression, and response to treatment involves multiple factors, including variation in both germline and somatic genomes. This PQ expands on the substantial investment the NCI has made in characterizing both host and tumor genomes and developing clinical trials, and asks for experimental approaches that integrate germline and somatic genetic data to better understand cancer risk and etiology or improve treatment and outcomes.
Feasibility: Tools and technologies such as high-throughput genotyping, next-generation genome sequencing, and bioinformatics analysis tools have revolutionized our ability to catalogue human genetic variation. The National Institutes of Health Big Data to Knowledge (BD2K) initiative may help address issues related to complex data analysis. While not the only source of genetic information, the Database of Genotypes and Phenotypes (dbGaP) can be used to provide controlled access to existing datasets that contain both germline and somatic data. In addition, NCI funded clinical trials and large scale research collaborations have generated treatment and cancer outcome data, many of which also include genetic data and biospecimen.
Implications of Success: The results of research responsive to this PQ will lead to studies that increase our understanding of the joint contributions of the germline and somatic genomes. Effective integrated analysis of germline and somatic genomic data will help us better understand whether and how cancer risk alleles contribute to carcinogenesis, whether germline risk alleles and somatic mutations interact, of the biology underlying development of different tumor subtypes, how germline and somatic variation affect treatment and outcome, and whether the pathways involved in cancer risk, initiation, progression, and prognosis intersect.
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?
Intent: Progression of human cancers are driven by the simultaneous dysregulation of multiple genes and gene products. However, these changes are often studied in isolation or in experimental systems that are not amenable to multiple genetic or epigenetic perturbations. This Provocative Question calls for development of approaches and systems that enable simultaneous, sequential, and/or spatially controlled tuning of the expression or function of multiple chosen genes in cancer-relevant mammalian systems. Applications must be grounded in a context of human cancer, and successful applications should demonstrate that the proposed approach facilitates modulation and quantification of phenotypes relevant to human cancer progression and/or response to treatment, ideally within an in vivo or ex vivo system.
Background: Recent advances in gene editing and epigenetic reprogramming have greatly increased the ability of researchers to control expression and function of individual genes across a broad range of biological systems. However, cancer progression and phenotypes are often driven by the dysregulation of multiple genetic factors, including gene mutations and copy number alterations, structural rearrangements, and alterations in the regulation of gene expression and function. Technologies that enable researchers to probe these multifaceted mechanisms via the simultaneous manipulation of multiple genes would provide a new level of experimental precision and quantitative control not currently widely available to the broader cancer research community.
Feasibility: Studies that address this question may develop tools de novo, leverage existing technologies in novel combinations for simultaneous manipulation, or adapt tools developed in non-mammalian systems for robust and reproducible use in mammalian systems. In addition, computational tools that aid in design, prediction, and analysis of resulting data may be important in adequately addressing this PQ. Applications that do not afford the user a meaningful choice of gene targets with respect to cancer relevance will not be considered responsive.
For this PQ, successful projects will demonstrate:
- the simultaneous, sequential, and/or spatially controlled tuning of the expression or function of multiple chosen genes.
- that these targeted alterations result in measurable phenotypic changes or other such clear indicators of control of the chosen genes.
- that the controlled phenotypes are relevant to human cancer progression and/or response to treatment in one or more cancer-relevant mammalian systems, preferably in vivo.
Though not required, additional elements could include the demonstrated repeatability of a tool in multiple systems or the ability to monitor gene expression or function changes in real time via imaging or other technologies.
Implications of Success: Successful development of tools described in this PQ will provide a new level of experimental precision and quantitative control not currently widely available to the broader cancer research community.
PQ5: 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, proteome, morphologic and spatial dynamics, 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. Successful applications will examine how mitochondria vary over time and how they alter or contribute to tumor development, adaptation, stemness, phenotypic plasticity, resistance, invasion and metastasis. Research that examines whether mitochondrial heterogeneity can be used as a basis for disease monitoring, understanding response to therapy, or in the development of new therapies is also encouraged.
