NIH/NCI – Provocative Questions (PQs) in Cancer with an Underlying HIV Infection (R01 Clinical Trial Optional)

The purpose of this funding opportunity announcement (FOA) is to continue advancing our understanding of the risks, development, progression, diagnosis, and treatment of malignancies observed in individuals with an underlying HIV infection or Acquired Immune Deficiency Syndrome (AIDS). These PQs are not intended to represent the full range of NCI’s priorities in HIV/AIDS-related cancer research. Rather, they are meant to challenge researchers to think about and elucidate specific problems and paradoxes in key areas of AIDS-related cancer research that are deemed important but have not received sufficient attention.

Provocative Questions in Cancer with an Underlying HIV Infection involves a set of 6 PQs. Each research project proposed in response to this FOA must be focused on addressing one particular research problem defined by one specific PQ selected from the list. Projects proposed to address specific PQs may use strategies that incorporate ideas and approaches from multiple disciplines, as appropriate. Transdisciplinary projects are encouraged as long as they serve the scientific focus of the specific PQ chosen.

This FOA is patterned on, but unrelated to, a series of FOAs for “Research Answers to NCI’s Provocative Questions”.

This FOA solicits applications only for well-developed research projects using the NIH R01 funding mechanism.

To be responsive to this FOA, each application must specifically address a particular scientific problem identified as one of the PQs listed in this FOA.

Research Objectives

The Nature of Scientific Problems Underlying PQs

Regardless of topical area, most scientific problems underlying PQs fall into one of four broad types:

  • Ignored or neglected cancer-relevant problems in the context of an HIV infection that are brought back into focus. These problems typically relate to intriguing older observations or unresolved issues, for which satisfactory, rigorous research answers may open up qualitatively new research avenues and/or result in substantial progress in a given area.
  • More recent findings that are perplexing or paradoxical, revealing important gaps in current knowledge. Research answers to these problems are expected to have exceptionally high potential to re-shape current key conception and paradigms.
  • Problems of recognized high importance that were previously particularly difficult to explore but became more addressable because of recent scientific discoveries and technical advances.
  • Questions that have arisen because combination antiretroviral treatment has resulted in dramatically increasing the life expectancy of patients living with HIV.

List of Provocative Questions for this FOA: 

Please note that each application must address one and only one specific PQ from the list below, exactly as defined in this FOA.  In order to facilitate the submission and peer-review processes, PQs are numbered 1-6. However, the order of the numbering of questions is arbitrary and should not be construed to indicate any order of priority or funding potential.

PQ1. Other than immune dysfunction (including inflammation) and known oncogenic mechanisms or risk factors that affect PLWA, by what other mechanism(s) does HIV infection promote the development or progression of tumors either directly or indirectly in patients with treated HIV infection?

Intent: Combination antiretroviral therapy (cART) significantly improves immune function in persons living with HIV/AIDS (PLWH) and as a result has reduced the incidence of some AIDS-defining malignancies (e.g. Kaposi sarcoma and non-Hodgkin lymphoma), especially those associated with profound immunodeficiency. However, there is increasing evidence that these patients are at increased risk for developing a number of other tumors, such as anal cancer, lung cancer, or hepatocellular carcinoma. In some cases, this increased risk occurs because PLWA often have higher exposure to other factors known to be linked to these tumors; for example, increased rates of cigarette smoking or increased exposures (i.e. human papilloma virus, hepatitis B or C viruses). Other factors may contribute as well and interact with HIV infection, such as heritable phenotypes, the microbiome, treatments with antiretroviral drugs, changes that occurred prior to HIV treatment, somatic mutations that result in clonal hematopoiesis of indeterminate potential (CHIP), mutation rates in aggressive cancers or those refractory to treatment; or geographic variation seen in the types, aggressiveness and/or incidence of HIV-associated tumors. This Provocative Question calls for the identification of factors by which HIV directly or indirectly causes cancer and the elucidation of mechanisms by which this occurs. Research proposed should focus on ferreting out the unexplored ways in which HIV could cause cancer in patients with treated HIV infection excluding immunodysregulation and known cancer risk factors.

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

PQ2. What if any are the contributions of transposable elements or endogenous retroviruses to cancer development in PLWH, and what role does HIV play in their mobilization across the genome?

