Overcoming RAS-driven Mechanisms of Resistance in Leukemia
Nicolas Nassar
PhDCincinnati Children's Hospital Medical Center
Project Term: July 1, 2022 - June 30, 2025
The mitogen-activated protein kinase (MAPK) pathway is activated in high-risk leukemia and is a hallmark of resistance to therapies. This project uses patient-derived xenograft models of relapsed pediatric ALL and AML with activated RAS/MAPK to test whether clinically relevant MAPK mutations activate the VAV3/RAC pathway and if pharmacological inhibition of that pathway by a small molecule we developed synergizes with a MAPK-inhibitor to provide a new treatment strategy for RAS-driven leukemia.
The mitogen activated protein kinase (MAPK) signaling pathway is an essential pathway for cell growth. Given its importance, this pathway is tightly regulated. Not surprisingly, in human cancers proteins in the MAPK pathway are commonly deregulated and they become the driving force behind mechanisms of resistance to treatments. Consequently, a treatment strategy focusing on inhibiting these proteins would likely provide additional benefit to patients with hyperactivated MAPK leukemia. Alas, very few drugs targeting hyperactivated MAPK are in clinical use. Example of MAPK inhibitors (MAPKi) include vemurafenib, trametinib, and SHP-099. However, despite some initial clinical success, leukemias in patients treated with these drugs, relapse.
Most patients go into remission, however their leukemias come back, or relapse, after which a different treatment is needed. If leukemia relapses a second time, very few options remain. Here, we specifically focus on relapsed leukemia and propose to explore a new treatment strategy by targeting a critical arm of the MAPK pathway - the pathway regulated by the protein RAC – via the novel inhibitor IODVA1 that we developed and validated. We take advantage of the fact that RAC is required for active MAPK and argue that a RAC pathway inhibitor such as IODVA1 will synergize with a MAPK inhibitor to prolong the time in remission in relapsed active MAPK leukemia. First, we will validate that inhibiting RAC signaling is a way to intervene and inhibit active MAPK leukemia. Using genetic approaches, we will test the hypothesis that constituents of the RAC signaling axis are activated downstream of patient mutations of the MAPK pathway. We will focus on oncogenic mutations of RAS and PTPN11, and on loss-of-function mutations of NF1. RAS, PTPN11, and NF1 are key players of the MAPK pathway. We will also test if pharmacological inhibition using IODVA1 suppresses genetic models of MAPK-driven leukemia progression.
Second, we will test which combinations of IODVA1 and MAPK inhibitors or chemotherapy are best in PDX models of relapsed pediatric leukemia with active MAPK. De-identified patient samples will be obtained from the clinic at our institution. Generated PDX mouse models will be treated with IODVA1 in combination with vemurafenib, trametinib, and SHP-099 or with chemotherapy. Survival, residual disease assessment and biochemical studies of PDX models will identify the best treatment combination in the context of tumor mutational landscape.
Although our PDX models represent the pediatric population, we anticipate that IODVA1 will also impact adult leukemia. Given MAPK and RAC pathways’ well-documented roles in solid tumors, this project is also expected to provide a new treatment for targeted intervention in multiple cancers including lung, colorectal and pancreatic cancers. By targeting RAC signaling, which controls cell survival, this work provides a novel therapy to inhibit active RAS/MAPK.