Background: Mitochondria perform an assortment of specialized cellular functions, which vary with cell type, development and physiological cues. Distinct functional tasks rely on cellular coordination of mitochondrial biochemistry, morphology, intracellular position, connectivity and organization that are dynamic at both the single mitochondrion and system level. The normal spectrum of mitochondrial complexity becomes enlarged and dysregulated in cancers. We currently lack a mechanistic framework to couple mitochondrial variation in cancer cells with certain phenotypic behaviors or how mitochondrial heterogeneity integrates with either common or unique processes of tumorigenesis overall. Aspects of mitochondrial heterogeneity within or among cancer cells may confer selective advantages to environmental or therapeutic stresses, but may also pose targetable vulnerabilities.
Feasibility: Mitochondrial heterogeneity can be seen across numerous scales: cellular, tissue, organism and population level. Applications that consider mitochondrial heterogeneity in any of these scales are welcomed. Successful PQ5 applications should expand our mechanistic understanding of how mitochondrial specializations are realized in cancer cells and integrated into functional or phenotypic states related to select stages of cancer development or progression, specific behaviors or processes of cancer and associated cells, or ways to improve cancer prevention and treatment. Projects may draw upon interdisciplinary abilities, such as those from cell biology, cellular anatomy, genetics, engineering, sensors, imaging, and computational biology. Applications focused solely on mitochondrial functions such as apoptosis or metabolism without linking these functions to heterogeneity are not responsive to this PQ.
Implications of Success: Investigation of how mitochondrial heterogeneity operates in tumors can provide basic mechanistic insights into how cancer cell morphology and organization leads to specific phenotypic behaviors, including resistance to therapy. This PQ5 should expand our knowledge of the intersection between the different roles mitochondria play and strategies that confer cancer cell plasticity and survival advantages.
PQ6: How do circadian processes affect tumor development, progression, and response to therapy?
Intent: Circadian processes, driven by natural 24-hour rhythms, maintain the internal clocks critical for physiological homeostasis and adapting to a fluctuating environment. On a molecular level, circadian processes are regulated by a core transcription-translation negative feedback loop that drives expression and oscillatory regulation of genes that coordinate processing information from both extrinsic (i.e., light/dark, wake/sleep) and intrinsic (i.e., nutrient/hormone/inflammatory) stimuli. This Provocative Question seeks research to understand the mechanisms by which circadian or other oscillatory processes, and the consequences of their disruption, influence cancer development and outcomes. Such influences likely involve interactions across multiple time scales and levels (molecular to organismal) and involve both circadian and other oscillatory processes. Applications that focus on one scale or bridge multiple scales are equally encouraged, as are applications from researchers across all cancer-related disciplines from cell biologists to biobehavioral and population scientists, oncologists, clinicians, translational scientists, and care givers. Understanding how circadian and other oscillatory processes influence cancer development, progression, and response to therapy should illuminate potential new avenues to manage or treat cancer.
Applications that do not explore issues presented in this Intent Statement will be withdrawn as scientifically nonresponsive to this Provocative Question.
Background: Circadian rhythms maintain physiological homeostasis through coordinated communication from the suprachiasmatic nucleus of the hypothalamus (referred to as the central clock) to the peripheral, cellular, and metabolic clocks. Because circadian rhythms regulate responsiveness of all organ systems, disrupting them has profound consequences on health and well-being. In cancer models, disruption of circadian processes is observed in both tumor and non-tumor tissues manifesting in multiple altered cellular parameters including changes in metabolism and proliferation, and promoting cancer development and progression. These disruptions are seldom directly attributable to mutations in canonical circadian regulatory components. In cancer patients, disruption of circadian processes can manifest in altered behaviors, including sleep disruption. The degree to which cancer phenotypic behaviors involve disruption of other non-circadian oscillatory processes is understudied. Of all drugs currently available, approximately half of them target gene products that are regulated by circadian or oscillatory processes. How coordinating timing of cancer drug delivery with appropriate target expression/function affects therapeutic efficacy and/or adverse side effects in preclinical and clinical trials is under investigated.
Feasibility: Circadian and oscillatory processes, and their regulation, cross multiple scales from molecular to organism to population. Understanding how such processes influence cancer and/or patient outcomes may require an integrated interdisciplinary approach when considering multiple scales; however, proposals that consider circadian and oscillatory processes on a single scale are equally welcomed. Successful PQ6 applications should inform our understanding of the interrelatedness of circadian processes and cancer phenotypes, behaviors, and/or therapeutic outcomes.