Intent: Transposable elements and endogenous retroviruses (ERV) are remnants of exogenous retroviruses that have become fixed in the human genome but are no longer considered capable of mobilization due to extensive deletions and mutations. The most recently active human retroelement, HERV-K and its transcripts and proteins have been observed in human cancers as well as inflammatory and autoimmune disorders. Host restriction factors such as the APOBECs act in the cytoplasm to degrade retroelement RNA while other host factors involve DNA repair enzymes or DNA methylation and histone modifications. However, these host response activities are diminished in cancer cells and in activities directed by the HERVs to thwart the host, tumor-derived exosomes enriched in HERV RNAs and other elements are sent into the tumor microenvironment.  Interestingly, these elements have been speculated to rewire gene regulatory circuits in cancer cells. This Provocative Question calls for research directed towards understanding the role of ERVs, long non-coding RNA (lncRNA), or transposable elements in causing cancer in PLWH. Some approaches could study the polymorphisms of restriction factors that could have an impact on cancer, the impact of antiretroviral drugs on transposable elements, or the role of exosomes in promoting a tumor microenvironment.

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

PQ 3. Other than direct effects of HIV infection, what are the factors that contribute to the poorer survival of PLWH with cancer when compared to HIV-uninfected patients with the same tumor type? How can this knowledge inform improvements in cancer care in patients with HIV and cancer?

Intent: PLWA are at increased risk of developing a number of tumors. For some of these tumors, there are substantial differences between the types that develop in HIV-infected vs. HIV-uninfected patients. For example, PLWH with Hodgkin’s disease most commonly have mixed cellularity or lymphocyte-depleted histology, whereas HIV-uninfected patients most often have nodular sclerosis histology. Even in cases where HIV-infected and HIV-uninfected patients have what appears to be the same histologic tumor type, there may be differences at the genetic level, the epigenetic level, or in the tumor microenvironment. This Provocative Question seeks to stimulate research to delineate the factors contributing to differences in survival between tumors arising in PLWH and the same tumor type or subtype arising in HIV non-infected patients. Research focusing on both differences in biology and diagnosis; access to care; polypharmacy; the microbiome; racial/ethnic disparities; or geographic locations could be proposed. Successful applications might include research exploring epigenetic differences, host genetic factors, differential expression of tumor biomarkers, or the microenvironment.

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

PQ 4. What are the determinants of the size and diversity of reservoirs of oncogenic agents that impact the development of malignancies in PLWH?

Intent: In addition to the HIV reservoir, oncogenic viruses associated with AIDS-defining malignancies also establish reservoirs. These non-HIV reservoirs are part of viral latency. Many factors can be attributed to why a virus is latent, including the host’s immune response, inadequate resources, or defective replication. The site and size of latent reservoirs can determine the stability of latency and the frequency of reactivation and different oncogenic viruses use different mechanisms and environments for establishing their viral reservoirs . This Provocative Question calls for research to address oncogenic viral reservoir(s) present in PLWH. Proposed viral reservoir research could include tropism, size, tissue diversity, evolvability, or range of locations; presence of other oncogenic or non-oncogenic viruses; effects of co-morbid diseases (e.g., diabetes, obesity); or the interrelatuionships between the pathway leading to oncogenesis and the biology and natural life cycle of the virus.

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

PQ 5. How does the biology of aging affect the development of cancer in PLWH?

Intent: The number of older PLWH (50 and older) has risen dramatically over the last decade, mainly due to the availability of effective combination antiretroviral treatment. Coupled with the increased survival is a substantial increase in the incidence of non-AIDS-defining cancers likely driven to a large extent by the growth and aging of the HIV/AIDS population. HIV-infected patients not infrequently manifest certain aspects of accelerated aging, such as increased frailty or cognitive changes. However, little is understood on the interplay between HIV infection, various aspects of aging, long-term exposure to antiretroviral or other drugs, and other risk factors, or disease sequela such as somatic mutation of indeterminate potential, in cancer development in the elderly HIV-infected population. This Provocative Question seeks to stimulate research in aging among PLWH. Proposed research should provide insight into how aging and HIV infection interact in promoting tumor development. A variety of eclectic approaches may be involved in addressing this question. Approaches may be through a study of elderly patients with HIV infection or studies addressing how multimorbidities and polypharmacy affect cancer development and outcomes in patients aging with HIV. Alternatively, it may involve investigation of similarities between aspects of aging and HIV infection at the cellular or molecular level and how these may interact to promote tumor development.

