Acute myeloid leukemia (AML) treatment remains highly variable, with survival improvement lagging in adolescent and young adult (AYA) patients compared to children and older adults. RUNX1-mutated AML is associated with poor prognosis, and in RUNX1-mutated familial platelet disorder (FPD), nearly 40-50% of patients aged 11–40 progress to leukemia. Children with FPD experience lifelong bleeding disorders, significantly impacting their daily lives. Recent estimates suggest that ~18,000 individuals may have FPD, yet no interventions exist to prevent leukemic transformation.
Our research indicates that many inflammatory cytokines are high in FPD. We prioritized clinically targetable inflammatory pathways, which regulate downstream signaling of mTOR and JAK1/2. Our efforts led to the first clinical trial for mTOR inhibitor sirolimus in RUNX1-FPD. Our preliminary data suggest that direct targeting of inflammation may also be beneficial for reducing cell growth and improving blood cell differentiation in RUNX1-FPD, which has not been evaluated comprehensively. In this proposal, we will conduct preclinical testing of direct targeting of inflammation using murine models and young population samples in cell culture and in vivo models. We proposed using FDA-approved inhibitors for autoimmune diseases with favorable safety profiles, enabling rapid clinical repurposing.
Our overarching objectives will be to 1) identify mechanisms driving leukemia progression in FPD and define prognostic and therapeutic markers. 2) Validate findings in primary samples. 3) Lay the groundwork for clinical trials on early intervention in FPD. 4) Expedite translation to clinical trials by repurposing FDA-approved drugs. To achieve these goals, we will use rare primary samples and unique murine models. These studies will be critical for designing Phase I clinical trials in collaboration with clinicians for RUNX1-FPD patients and may be useful for patients with somatic RUNX1 mutations. To achieve our goals, we assembled a multidisciplinary team of investigators and collaborators, including leukemia biologists, clinicians, and bioinformaticians. Additionally, we are supported by the robust environment and resources at Knight Cancer Center.