Implications of Success: Understanding the interplay between circadian or other oscillatory processes and cancer, from development to treatment and patient outcomes, should yield insight into ways to improve identification of phenotypes associated with their dysregulation. Although characterization of phenotypes may help improve consideration of circadian disruption in clinical practice for better management or treatment of cancer, this PQ is intended to expand our knowledge of the relationships between circadian-regulated processes and cancer outcomes across all cancer-related disciplines, from basic cancer biology approaches, to translational and clinical applications, and to population and biobehavioral studies.
PQ7: How do cancer-specific subcellular pathognomonic structures develop, what is their function, and can they be a source of novel therapeutic targets?
Intent: Our current understanding of pathognomonic structures characteristic for cancers is limited. Pathologists are trained to recognize and classify cancers based on distinct features and patterns in cells and tissues, most routinely aided by stains and conventional microscopy. This provocative question seeks research applications that expand the concept of pathognomonic figures. Can technologies be advanced to reveal the existence of new pathognomonic forms or features at the subcellular scale or bridging multiple scales? Mechanistically, how are pathognomonic structures formed, what are their cancer biology dynamics and function, and how do they contribute to distinct cancer phenotypes? How might this information be leveraged to improve detection, diagnosis or develop new treatment strategies? One goal of the PQ7 is to encourage interdisciplinary science that fosters innovation and new insights on basic pathognomonic cancer biology and its utility to inform and advance strategies to advance our understanding of cancer biology on a subcellular level.
Background: For two centuries, anatomic pathologists have used pathognomonic features to aid in the histologic and pathologic classification of certain tumors. These features facilitate the diagnosis of cancer and can often define subclasses of tumors that determine different treatment options and prognostic outcomes. Interestingly, while these pathognomonic features are well characterized at the light microscope level using conventional histology stains, the biomolecular characterization of these features and how they are related to tumor biology and prognosis is largely unknown. Recent advances in super resolution microscopy, magnetic resonance imaging, and x-ray tomography have opened new possibilities in the research on pathognomonic structures that includes but is not limited to;
- identifying the evolution of new pathognomonic structures that can be linked to cancer development, progression, and/or response to treatment.
- analysis of the molecular pathways underlying the evolution or function of pathognomonic structures that can correlate these structures’ progression to cancer diagnosis, treatment, and/or outcomes.
- development of new tools, technologies, or platforms that facilitate a and/or b.
Feasibility: Pathognomonic structures include any structures in the cancer cell, tumor associated cells, tumor microenvironment, lymphatic system, or circulating in the blood whose evolution can be directly linked to the development, progression, or response to treatment of a specific cancer or cancer subtype.
To be responsive to this PQ, research projects should focus on one or more of the following areas:
- discovery and/or validation of novel pathognomonic structures
- correlation of specific molecular pathways to the evolution of pathognomonic structures specific for the diagnostic and/or prognostic assessment of cancer
- investigation of pathognomonic structures as they relate to cancer phenotypic processes or behaviors
- correlation of cancer specific pathognomonic structures to specific treatments, advent of resistance, and prognoses
- development of new methods, tools, technologies, and/or platforms that facilitate a, b, or c
Exploratory R21 projects that have a sound scientific rationale that addresses any of the four criteria stated above but lack preliminary data will be considered responsive.
Implications of Success: Successful applications will have the potential to enable new basic understanding of cancer biology, development of diagnostic and/or treatment paradigms that are based on the presence and/or function of pathognomonic structures in the tumor and/or the tumor microenvironment. In addition, novel platforms that facilitate the diagnosis and/or monitoring of treatment response and outcome based on dynamic changes in pathognomonic structures in the tumor and/or the tumor microenvironment will also be deemed to be a success.
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?
