Precision targeting of BFL-1 and MCL-1 in pediatric leukemias to overcome treatment resistance
Loren Walensky
PhD, MDDana-Farber Cancer Institute
Project Term: July 1, 2019 - June 30, 2022
Pediatric leukemia cells hijack the BCL-2 family signaling network to overexpress a range of anti-apoptotic proteins, including BFL-1 and MCL-1, and thereby enforce cellular immortality and cause treatment resistance. Here, we will harness novel and unique stapled peptides with the capacity to selectively target BFL-1, MCL-1, and importantly, both targets simultaneously, in order to reactivate the cell death pathway in MCL-1 and BFL-1 dependent pediatric leukemias.
Despite major progress in the curative treatment of pediatric leukemias, specific subtypes of pediatric blood cancer and treatment-resistant disease remain a formidable challenge, mandating the development of new therapeutic strategies. We have pioneered the development of a new class of drugs called “stapled peptides”, which are designed to take advantage of the natural binding activity of the body’s proteins to target cancer-causing signals. One of the most effective strategies used by cancer cells to thwart modern treatment is to overexpress a class of proteins called the BCL-2 family, which normally maintain cell survival in the face of stress. Cancer cells hijack these survival proteins and massively overproduce them to prevent cancer cell death, even in the face of treatment. Whereas small molecules have been developed to inhibit certain BCL-2 family proteins that cause chemoresistance, such as the FDA-approved drug venetoclax, other cancer-causing members, such as BFL-1, remain undrugged. What’s more, there are no small molecule drugs capable of targeting two such resistance proteins at the same time, namely BFL-1 and MCL-1. Pediatric leukemias harbor a diversity of BCL-2 family survival proteins, making the development of single- and dual-targeting inhibitors an urgent and unmet medical need. For this application, I propose to take advantage of our nearly two decades of experience in developing stapled peptides for basic research and clinical translation to test three new classes of agents that we have recently developed: (1) selective BFL-1 inhibitors; (2) selective MCL-1 inhibitors; and (3) dual-targeting BFL-1 and MCL-1 inhibitors. Since one my laboratory’s prototype stapled peptide inhibitors that targets two cancer-causing proteins simultaneously, namely HDM2 and HDMX, has now been transformed into a clinical-grade stapled peptide being tested in phase 1 and 2 clinical trials, we are ideally-positioned to harness our drug development experience to execute the proposed project. Specifically, we aim to test our BFL-1 and MCL-1 targeting stapled peptides in leukemia samples obtained from newly diagnosed pediatric patients, catalogue and correlate drug responses to specific dependence of these leukemias on BFL-1 and/or MCL-1, determine whether our compounds could be used as a test to predict patient responses to BFL-1 and MCL-1 targeting, and develop proof-of-concept for on-target treatment efficacy in mouse models bearing patient-derived leukemias. Thus, the overarching goals of this project are to validate a new strategy for reactivating pediatric leukemia cell death and to evaluate therapeutic potential in experimental models. Ultimately, the results that emerge could provide a compelling basis for advancing our unique compounds to phase 1 clinical testing in children with relapsed and refractory leukemia.