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National Cancer Institute (NCI)

This Notice is to inform the research community that the National Cancer Institute intends to issue a Funding Opportunity Announcement (FOA) to solicit applications for the Precision Approaches in Radiation Synthetic combinations (PAIRS) program. The PAIRS program seeks to incentivize research that examines vulnerabilities created by cancer reprogramming in association with responses to radiation therapy. PAIRS will support projects that range from pre-clinical research to early clinical trials that foster development of radiation treatment-based synthetic combination strategies and facilitate their adoption into the precision medicine toolkit toward building new and effective anticancer combination treatments.

This Notice is being provided to allow potential applicants sufficient time to develop a responsive proposal.

This FOA will utilize the R01 (clinical trial optional) activity code and is expected to be published in June 2022 with an expected application due date in October 2022.

Reprogramming contributes to plasticity and robustness that cancer cells use to maintain advantages in response to selection pressures exerted by intrinsic molecular alterations and changes in the tumor microenvironment. Fitness trade-offs and reductions in functional redundancies in cancer cells can give rise to targetable vulnerabilities through synthetic combination strategies. Underpinning the PAIRS program is the concept that radiation treatment can promote precise (time and space) and predictable demands on essential control nodes that serve to coordinate diversion of critical resources into tumor damage repair and cancer cell survival. The basic premise of PAIRS is that the conditional effects of radiation therapy responses can be leveraged to either create or enhance actionable vulnerabilities that work in tandem with synthetic combination targeting agents. In this manner, conditional PAIRS strategies have potential to optimally target specific essentiality in tumors relative to normal tissues, thereby greatly enhancing the therapeutic index. It is anticipated that applications to the PAIRS program will have one or more of the following attributes:

1) Testing synthetic combination agents targeting intrinsic vulnerabilities that are greatly augmented (or triggered) when coupled with conditional responses to radiation treatment;

2) Testing synthetic combination agents that target adaptations (e.g., reprogramming) integral to cancer cell survival in response to radiation treatment;

The PAIRS program is agnostic to the type of radiation proposed in synthetic combination approaches, including external beam radiation treatment, radiopharmaceuticals, and studies where radionuclides are incorporated into the molecular-targeted agent. Multi-PI applications will be encouraged to maximize the potential of team science efforts and combine capabilities that might be necessary to integrate approaches across targeted therapeutics, pre-clinical cancer cell biology, radiobiology, and radiation oncology. Studies supported by the PAIRS program are expected to inform the design and implementation of radiation synthetic combination-based clinical trial strategies.

The scope of the PAIRS program is to support research ranging from pre-clinical experiments to early-phase clinical trials that brings together design and testing of synthetic combination strategies. A project that focuses on screening and developing targeted agents where radiation is not an integral component of the synthetic combination design would not be responsive to this FOA. Therefore, it is anticipated that R01 projects would stem from a foundation of preliminary data supporting the premise for the radiation synthetic combination strategy as well as a path for translational potential in the project period. The PAIRS program seeks to broaden the range of synthetic combination research from the context of conditional responses to radiation treatment, emphasizing the targeting of cancer processes from a more holistic radiobiology perspective. It is anticipated that research supported through the PAIRS program will include, but is not limited to the following target areas:

• Epigenetic reprogramming

• Organelle-linked processes (e.g., mitochondria, nuclear pore complex, DNA damage-repair, ribosome, endoplasmic reticulum, lysosomes, autophagy, and proteotoxic stress)

• Membranes (e.g., lipid peroxidation)

• Metabolic reprogramming

• Stemness and state transition pathways

• RNA processing – spliceosome

• Tumor microenvironment targets (e.g., cancer associated fibroblasts, myeloid-derived suppressor cells)

TBD

Applications are not being solicited at this time. 

Please direct all inquiries to:

Michael Graham Espey, Ph.D.

National Cancer Institute (NCI)

240-276-7619

SP@nih.gov