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

Award Number: R01CA302945
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $683,698 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Treatment Research	000	1	5/26/2026	NEW	$683,698
														Subtotal = $683,698

Grand Total All Awards = $683,698

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

Award Number: R01CA302945

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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