The Interplay of Cell Death Pathways in Cancer Cell Survival and Resistance to Therapy (R21) | PA 17 449

Opportunity Information: Apply for PA 17 449

The National Institutes of Health (NIH) funding opportunity titled "The Interplay of Cell Death Pathways in Cancer Cell Survival and Resistance to Therapy (R21)" (Funding Opportunity Number: PA-17-449; CFDA: 93.396) is a discretionary grant program designed to spur exploratory, early-stage research on how different regulated cell death pathways interact in both treatment-naive (often written as "naive") cancers and cancers that have become resistant to drugs. The scientific premise is that regulated cell death programs, particularly apoptosis and necroptosis, act as built-in protective barriers that normally limit how long malignant cells can survive and how effectively they can spread. Because avoiding cell death is a core hallmark of cancer, tumors that learn to sidestep these pathways often become more aggressive, more metastatic, and harder to treat.

A central focus of this FOA is the idea that cancer cells frequently retain the molecular machinery needed to trigger multiple forms of cell death at the same time, yet the field has not comprehensively mapped how these pathways "talk" to each other in real tumor settings, especially under therapeutic pressure. In practice, a tumor may block apoptosis to survive chemotherapy, but that same adaptation may expose dependencies or vulnerabilities in necroptosis (or other regulated death programs), and vice versa. The FOA encourages studies that look beyond a single pathway in isolation and instead examine the crosstalk, switching behavior, compensatory signaling, and shared regulators that determine whether a cancer cell survives or commits to death.

The opportunity also emphasizes the translational value of understanding this intersection. By clarifying the molecular markers that indicate which death program is engaged (or suppressed) in a given tumor context, researchers may be able to develop better biomarkers for response and resistance. Just as importantly, the FOA highlights therapeutic possibilities: inhibiting specific mediators of cell survival and/or enhancing mediators of cell death could push both naive and drug-resistant cancer cells toward more effective, irreversible cell death. In other words, rather than only trying to kill cancer cells with standard cytotoxic stress, the research supported here aims to reveal how to reactivate or redirect death pathways that cancers have learned to evade.

This FOA uses the NIH R21 mechanism, which is typically intended for high-risk, high-reward projects that generate foundational insights or proof-of-concept data rather than fully mature programs. The listed award ceiling is $200,000. The original closing date shown in the provided source data is 2020-09-07, and the FOA record indicates it was created on 2017-08-04. As with many NIH opportunities, the exact number of expected awards is not specified in the provided excerpt.

Eligibility is broad and includes many types of U.S.-based organizations as well as certain non-U.S. entities. Eligible applicants include state, county, and local governments; special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; federally recognized Native American tribal governments; Native American tribal organizations other than federally recognized governments; public housing authorities/Indian housing authorities; nonprofits with or without 501(c)(3) status (other than institutions of higher education); for-profit organizations other than small businesses; small businesses; and other organizations. The FOA additionally calls out a wide range of other eligible applicant categories such as Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), Hispanic-serving Institutions, Historically Black Colleges and Universities (HBCUs), Tribally Controlled Colleges and Universities (TCCUs), faith-based or community-based organizations, eligible federal agencies, U.S. territories or possessions, regional organizations, tribal governments other than federally recognized ones, and non-domestic (non-U.S.) entities (foreign organizations).

Overall, the grant opportunity is aimed at accelerating a more integrated understanding of regulated cell death in cancer biology, with the practical goal of identifying actionable molecular levers that can overcome therapeutic resistance by forcing cancer cells back into effective death programs.

• The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "The Interplay of Cell Death Pathways in Cancer Cell Survival and Resistance to Therapy (R21)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.396.
• This funding opportunity was created on 2017-08-04.
• Applicants must submit their applications by 2020-09-07. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Each selected applicant is eligible to receive up to $200,000.00 in funding.
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

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