Targeting chromatin acetylation factors in multiple myeloma

PROJECT SUMMARY Multiple myeloma is a disease characterized by aberrant chromatin accessibility and gene expression. Principle mediators of this dysregulation are chromatin regulators that coordinate transcription through enhancer activation. Our recent efforts have led to the creation of chemical 'degrader' tools that specifically target two enhancer-activating chromatin regulators critical for the survival and proliferation of multiple myeloma cells, CBP and p300. While inhibitors of these factors have recently begun to undergo clinical investigation, the central hypothesis of this project is that pharmacologic degradation offers a superior strategy for treatment. To interrogate the unique mechanisms of CBP/p300 degradation in myeloma and to credential these new chemical tools as candidates for therapeutics development for multiple myeloma patients, we will prosecute the following two specific aims: Aim 1 will use CBP/p300 inhibitors and degraders to assess comparative consequences of CBP/p300 perturbation in multiple myeloma cells. For this aim we will utilize a variety of epigenomic, transcriptomic, and chromatin conformation assays to describe the primary acute effects of these drugs. We will also systematically interrogate the unique consequences of CBP and p300 loss alone using selective degradation tools. Aim 2 will use xenograft models of multiple myeloma to determine the optimal dosing and drug-drug combinations required for CBP/p300 degraders to induce tumor regression in vivo. These studies will be performed using a variety of multiple myeloma model systems that display variable sensitivity and resistance profiles to CBP/p300 inhibitors. We expect that these efforts will reveal mechanisms of gene regulatory dysfunction in multiple myeloma, describe in high resolution the effects of a drug currently undergoing preliminary clinical investigation, and nominate a promising new class of chemical degraders for the treatment of this deadly disease.