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

PQ 6. Can novel in vitro and in vivo models of HIV/AIDS-associated malignancies be developed to study their development, pathogenesis, and the potential evaluation of novel treatments for common HIV/AIDS-associated malignancies?

Intent: Currently there is a paucity of animal models or engineered in vitro or ex vivo systems to study pathogenesis, persistence, and tumor development that recapitulate HIV/AIDS-associated malignancies. Animal models can be informative in the identification of targets for developing therapeutic agents and may lead to a better understanding of the immunopathogenic interactions between the host and the HIV/AIDS-associated malignancy. Likewise, cell culture or ex vivo tumor models may be appropriate stand-alone methods or in addition to studies of HIV/AIDS-associated malignancies. The effectiveness of models depends in part on acquiring high-quality, robust experimental data. Additionally, integral use of different kinds of models is crucial, the choices of which models to use are governed by the questions and using more than one modeling approach may be appropriate in some circumstances. This Provocative Question seeks applications that propose either animal models or engineered in vitro or ex vivo systems that are informative for mechanistic understanding of the development, progression, persistence, or treatment of HIV/AIDS-associated cancers. Examples include engineered systems such as a cell on a chip or tumor on a chip.  Infection models that rely on a natural host pathogen that leads to malignancy in the host are not appropriate for this provocative question (i.e. MHV-68; RRV).

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

It is proposed that the initial issuance of the RFA will address these six questions. The success of the research efforts from these PQs will provide information on the specific contributions resulting from HIV infection and identify potential interactions with other pathogens in the development and pathogenesis of certain cancers that may ultimately inform screening approaches and therapies targeted to the HIV-infected population.

Specific Requirements

Scientific Scope. The collective scientific scope of this FOA is defined by the list of PQs. These PQs define research areas appropriate for this FOA. 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 above. 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 all the sections for each PQ.

Individual Goals. Within the research area defined by a specific PQ chosen, the overarching goal of the proposed research project must be an attempt to provide definitive, comprehensive, and thorough research answers to the problem or portions of the problem presented by that question. The proposed research solutions are expected to be creative and highly original with a high potential for transformative impact on current concepts and paradigms in cancer-related AIDS research.

Within this general requirement, specific topics for the proposed investigations, strategies, priority directions, and other details of study design and execution are left to the discretion, originality, and creativity of the applicants. The creativity and originality (combined with scientific rigor) are particularly important, given that the areas identified by the individual PQs are generally understudied. Therefore, the applicants have the full freedom to identify the most promising direction(s) to address the selected PQ, formulate Specific Aims, choose optimal experimental approaches, and adapt appropriate specific benchmarks as measures of accomplishing the overarching goal of the project. It is expected that these specific benchmarks will be in line with the Implications of Success statements for the selected PQ.

Original Rigorous Concepts versus Preliminary Data. In general, the R01 funding mechanism is used for research projects for which research approaches, methodologies, and background information are well established and usually documented by extensive preliminary data from researchers’ laboratories. The requirement for well-developed projects extends to this FOA.

However, it is realized that for many of the PQs there could be gaps in background information and original preliminary data may be scarce or difficult to obtain beforehand. Since the intention of this FOA is, by definition, to exploit understudied areas, the emphasis is on the novelty and significance of the concepts to be explored with a relaxed requirement for preliminary data. These concepts must be original but also rigorous in terms of integrating to the extent possible the available incomplete information for a given area from various sources. Reviewers will assess both aspects jointly; if the conceptual aspects of the proposed project are viewed as exceptionally strong, applicants will not be penalized for some gaps in the preliminary data. The focus of the FOA is definitely on the “power of the ideas” (but combined with rigorous plans to validate those ideas in a well-developed project).

Non-Responsive Projects

The following types of projects will be viewed as non-responsive to this FOA (applications proposing non-responsive projects will not be reviewed):

  • Applications that fail to choose a specific PQ from the list above, address more than one PQ within a single application, and/or re-write a PQ. Applicants wishing to address more than one PQ may do so by submitting separate applications that are scientifically distinct.
  • Applications that do not explore issues presented in the Intent Statement for the selected PQ.

IMPORTANT NOTE: Applicants uncertain as to whether their intended project meets the requirements of this FOA are encouraged to contact one of the Scientific/Research Contacts listed in the announcement.

Deadlines:  August 1, 2019; August 3, 2020 (letters of intent due 30 days prior to the deadline)