Intent: Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) or its ligand 1 (PD-L1) monoclonal antibodies (mAbs), enhance anti-tumor immune responses in multiple cancers through restoration of T-cell function. However, many patients treated with immune checkpoint inhibitors experience variable degrees of immune-related adverse events (irAEs) in diverse organ systems. If these irAEs are identified early, they can be managed properly. It has also been reported that clinical response to anti-CTLA-4 mAb is potentially associated with the presence of irAEs. This Provocative Question (PQ) invites research applications for identification and/or validation of mechanistic biomarkers for prediction of on- or post-treatment irAEs associated with therapies involving immune checkpoint inhibitors. This PQ also encourages unbiased evaluation of the relationship between biomarkers of irAEs and extended survival benefits in cancer patients treated with immune checkpoint inhibitor therapies. The ultimate goals of this PQ are to provide clinically-validated biomarkers that may inform clinical trial designs, and guide physicians to select and sequence therapies involving immune checkpoint inhibitors for the purpose of reducing or avoiding life-threatening irAEs in individual cancer patients.
Background: The immune system recognizes and eliminates transformed cells prior to their development into tumors. Once developed, tumor cells gradually escape from this immunogenicity by multiple mechanisms, including elevated expression of inhibitory checkpoint molecules such as PD-L1 on tumor cells and CTLA-4 and PD-1 on infiltrated T lymphocytes in the tumor microenvironment. Suppression of these immune checkpoints helps recover anti-tumor immunity in a variety of cancer types. As checkpoint inhibitors have demonstrated enhanced durability of tumor responses to other anti-cancer regimens, benefits of combining the checkpoint blockade with standard-of-care cancer therapies are increasingly investigated. Non-overlapping mechanisms of CTLA-4 and PD-1 pathways have rationalized combination of anti-CTLA-4 mAb and PD-1/PD-L1 blocker as well. Hence, the numbers of patients who will be exposed to immune checkpoint inhibitors will continue to increase in the near future.
However, checkpoint blockade can cause inflammatory and immune-related adverse events (irAEs), which can be severe and limit the use of these inhibitors. The major irAEs reported include disorders in the skin, gastro-intestinal tract, endocrine glands, liver, and lung. Nevertheless, potentially any tissue can be injured as checkpoint inhibitors may disrupt self-tolerance protection of normal tissues. Although treatment with steroids can reverse these irAEs, steroid-associated immunosuppression may compromise the anti-tumor activity of the checkpoint blockade. Potential positive or negative relationships between irAEs and anti-tumor efficacy resulting from checkpoint blockade also need to be investigated fully. There is thus an unmet need for availability of clinically-validated, non-invasive biomarkers for prediction of on- or post-treatment irAEs for improved therapeutic efficacy and proper management of cancer patients who are exposed to immune checkpoint inhibitors.
Feasibility: In response to PQ8, multidisciplinary teams of investigators are invited to identify and/or validate mechanistically-informative biomarkers for prediction of on- or post-treatment irAEs associated with therapies involving immune checkpoint inhibitors. Research projects focused on the development of non-invasive molecular or imaging biomarkers for measuring serious irAEs are highly encouraged. Demonstration of analytical validity and standardization of assays or tools for quantitating these markers in high-quality specimens is desired. For example, the applicants may propose to:
- Conduct well-designed studies in clinically-relevant animal models to elucidate mechanisms underlying severe irAEs from exposure to checkpoint inhibitors, which may be confirmed and evaluated in the clinic using candidate biomarkers;
- Identify non-invasive candidate biomarkers (e.g., genome including genetic polymorphisms, proteome including enzymes, cytokines and cell surface antigens, metabolome, microbiome, T-cell receptor repertoires, autoantibodies against specific tissues affected, etc.) of on- and/or post-treatment irAEs by analyzing pre-treatment specimens from patients who experience irAEs after being treated with checkpoint inhibitors;
- Prospectively validate biomarkers (during multicenter clinical trials) that may be used in predicting, controlling, and managing checkpoint blockade-associated irAEs in cancer patients.
Applicants are also encouraged to evaluate the relationship between biomarkers of irAEs and extended survival benefits in cancer patients treated with therapies involving immune checkpoint inhibitors.
