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Background

The formation of cancer is orchestrated by a confluence of external, cell-nonautonomous, factors and internal, cell-autonomous, factors. Discovering medical interventions that can disrupt this complex interplay of factors is challenging but necessary.

In the bone marrow, the acquisition of somatic mutations in leukemia-associated genes, resulting in clonal mosaicism, is termed clonal hematopoiesis (CH). CH is unequivocally associated with hematologic malignancies (HM) and, therefore, considered a precancerous condition.

While in the general population CH is common in the elderly (more than 10% in people aged 70 and older), the overall risk of malignant transformation is low.

However, in high-risk populations, like those with germline predispositions to HM, CH rates are much higher, and the risk of HM development is significantly greater.

One such high-risk population includes people with RUNX1 familial platelet disorder (RUNX1-FPD), a rare heritable disease caused by germline RUNX1 mutations. Individuals with RUNX1-FPD have a 35 to 50% lifetime risk of HM with acute myeloid leukemia as the most common and second deadliest HM.

Despite the established link between RUNX1-FPD and hematologic malignancies, there remains a significant gap in understanding the cell-nonautonomous factors that contribute to clonal evolution and malignant transformation, as well as the precise mechanistic pathways by which RUNX1 mutations promote cancer development. This knowledge gap impedes the development of targeted strategies for early intervention and prevention.

A deeper understanding of how extrinsic signals and the broader microenvironment interact with intrinsic RUNX1 mutations is critical to uncovering novel therapeutic targets. The RUNX1-FPD community of families is in urgent need of cancer interception and prevention therapies.??

LEAP Grant Program Overview ?

The RUNX1 Research Program and the PÕ¾ÊÓƵ (PÕ¾ÊÓƵ) have partnered to make a demonstrable leap forward in the pursuit of cancer interception and prevention treatments for patients with RUNX1-FPD. The grant mechanism is called Leukemia Exploration and Prevention, or LEAP, to symbolize this overarching goal.

Grant proposals are investigator-initiated and pursue questions specifically designed to enable the discovery of cancer interception or prevention therapies for RUNX1-FPD HMs.

Applicants for the LEAP grant program must propose a research project in one of the two areas of focus below:

The first area is focused on deepening our understanding of the mechanisms that cause each leukemogenic step, beginning with germline RUNX1-mutated hematopoietic stem/progenitor cells (HSPCs) that acquire deleterious somatic mutations and expand over time, culminating in overt RUNX1-mutated leukemia. Projects should consider experimental designs that address both cell-autonomous and cell-nonautonomous factors.

The second area of the LEAP grant program is committed to supporting high-risk projects with strong scientific rationale to pursue a cancer interception treatment. Projects could focus on preclinical studies and/or clinical trials designed to test innovative approaches to treatment. This can include repurposing existing regulatory-approved treatments or novel therapeutics. The intent here is to act on behalf of the urgency felt by the patient community.?

Eligibility

You ARE eligible to submit a proposal if you:

• Work at a US academic institution or eligible non-profit
• Are a full-time independent investigator at any career stage

Grant Mechanisms

Applicants may only apply for one of the two funding mechanisms: the LEAP-Research Scholar Grant or the LEAP-Team Award.

LEAP-Research Scholar Grant

Intent: Supports an independent research project that aligns with one of the two LEAP program focus areas. Research Scholar Grants (RSGs) provide support for independent, self-directed researchers.

Term and Budget: Awards are for up to $215,000 per year for up to 4 years ($860,000 total direct costs) plus 10% allowable indirect costs.?

LEAP-Team Award

Intent: Supports a team research project that aligns with one of the LEAP program research focus areas. The application must clearly articulate how the team will synergize to accelerate scientific advancement and clinical benefit. ?

Applicants must clearly demonstrate the assembly of an interdisciplinary team with diverse expertise, ensuring a comprehensive approach to address the research objectives. Each team should have 1 Lead PI and at least 1 Team Principal.

• Lead PI: Coordinating PI; assumes the authority and responsibility to direct the project.
• Team Principal: Directs a specific area of the scientific and technical work and leads a component of the research based on their area(s) of expertise. Full-time independent researchers at any career stage can serve as Team Principals.

The Lead PI and all Team Principals share authority for scientific leadership.

Term and Budget: Team awards are for up to $430,000 per year direct costs for up to 4 years ($1,720,000 direct costs), plus 10% allowable indirect costs.

A formal review of each LEAP grant will occur after 2 years. At this time, the project¡¯s progress will be assessed, and PIs will have the opportunity to adjust the project¡¯s specific aims if necessary for the remaining 2 years of the LEAP grant.

Anticipated Funding: Funds are available for 3 LEAP-RSG awards or 1 LEAP-RSG award and 1 LEAP-Team award.