Developing Novel Transcription Factor PROTACs to Disrupt the HMGA1 Epigenome in Relapsed Leukemia
Acute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia and the leading cause of death in children with cancer. While therapy is often curative, ~10% of children will relapse with recurrent disease and abysmal outcomes. Unfortunately, recent efforts to increase the dose or frequency of standard therapy have failed to prevent relapse. Thus, we have reached the ceiling of efficacy for current therapy and new strategies are needed. Here, we take a novel approach by focusing on HMGA1 proteins as drivers of relapse in leukemia. HMGA1 is activated in ALL with highest levels at relapse. In genetically engineered mouse models, HMGA1 transforms normal blood cells into aggressive leukemia, recapitulating salient features of childhood leukemia. This protein acts as a “leukemia switch” that flips on genes required by leukemia cells for rapid growth and resistance to therapy, while flipping off genes that activate an immune attack. Using an innovative gene editing approach called CRISPR, we discovered that silencing HMGA1 gene expression prevents leukemic cells from surviving and expanding in experimental models of relapsed ALL. These results suggest that therapy to block HMGA1 function will be effective in aggressive childhood ALL. Based on these exciting results, we have begun to develop novel technology, called PROTAC degraders, to be deployed to destroy HMGA1 and treat, or even prevent, relapse in children. Here, we will test these HMGA1-PROTACs in preclinical studies and translate our most promising results to the clinics for children at risk for relapsed leukemia.
Project Goals:
Building on our exciting preliminary data demonstrating that specialized PROTACs can be linked to small tags that resemble DNA as “bait” to trap and destroy proteins like HMGA1, we propose to optimize this technology for therapy for children at risk for relapsed leukemia. In preliminary studies, we designed DNA tags that effectively trap HMGA1 in relapsed leukemia cells. We will test our hypothesis that degrading HMGA1 with HMGA1-PROTACs will be effective in therapy to prevent or treat relapse in pediatric ALL with the following Specific Goals: 1) First, we will design 5-10 HMGA1-PROTACs to test for optimal HMGA1 destruction in cell lines from children with relapsed ALL, and, 2) Second, we will begin to test the most effective PROTAC degraders for anti-leukemia effects using preclinical mouse models of relapsed ALL. At the completion of our work, we expect to: 1) Generate at least 5-10 novel HMGA1-PROTACs to target HMGA1 in relapsed, childhood leukemia, and, 2) Complete studies of their efficacy in preclinical models of relapsed leukemia. We will translate our most promising results to the clinics for children with high risk and refractory disease. We assembled an expert team of investigators from Johns Hopkins University (JHU), the Icahn School of Medicine at Mount Sinai (ISMMS), and New York University (NYU), and we are optimally positioned to complete this work. This work should uncover novel PROTACs to target an “undruggable” protein that causes leukemia, and could provide new treatment paradigms for relapsed ALL and other pediatric cancers.
