The purpose of this Funding Opportunity Announcement (FOA) is to solicit R01 research projects that investigate actionable synthetic vulnerabilities that can be conditionally paired with tumor responses to radiation therapy. The goal the PAIRS program is to the development of radiation-synthetic combination strategies and facilitate their adoption into the precision medicine toolkit toward building new and effective anticancer treatments.Funding Opportunity Description
Purpose

Through this Funding Opportunity Announcement (FOA) entitled, Precision Approaches in Radiation Synthetic combinations (PAIRS)", the National Cancer Institute (NCI) solicits research projects that examines actionable vulnerabilities created by cancer reprogramming in association with responses to radiation therapy. The PAIRS program will support projects that range from pre-clinical research to early clinical trials that develop radiation treatment-based synthetic combination strategies and facilitate their adoption into the precision medicine toolkit toward building new and effective anticancer treatments.

This FOA utilizes the Research Project Grant (R01) mechanism and runs in parallel with a companion FOA of identical scope, PAR-22-199, which utilizes the Research Exploratory/Developmental Research Grant (R21) mechanism.

Key Terms used in this FOA (listed alphabetically)

Essentiality: the condition of being required for cell survival.
Radiation: the PAIRS program is agnostic to the type(s) of radiation modality used, which may include, but is not limited to, external beam ionizing radiation, radiopharmaceutical agents.
Molecularly targeted agent: a type of treatment that uses drugs or other substances to selectively target tumor-associated molecules involved in the growth, signaling, repair, or survival of cancer cells.
Synthetic combination: classically synthetic lethality is defined by the co-occurrence of mutation in two interacting genes that result in cell death. For this FOA, synthetic combination pertains to interactions or relationships that are not exclusively limited to genetic mutations. A PAIRS synthetic combination design ideally exploits a tumor-associated vulnerability or essentiality created by a conditional response to the preceding member in the treatment tandem.
Therapeutic index: a ratio that compares the desired cytotoxic effects of treatment on cancer cells relative to toxicities towards normal cells and tissues not associated with cancer cells.
Background

Cancer cells exploit plasticity and robustness to adapt and overcome challenges across the continuum between transformation and disease progression. While mutations and other genomic aberrations overall provide cancer cells with fitness advantages, they often incur limits on inherent functional redundancies built into critical networks. While synthetic lethality-based treatment approaches in cancer were originally rooted in mutations or other genomic anomalies, a context-dependence built upon the intrinsic mutational landscape and/or adaptations has emerged as an important determinant in delivering clinical benefit. Consideration of tumors as systems (e.g., dynamical) suggests synthetic combination liabilities may manifest themselves in critical stabilization and reprogramming feedback controls in networks, and these vulnerabilities can be conditionally amplified by clinically actionable perturbations. The PAIRS program seeks to support innovative cancer therapy designs that directly connect context dependencies created by radiation treatment (RT) into synthetic combination targeting strategies. From the radiobiological perspective, tumor irradiation sets in motion response cascades across multiple sites (e.g., DNA, mitochondria, ribosomes-ER, membranes, tumor microenvironment) that are required to divert resources and execute repairs for cancer cell survival. Importantly, RT places unique and predictable demands on key control points in networks that have been rendered essential by underlying mutations or other cancer-related processes (e.g., adaptation). The basic premise of PAIRS is that the conditional effects of RT responses can be leveraged to either generate or enhance actionable vulnerabilities that work in tandem with molecularly targeted agents. Precision Approaches in PAIRS emphasizes that RT effects are clinically titratable through both accuracy and flexibility in delivery systems at the levels of dosing, scheduling, and spatial targeting. In this manner, conditional RT-synthetic combination strategies have the potential to optimally target specific essentiality in tumors relative to normal tissues, thereby greatly enhancing the therapeutic index.

Research Scope

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 triggered or greatly augmented 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. The scope of the PAIRS program is to support research ranging from pre-clinical experiments to early-phase clinical trials that bring 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 cancer treatment research supported through the PAIRS program will include, but is not limited to the following target areas in the proposed synthetic combination design:

Epigenetic reprogramming
Membranes (e.g., lipid peroxidation)
Metabolic reprogramming
Organelle-linked processes (e.g., mitochondria, nuclear pore complex, DNA damage-repair, endoplasmic reticulum, lysosomes, autophagy, and proteotoxic stress)
RNA processing (e.g., ribosome, spliceosome)
Stemness and state transition pathways
Tumor microenvironment targets (e.g., cancer-associated fibroblasts, myeloid-derived suppressor cells)
Non-Responsive Applications

The following projects would be considered non-responsive to the PAIRS FOA and will not be reviewed:

Applications that do not integrate radiation into the proposed synthetic combination treatment design;
Applications that focus on screening for interactions for which no actionable molecularly targeted agent exists, or requires support for extensive agent development in the project period.
It is strongly encouraged that applicants address questions concerning responsiveness to NCI staff contacts listed in Section VII. Agency Contacts well in advance of the application receipt deadline.

See Section VIII. Other Information for award authorities and regulations.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.