Implications of Success: Research findings resulting from successful completion of projects under PQ8 are expected to yield clinically-informative, predictive biomarkers of irAEs resulting from immune checkpoint blockade. These biomarkers correlated with clinical outcomes may inform optimization of anti-cancer regimens involving checkpoint blockade to more effectively realize their full therapeutic benefits to individual patients, and guide therapies in combination with immune checkpoint inhibitors for the purpose of minimizing risks of irAEs.
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?
Intent: Proteolysis Targeting Chimeras, or PROTACs, are heterobifunctional small molecules that link targeted proteins to the E3 ubiquitin ligase system, leading to target protein degradation through the ubiquitin-proteasome system. This Provocative Question seeks to extend the concept of inactivating oncoproteins or cancer-causing molecules through the use of bifunctional molecules, defined as small molecules that include a ligand moiety specific for a target oncoprotein or cancer-causing protein, linked to a second moiety involved in protein inactivation (inactivation moiety). The ultimate goal of this PQ is identification and/or preclinical development of novel bifunctional molecules that lead to tumor-specific loss or inactivation of selected target proteins for therapeutic benefit. Studies that test this concept on currently “undruggable” targets are encouraged as are studies that use novel protein inactivation moieties. Responsive applications may focus on design of bifunctional molecules, and/or testing of the biological functions of new or existing bifunctional molecules.
Background: Processes of oncogenesis, cancer cell growth, cancer progression and metastasis are characterized by aberrant expression or function of proteins and other biomolecules, which can serve as therapeutic targets (and are thus referred to as oncotargets). Many oncotargets with enzymatic function have been successfully inhibited by small molecules discovered through activity-based drug discovery strategies. A majority of oncotargets have non-enzymatic functions and/or lack accessible binding pockets that modulate protein functions and are considered “undruggable.” Examples include transcription factors and scaffolding proteins. New approaches are needed to design alternate therapeutic strategies for these important molecules. One promising approach is to use bifunctional small molecules to recruit oncoproteins to degradation or inactivation machinery. This approach is used by proteolysis-targeting chimaera (PROTAC) technology to direct a target-of-interest to tumor cell intrinsic protein degradation machinery to be degraded. One key feature of this approach is that it may be applied to both druggable and undruggable oncotargets. Several PROTAC molecules have been developed and several in vivo studies have been carried out, demonstrating proof-of-principle for this strategy. This Provocative Question asks whether novel bifunctional molecules that lead to tumor-specific loss or inactivation of selected oncotargets can be developed for therapeutic benefit.
Feasibility: A novel bifunctional molecule may be designed against a potential oncotarget(s) confirmed to be critical for cancer survival, progression, or metastasis. Fusion proteins known to be involved in oncogenesis of childhood cancers are of particular interest to NCI as oncotargets for bifunctional molecule technology. The oncotarget ligand moiety may be derived from existing drugs (clinically tested or preclinical), or from chemical entities newly designed or discovered through high-throughput or virtual screening. An array of inactivation moieties may be explored to direct the target-of-interest to a unique inactivation or degradation pathway existing in tumor cells. The specificity and potency of a bifunctional molecule may also be regulated by the linker connecting the ligand and the inactivation moiety.
Early discovery projects will be considered responsive if their goal is to develop and perform functional analyses on novel bifunctional molecule(s). Projects focused only on identification of the components (i.e. oncotarget ligand, linker or inactivation moiety) will not be considered responsive. Early discovery projects at stages from identification of new bifunctional molecules to lead optimization should clearly lay out the key discovery process and activities as appropriate to the stage of the project, including, but not limited to: screening strategy, triage assays, biophysical characterization such as direct binding affinity measurement, binding specificity, Structure Activity Relationship (SAR) assay(s), target modulation, and biologically relevant in vitro potency assay(s). An existing bifunctional molecule with favorable lead properties in aspects of specificity, potency, and in vitro ADME may be proposed for preclinical development. Studies to enable translation of the technology into the clinic such as in vivo ADME properties, stability, pharmacodynamics and pharmacokinetics characterization, in vivo efficacy, and preliminary toxicity are appropriate. In vivo models should be relevant for the selected indication(s) and biological function of the target.
