Dana-Farber Cancer Institute
Project Term: July 1, 2022 - June 30, 2025
Small molecule inhibitors that target the Menin-MLL-fusion interaction have emerged as therapeutic opportunities for MLL1-r leukemias and are currently in clinical trials. We are now focused on identifying other factors that modulate sensitivity and resistance to Menin inhibition using complementary genomic and biochemical assays. Our goal is to find other druggable dependencies that can further sensitize leukemic cells to this epigenetic therapy and devise more effective treatment strategies.
Leukemia is a progressive and malignant disease that along with other blood cancers, is projected to account for approximately 10% of all deaths from cancer in 2021. Acute forms of leukemia affect both pediatric and adult patients who often go through chemotherapy regiments with substantial therapy-related toxicities. While improved care and treatment options have enhanced the survival outcome for patients with Acute Myeloid Leukemia (AML), many still relapse and succumb to the disease. A primary cause for patient relapse is that after a while, cancer cells develop resistance to treatment drugs and this is much more pronounced when single agents are used for therapy. Therefore, there is a critical need for developing more effective therapeutic approaches. The research proposed here aims to understand the molecular relationship between a number of key leukemia drivers that would subsequently allow for the development of new treatment strategies. This work will investigate the mechanisms of acquiring resistance to inhibition of the MLL-fusion protein complex that is a key promoter of leukemic programs. Delineating such mechanisms is of great significance given that small molecule inhibitors that abrogate interactions between MLL-fusion and the DNA anchoring protein, Menin have emerged as promising therapeutic tools and are currently in clinical trials. Moreover, the proposed studies will also mechanistically examine how AML cells can be further sensitized to therapy by additional targeting of other molecular vulnerabilities in these cells. Specifically, we have identified the epigenetic modifying enzyme, MOZ to be one of such targets. Thus, I aim to first examine the crosstalk between MOZ and MLL-fusion proteins by defining the composition of each complex and assessing the physical association between the two. Second, I will determine how simultaneous inhibition of Menin and MOZ can lead to augmented silencing of cellular programs that fuel leukemic transformation. Altogether, successful completion of the proposed aims will provide critical insights into the dynamic relationship between MLL-fusion and MOZ. These studies will also reveal how this epigenetic writer can be manipulated as a vulnerability which will be key for developing effective combinatorial therapies for AML patients.