Cancer Target Discovery and Development (CTD2) (U01 Clinical Trial Not Allowed) | PAR 21 274

Opportunity Information: Apply for PAR 21 274

The Cancer Target Discovery and Development (CTD2) (U01 Clinical Trial Not Allowed) opportunity, listed as PAR-21-274, is a National Cancer Institute (NCI) funding announcement that supports research meant to translate the massive amount of cancer molecular profiling data into actionable biological understanding and, ultimately, more effective therapeutic strategies. In practical terms, CTD2 is designed to close the gap between knowing what genetic and molecular alterations are present in tumors and clearly understanding how those alterations drive cancer behavior such as initiation, progression, metastasis, and treatment resistance. The mechanism is a U01 cooperative agreement, which typically means awardees should expect substantial programmatic involvement from NIH/NCI staff, emphasizing coordinated goals, sharing of resources or data, and alignment with broader program priorities. Clinical trials are not allowed under this FOA, so the supported work is expected to be preclinical or translational in nature rather than interventional studies in human participants.

A central scientific focus of CTD2 is clarifying how cancer-associated mutations actually change protein function and cellular circuitry. Many cancer studies can identify recurrent mutations, but the harder problem is determining whether a given alteration produces a gain-of-function effect, a loss-of-function effect, or a neomorphic function (a new or altered activity not present in the normal protein). CTD2 encourages projects that move beyond cataloging mutations to rigorously mapping how these changes impact the pathways the proteins participate in, what downstream cellular states emerge, and how these effects differ depending on tumor type and the tumor microenvironment. That microenvironment emphasis matters because the same mutation can lead to different outcomes depending on surrounding immune cells, stromal interactions, oxygen levels, nutrient availability, and other context-specific pressures that shape tumor evolution.

Another major goal is discovering and validating new molecular targets and understanding how those targets are "wired" into cancer cell survival networks. The program is especially attentive to therapy resistance, including both innate resistance (present before treatment) and acquired resistance (emerging under treatment pressure). A key theme is heterogeneity: tumors often contain multiple subclones with different vulnerabilities, and even within the same patient there can be meaningful variation between lesions (inter-tumor heterogeneity) and within a single lesion (intra-tumor heterogeneity). CTD2-supported research is therefore aimed at identifying targets and mechanisms that explain why some tumor cell populations evade therapy, and at generating evidence that can inform more durable treatment strategies.

CTD2 also emphasizes the need for efficient ways to identify combinations of targets and combinations of perturbagens capable of eliminating all cancer cells, not just the most sensitive fraction. "Perturbagens" here is used broadly to include chemical agents as well as biological modalities, and the FOA explicitly notes immunotherapeutics as an important example of biological perturbagens. The underlying idea is that single-agent approaches often fail because heterogeneous tumors can route around a blocked pathway or because resistant subclones expand. In contrast, rational combination strategies can, in principle, cover multiple survival routes at once, prevent escape, and account for the protective effects of the microenvironment. Projects aligned with this goal would typically involve systematic approaches to identifying synergistic combinations, prioritizing multi-target strategies, and determining which combinations are most likely to be robust across variable tumor contexts.

From an administrative and eligibility perspective, the opportunity is offered by the Department of Health and Human Services through the NIH (NCI) and is categorized under discretionary funding. It uses the cooperative agreement funding instrument (U01) within the health and education activity space, and it is associated with CFDA numbers 93.395 and 93.396. Eligible applicants are broad and include a wide range of U.S. entities: state, county, and local governments; special district governments; independent school districts; public and private institutions of higher education; federally recognized tribal governments and other tribal organizations; public housing authorities/Indian housing authorities; nonprofits with or without 501(c)(3) status (excluding higher education institutions where specified); for-profit organizations (other than small businesses); and small businesses, plus additional categories as clarified in the FOA. The posted award ceiling is $750,000, and the announcement indicated an expectation of about 12 awards. The FOA record shows a creation date of July 12, 2021, and an original closing date of October 6, 2022.

Overall, CTD2 is best understood as a targeted NCI effort to turn cancer genomics and other comprehensive molecular characterizations into mechanistic insights and actionable target strategies, with a strong emphasis on functional validation, pathway and network understanding, resistance biology, tumor heterogeneity, and rational multi-target or combination perturbation approaches, all conducted without proposing a clinical trial as part of the funded work.

• The Department of Health and Human Services, National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Cancer Target Discovery and Development (CTD2) (U01 Clinical Trial Not Allowed)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.395, 93.396.
• This funding opportunity was created on Jul 12, 2021.
• Applicants must submit their applications by Oct 06, 2022. (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 $750,000.00 in funding.
• The number of recipients for this funding is limited to 12 candidate(s).
• 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 (see text field entitled Additional Information on Eligibility for clarification).

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