Implications of Success: Research findings resulting from this PQ are expected to extend and expand the field of bifunctional molecules that cause either degradation or inactivation of oncotargets. Successful projects will identify and test a collection of diverse, novel bifunctional molecules that can be used to understand target cancer biology and possibly be further developed into therapeutic agents. These studies will also leverage new cancer targets as they are discovered, as well as discrete, tumor-selective, cellular inactivation or degradation machineries. Successful projects may also define factors critical for translating these bifunctional molecules to the clinic.
PQ10: How do microbiota affect the response to cancer therapies?
Intent: This Provocative Question seeks grant applications that use our increasing knowledge of the resident 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 (i.e. their alteration of host barrier, metabolic, and immune functions) 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.
Background: Recent studies demonstrate an altered GI microbiota in many cancer patients, and in patients at increased risk for cancer, such as those with inflammatory bowel disease (IBD). In addition, changes in the microbial communities of the lung and oral cavity have been associated with tumor development in both local and distal tissues. Additional studies have shown when bacterial communities are compromised, for example by immunodeficiency or antibiotics, standard chemotherapy regimens may lose efficacy either through direct bacterial biotransformation or by inhibition of therapy-induced anti-tumor immune responses. Since microbial regulatory mechanisms are involved in establishing and maintaining tissue homeostasis, immune responses, and altering drug metabolism, understanding how a patient’s microbiota may enhance or inhibit cancer therapies will help to optimize anti-tumor therapies.
Feasibility: Drug metabolism and microbiome-related studies in humans and preclinical models suggest a number of approaches that can be used to study how anti-tumor therapies are affected by microbial metabolic capacity. New information from metagenomic and metabolomic analyses provide a rich resource of technical approaches to characterize and test if changes in the microbiota during tumor development or anti-tumor therapy affect response to therapy. Drug metabolism approaches can be used to determine how drugs are modified by various microbial populations. Since microbial genetics and function can be readily manipulated either in vivo or ex vivo using standard molecular biology techniques or by drug and dietary interventions, alterations in the microbiota can be easily achieved and used to study changes in drug metabolism or in markers of drug effectiveness. A fundamental understanding of microbial physiological regulation, metabolism, and composition in the context of a cancer therapy will provide insights into an individual’s response to the therapy (including initial efficacy and development of resistance) and guide potential intervention strategies.
Implications of Success: Research findings resulting from successful completion of work under this PQ are expected to lay the foundation for adjuvant targeting of microbiota functions, offering many potentially attractive strategies for therapeutic manipulation and engineering of optimized anti-tumor chemo, targeted, and immunotherapies. A detailed knowledge of each cancer patient’s unique microbial drug metabolizing capacity and activity has high translational value to clinical practice, since this new information could be exploited to optimize individual therapeutic responses. This knowledge could also be used in the future to develop approaches that include: the direct manipulation of a patient’s microbiota, alteration of microbial signals to change host metabolic regulation, or development of new metrics for patient stratification, based upon matching therapeutic agents with an individual’s microbial drug metabolism profile.
PQ11: Through what mechanisms do diet and nutritional interventions affect the response to cancer treatment?
Intent: This Provocative Question seeks grant applications that address how diet and nutritional interventions affect the response to cancer treatment, treatment-related adverse events, cancer prognosis and related health outcomes. All types of studies that serve to elucidate the mechanisms of how diet and nutrition effect cancer outcomes are encouraged, including clinical trials, observational studies, and mechanistic studies in animals and humans. Transdisciplinary research and studies which consider multidimensional and/or dynamic dietary patterns (where dynamism includes the timing of meals and circadian rhythms, as well as changing diets over the course of treatment and survival) are also encouraged. Research applications may examine the association of diet and nutritional interventions with a range of outcomes among cancer patients and survivors, but should also address the mechanisms (such as influence of the microbiome, metabolome, immunology, and epigenetics) by which these relationships occur. Proposed studies should take into account other known prognostic factors that may influence cancer and related outcomes, such as weight/body composition, activity levels, and other lifestyle factors.
