Project Term
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Stanford University
Stanford, CA
United States
Project Summary
TP53-mutant clonal hematopoiesis (CH) is prevalent in populations that received genotoxic cancer therapy and is associated with elevated risk for therapy-related myeloid neoplasms (t-MNs). Here, I developed a human model of TP53-mutant CH that exhibits clonal expansion upon exposure to olaparib or paclitaxel treatment and identified a targetable synthetic lethality target DOCK1 that might prevent this clonal expansion. I aim to develop targeted therapies of high-risk TP53-mutant CH and t-MNs.
Lay Abstract
TP53-mutant acute myeloid leukemia (AML) is one of the most aggressive blood cancers, which progresses rapidly and does not respond adequately to standard or novel therapies, resulting in a dismal two-year overall survival rate of merely 12.8%. Recent reports have revealed that TP53 mutations presented in the blood years before a patient is diagnosed with AML, indicating that these mutations may serve as the initial trigger for AML. Unfortunately, there are currently no established clinical strategies to manage these TP53-mutant blood cells before they transform into leukemia.
My goal is to address this gap by developing novel and effective strategy to prevent and treat TP53-mutant AML. To achieve this, I have established the first innovative human model using advanced genetic engineering in primary human blood stem and progenitor cells. In this model, TP53-mutant preleukemic blood cells exhibit similar fitness as control under normal conditions yet gain a significant competition advantage upon genotoxic treatment. This closely mirrors the clonal expansion of TP53-mutant blood cells observed in cancer patients undergone chemotherapy or radiotherapy. This advanced model serves as a powerful tool to validate targeted therapeutic interventions that selectively attack TP53-mutant cells. First, by employing the synthetic lethality strategy and an advanced computational algorithm, we identified DOCK1 is specifically vulnerable gene to TP53-mutant blood cells. My early results show DOCK1 inhibitor significantly slows down the clonal expansion and reduces the self-renewal of preleukemic TP53-mutant blood cells compared to the control. I will continue studying on the downstream molecular pathway of DOCK1 in TP53-mutant preleukemic cells to understand the mechanism of action. Second, to further investigate whether the vulnerability of DOCK1 extends to overly transformed leukemic cells, I edited both DOCK1 and TP53 in leukemia cell lines. Remarkably, the complete DOCK1 disruption resensitizes TP53-mutant leukemic cells to chemotherapies, suggesting a potential role of DOCK1 ablation for enhancing treatment efficacy. I plan to further test if DOCK1 inhibitor resensitize TP53-mutant AML cells to novel therapy in primary patient samples.
In summary, our research on DOCK1 is establishing a foundation for future clinical trials of DOCK1 inhibitors in treating TP53-mutant AML, paving the way for new clinical strategies for preventing and treating TP53-mutant AML.
Program
Grant Subprogram