Bi-functional degrader with treatment potential for B-cell lymphoma - Project Summary Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma and is highly aggressive, with a relapse rate of >40%. Additionally, current salvage therapies for relapsed cases, including bone marrow transplant and cellular therapies, pose significant risks and are limited to patients that qualify, indicating an urgent need for novel and more targeted and efficacious therapeutic strategies. Notably, DLBCLs that have mutated the p53 tumor suppressor and/or overexpress MDM2, an oncoprotein that negatively regulates p53, as well as has p53- independent functions that contribute to genomic instability in cancer, have worse overall survival and are more refractive to conventional therapies. The Eischen lab discovered that, in contrast to what was believed in the p53/Mdm2 field, p53 mutant cancer cells may require MDM2 for their continued growth and survival. Consequently, the Eischen lab has recently reported the design, generation, and extensive evaluation of a novel MDM2-targeted degrader that showed efficacy in p53 mutant breast cancer. Moreover, we now have a new bi- functional MDM2 degrader that requires further characterization. Thus, how our two distinct MDM2 degraders compare biologically, their effectiveness at inducing robust DLBCL cell death, and the precise mechanism of how MDM2 degradation kills in a p53-independent manner remain unclear. To address these questions, we will use a combination of cellular, molecular, and biochemical approaches in DLBCL cell lines and mouse models, as well as patient samples. In Aim 1, we will compare the biological effects of our novel MDM2 degraders and investigate MDM2 degradation as an exploitable vulnerability with therapeutic potential in DLBCL. In Aim 2, we will elucidate the mechanism by which MDM2 loss leads to activation of DLBCL cell death, which could result in revealing other targetable proteins. Our proposed studies will not only identify a possible novel means of therapeutic intervention for DLBCL, but also profoundly enhance understanding of the p53-independent functions of MDM2 that can then be exploited. Thomas Jefferson University’s PhD program, which offers a diverse array of educational and career development opportunities, as well as the Eischen lab, provide a highly rigorous, collaborative, and resource rich environment that will facilitate the successful completion of the studies outlined in this application and my career development. Throughout the remainder of my PhD training, the exceptional mentorship of Dr. Eischen, invaluable insight from my thesis committee and collaborator, and other experts in their fields, will ensure that I acquire the scientific knowledge, technical expertise, and professional skills necessary to become a successful, independent academic cancer researcher.
