Concomitant Inhibition of VAV3 and ERa to Treat High-Risk B-ALL

About This Grant

PROJECT ABSTRACT B-cell acute lymphoblastic leukemia (B-ALL) remain poor prognosis diseases, especially in adults, due to frequent relapse and the emergence of therapy resistance despite advances in tyrosine kinase inhibitors and immunotherapies. Although treatment options have improved, relapse continues to limit long-term survival, re­flecting a critical gap in our mechanistic understanding of resistance. This gap has hindered the development of effective, non-toxic targeted therapies. The goal of this project is to validate the RAC activator VAV3 as a negative regulator of estrogen receptor a (ERa) in B-ALL and to evaluate a novel therapeutic strategy combining a VAV3 inhibitor with the selective es­trogen receptor degrader fulvestrant in preclinical models of relapsed/refractory B-ALL including anti-CD19 ther­apy-resistant models. Our preliminary data demonstrate that pharmacological inhibition of VAV3 using IODVA 1, a small molecule we developed, enhances ERa activity and induces ERa dependency in B-ALL cells. Sequential treatment with IODVA 1 followed by fulvestrant significantly prolongs survival in preclinical models of treatment­resistant B-ALL, with durable responses after treatment cessation. We hypothesize that coordinated targeting of VAV3 and ERa represents a viable therapeutic strategy in high-risk B-ALL. In Aim 1, we will use genetic, biochemical, and pharmacological approaches to define how VAV3/ERa co-dependency regulates B-ALL proliferation and to identify growth factors besides estradiol/E2 se­creted by leukemic cells following VAV3 inhibition. In Aim 2, we will test the therapeutic efficacy of sequential VAV3 and ERa inhibition in xenograft models of relapsed/refractory and anti-CD19-resistant B-ALL, and identify mechanisms of treatment escape. Xenograft studies in immunodeficient mice are essential for evaluating effec­tive drug dosing, systemic toxicity, tumor microenvironment interactions, CNS invasion, and clonal evolution in vivo and superior in these regards to alternative in vitro or ex vivo approaches. In Aim 3, we will define the functional role of VAV3/ERa co-regulated regions, characterize clonal evolution following VAV3 inhibition using barcoding and orthogonal single-cell sequencing, and determine how ERa remodels the epigenome to sustain proliferation after VAV3 inhibition. Our long-term objective is to establish IODVA 1 plus fulvestrant as a novel, broadly effective therapeutic strategy for high-risk B-ALL. This approach has the potential to overcome resistance independent of genetic background or driver oncogene. Given the established roles RAC and VAV3 in solid tumors, these studies may also inform new targeted therapies for metastatic lung, colorectal, and breast cancers.