Project Term
–
Stanford University
Stanford, CA
United States
Project Summary
There is a critical need for new strategies to prevent and treat an aggressive form of leukemia linked to TP53 mutations, which are prevalent in patients who have received cancer treatments and are associated with a poor prognosis. Our preliminary studies suggest that targeting DOCK1 may be a promising therapeutic strategy for eliminating TP53-mutant cells in AML and clonal hematopoiesis, a high-risk condition often preceding AML. In this proposal, we will determine the potential of DOCK1 targeting using both genetic and pharmacologic approaches, and investigate the underlying molecular mechanisms of DOCK1 inhibition to gain a deeper understanding of its function.
Lay Abstract
TP53 mutations in acute myeloid leukemia (AML) are linked to aggressive disease and are recalcitrant to current treatment strategies, leading to low response rates and poor survival outcomes of only 4-6 months. These mutations are also present in clonal hematopoiesis (CH), a high-risk condition affecting many cancer survivors that frequently progresses to TP53-mutant AML. The idea of Synthetic Lethality (SL) offers a promising approach for targeting TP53-mutant CH and AML. SL occurs when mutations in two or more genes together cause cell death, whereas a mutation in just one of these genes does not. Leveraging pan-cancer primary tumor datasets, our computational pipeline called Mining Synthetic Lethals (MiSL), identified DOCK1 as a potential synthetic lethal partner of mutant TP53. Our preliminary data show that treatment with a DOCK1 inhibitor leads to decreased clonal expansion and reduced self-renewal of TP53-mutant hematopoietic stem and progenitor cells. Based on these observations, we hypothesize that DOCK1 inhibition can target and eliminate TP53-mutant pre-leukemic cells and AML. To test our hypothesis, we will employ our established and innovative human models of TP53-mutant AML and CH, which have been shown to mimic key clinical features critical for therapy development. We propose the following aims:
Aim 1: To investigate genetic and pharmacologic inhibition of DOCK1 to prevent clonal expansion of TP53-mutant CH
Aim 2: To investigate genetic and pharmacologic inhibition of DOCK1 to target TP53-mutant AML
Aim 3: To investigate the mechanisms of the DOCK1/Rac pathway effects in TP53-mutant CH and AML
Our work has the potential to validate DOCK1 as a therapeutic target in TP53-mutant CH and AML, potentially leading to the pre-clinical and clinical development of DOCK1 inhibitors for patients with TP53 mutations. The proposed mechanistic studies to examine the DOCK1/RAC pathway could lead to immediate clinical translation, as Rac inhibitors are currently in clinical trials and can be investigated for TP53-mutant AML and CH. Together, our proposal has the potential to identify a novel target and lead to the development of a targeted therapies to prevent and treat this aggressive blood cancer.
Program