Characterize Drug Resistance in Multiple Myeloma

Central Arkansas Veterans Hlthcare Sys, North Little Rock AR

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Abstract

PROJECT SUMMARY The objective of this work is to define reliable biomarkers of drug-resistant multiple myeloma (MM) cells with the goal of using this information to design novel therapies that can prevent MM relapse by targeting those cells resistant to current treatment modalities. MM is the 2nd most common hematological cancer in humans and a difficult-to-cure malignancy. Although advances have been made in treating MM, most patients relapse eventually and then die from their disease due to the persistence of drug-resistant tumor cells. We have identified molecular signatures and regulatory elements of malignant clonal evolution in MM using single cell multi-omics profiling of MM cells. We are the first to conduct a large proteomic study relating patient overall survival risk with protein expression and have developed a prognostic protein risk score (PEP60) of 60 high- risk proteins (34 up-regulated, 26 down-regulated) in MM. Chimeric antigen receptor (CAR)-T cell therapy is an expanding oncology treatment approach in which a patient’s T cells are collected, modified, and reinfused to target cancer immunologically. We have developed bispecific-CAR-T cells targeting BCMA (B-cell maturation antigen) and CD24, and we have shown that these cells can eliminate both drug-resistant CD24+ MM cells and bulk MM cells with profound efficacy. We hypothesize that drug-resistant MM cells, owing to their distinct gene expression pattern and signaling pathways, cause MM relapse. We intend to test this hypothesis by way of two specific aims involving experiments with primary human MM samples and both in vitro and in vivo models. In Aim 1, we will define drug-resistant clones and biomarkers in sequential primary human myeloma samples using multi-omics profiles. In Aim 2, we will develop novel treatment strategies to overcome drug resistance in myeloma. Achieving these aims will provide new insights into how drug-resistant MM cells influence cancer cell behavior and suppress chemo- or immune-therapeutic responses in MM, and develop novel immunotherapy to prevent MM relapse.