SHP2 and BCL2 Inhibition in Acute Myeloid Leukemia
Catherine Smith
MDUniversity of California San Francisco
Project Term: October 1, 2021 - September 30, 2026
The goal of our work is to use a “bench to bedside and back” approach to develop new treatments for patients with relapsed/refractory AML. Through genetic analysis of patients who relapse or do not respond to standard and investigational treatments, we discover potential resistance mechanisms. In the lab, we test novel drugs and identify new drug targets that may address these resistance mechanisms when used in combination with other therapies. The overall goal of our research program is to improve treatment options and survival of patients with refractory AML.
Patients with acute myeloid leukemia (AML) who relapse or do not respond to standard therapy have extremely poor prognoses. AML patients with mutations in the genes FLT3 and KIT are particularly prone to relapse. These mutations cause uncontrolled growth and survival of AML cells. New drugs which inhibit the protein SHP2, an intermediate that promotes growth and survival of cancer cells, have been developed and are in clinical trials in other tumors. In our lab, we have identified that SHP2 inhibitors in combination with inhibitors of the anti-death protein BCL2 are very effective at disrupting the growth of AML cells with FLT3 and KIT mutations. In this project, we will translate these findings to test the effectiveness of combining a SHP2 inhibitor (RMC4630) and a BCL2 inhibitor (venetoclax) in AML. We will take a “bench to bedside” approach to testing this combination. We will first test RMC4630 and venetoclax in the laboratory using AML cell lines, patient samples, and mouse leukemia models to identify all the potential different AML patient populations that might benefit from this new therapy. We will also predict potential resistance mechanisms to the combination using these models. Secondly, we will conduct a clinical trial in AML patients who have relapsed or not responded to initial chemotherapy. For this trial, we will focus on the AML patient populations that we have identified in the laboratory to be most susceptible to this combination. We will assess any patients who may relapse or do not respond on this clinical trial for the resistance mechanisms we identified in the lab. The success of this project will be judged by how many patients respond to the clinical trial combination. If successful, this combination can be tested in a randomized trial of the combination versus standard therapy to assess if this combination is superior to current treatment. Our overall goal is harness findings in the lab to design clinical trials which will improve the survival of patients with AML who do not respond to standard therapies, a group of patients who currently have very poor outcomes.