Background: Malnutrition, which includes both over- and under-nutrition, is prevalent among cancer patients and is associated with poor outcomes. The multiple acute effects of cancer treatment such as nausea, fatigue, appetite and taste changes, nutrient malabsorption, and metabolic derangements may result in changes in dietary patterns that limit macro- and micronutrient intakes, which in turn may result in sarcopenia, under- or over-weight, or nutritional deficiencies. These physiological and metabolic alterations may compromise the ability to complete treatment, increase the risk of infection and other co-morbid conditions, and in the long-term, may affect survival. Despite the strong associations of malnutrition with poor health outcomes, little is known regarding how nutritional interventions and dietary patterns affect the response to cancer therapies.
Cancer survivors also may experience several comorbid conditions resulting from cancer treatment that may be influenced or prevented by dietary modification, including cardiovascular disease due to chemotherapy-induced cardiotoxicity, hypertension, dyslipidemia and type II diabetes mellitus. Many cancer patients and survivors seek nutritional guidance to optimize treatment completion and complication-free survival, yet evidence regarding the impact of diet on cancer outcomes both during and in the years following treatment is limited.
Feasibility: Researchers may be able to expand or utilize existing studies or initiate new studies to learn whether and how nutritional interventions or therapies may impact health outcomes in cancer patients and survivors at various stages of disease and along the continuum of care. Nutritional interventions may include education or counselling, dietary interventions related to the composition or timing of food intake, medical nutrition therapy, and other novel approaches. Mechanisms may include: host-microbial metabolism; immunologic/inflammatory signaling; nutrient metabolism and genetic variant interactions, and omic approaches. Health outcomes may include the ability to adhere to scheduled treatment, cancer prognostic biomarkers, decreased risk of cancer recurrence and subsequent primary cancers, better disease-free and overall survival, and other short- and long-term health outcomes.
Implications of Success: Better understanding of how nutrition affects cancer outcomes could help guide future research designed to:
- identify beneficial and detrimental interactions between nutritional interventions and specific cancer therapies
- identify patients most likely to benefit from specific nutritional interventions,
- optimize, and eventually individualize, nutritional interventions for specific patients.
The results of such research could lead to changes in standard oncology care that improve a patient’s response to treatment, quality of life and, ultimately, survival.
PQ12: 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.
Background: Cancer therapy-induced adverse sequelae are a major problem for cancer survivors. Adverse sequelae persisting or developing after cancer therapy are difficult to predict and vary across patients and therapeutic regimens. Without knowing the mechanisms by which cancer therapies lead to adverse sequelae, it is difficult to design clinical management strategies and/or to improve anti-cancer drug development. Thus, understanding the mechanism(s) of adverse sequelae, which therapies cause them, and/or strategies to avoid, minimize, or reverse their occurrence should be principle objectives of research applications responding to this Provocative Question.
Feasibility: One of the challenges in this arena is the ability to explore mechanisms of toxicity and determine whether these mechanisms represent on-target mechanisms that are also responsible for therapeutic efficacy. Preclinical or non-clinical models may be effectively used to obtain mechanistic insights that would be difficult to investigate in detail clinically. Careful evaluation of anti-tumor mechanisms and mechanisms of target organ toxicities are key to understanding whether a given adverse effect can be managed. Preclinical or non-clinical models might also be employed to evaluate initial mitigation strategies, with concurrent evaluation of efficacy of anti-cancer therapies and mitigation of adverse effects. An important prerequisite for preclinical or non-clinical studies in response to this question will be justification of the appropriateness of the systems (i.e., their suitability and validation) chosen to study molecular/cellular mechanisms of toxicity.
Efforts that focus on unique mechanisms are particularly useful. It is also desirable to translate mechanistic understanding of molecular/cellular pathways deemed responsible for adverse effects into testable hypotheses for preventing such adverse effects, or development of new anti-cancer drugs designed to avoid such pathways. The goal of successful applications should be to translate the understanding of the molecular/cellular mechanisms of toxicity into informed drug design, alternate treatment regimens, prevention strategies, or other management modalities.
Implications of Success: Better understanding of the molecular and/or cellular mechanisms leading to adverse sequelae may guide selection and development of therapies for individual patients and may lead to better adverse sequelae management and remediation strategies. Further, it is hoped that new mechanistic insights will lead to effective prevention strategies and treatments by minimizing or reversing adverse sequelae entirely.