Novel RAC Pathway Inhibitors for the Treatment of Metastatic RAS/MAPK Activated Leukemia
Abstract
The invasion of the central nervous system (CNS) by leukemic cells in childhood leukemia is rare at initial diagnosis (3%-5%) but more frequent at relapse (30%-40%), when the leukemia becomes irresponsive to therapies. Leukemia is the number one cancer in the pediatric population. If leukemia treatment has significantly improved patients’ outcome, this success is primarily due to the elimination of leukemic cells outside the CNS. Preventing leukemia from entering the CNS and treating leukemia that has already invaded the CNS remain a serious problem in the clinic. Leukemic cells often infiltrate the CNS to hide from cancer treatments, preventing complete disease eradication. Some patients thus undergo prophylactic cranial irradiation or receive very high doses of chemotherapy to reduce rates of CNS recurrence. Although these options can reduce leukemia in the CNS in high-risk patients, the toxicity of such approach has lifelong devastating effects on patients, such as neuropathy, infertility, and cognitive problems. Thus, novel safer targeted therapies are urgently needed to prevent leukemia invasion into the CNS and to treat patients who already have leukemia in the CNS at the time of diagnosis. The broad objective of this Impact Award research project is to test the efficacy and therapeutic promise of IODVA1, a nontoxic small molecule inhibitor of the VAV3/RAC pathway on models of high-risk patient-derived relapsed pediatric leukemia. Our goal is to move IODVA1 into the clinic as a novel targeted therapy for CNS- invasive leukemia. Our ultimate goal is to develop a therapeutic regimen that doesn’t only treat cancer, but also allows patients to lead normal lives. We take advantage of the dependency of leukemic cells on the activation of VAV3 and RAC for proliferation and metastasis to devise a novel treatment for leukemia. RAC regulates cell survival and cell growth, which allows leukemic cells to multiply. RAC also binds to and regulates the activity of cellular components that guide how leukemic cells may change their shape and interact with other cells and their immediate environment to travel long distances, burrow through cell layers, and establish themselves in the CNS. RAC itself must be activated, so we propose to test the first-in-class non-toxic inhibitor of its activator VAV3, IODVA1. We initially developed IODVA1 and validated its efficacy in patient-derived models of high-risk leukemia and in xenograft cell line models of solid tumors. Given its promise at prolonging the survival of leukemic mice, at eliminating leukemic cells from circulation and incidence of CNS-invasion in vivo, and at reducing leukemic cell migration and interactions with their environment, we want to test if IODVA1 can be used as a novel therapeutic strategy in CNS-invasive leukemia. The approach we are undertaking is highly innovative because it tackles an old problem, leukemia in the brain, with a novel approach. IODVA1 is the first inhibitor of VAV3 and has a novel chemical structure with untapped potential. In addition, IODVA1 synergizes with U.S. Food and Drug Administration (FDA)-approved targeted therapies. By generating novel therapeutics to treat CNS-invasive leukemia, this proposal addresses the Peer Reviewed Cancer Research Program Topic Areas Blood Cancers and Pediatric, adolescent, and young adult cancers, as the PDX models used throughout are from relapsed/recurrent pediatric leukemia. The overall hypothesis to be tested in this proposal is that IODVA1 inhibits mechanisms used by leukemic cells to attach to blood vessels and cell layers and invade the CNS. As such, IODVA1 or a next generation analog we are generating could be developed into novel therapeutic for leukemia without the side effects of current treatments. Our goal is to develop a combination of drugs (IODVA1 + FDA-approved drug) that can be introduced early during treatment to improve outcomes. We present convincing preliminary dat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310960
Entities
People
- Nicolas Nassar
Organizations
- United States Army