Modeling, unraveling, and beating acquired resistance to BCMA and GPRC5D targeted agents in multiple myeloma

Description

In the current proposal we will use our recently developed mouse models of MM (Larrayoz et al, Nature Medicine 2023) carrying a new set of humanized therapeutic targets (BCMA and GPRC5D in MM cells and CD3 in T cells), with the aim of testing bi-specific antibodies in clinical use that otherwise cannot be tested against mouse cells. In these models we are reproducing the process of acquired refractoriness to BCMAxCD3 and GPRC5D agents, drugs that represent a breakthrough in MM therapeutics. However, despite encouraging data in clinical trials, most patients develop resistance and relapse. Therefore, we need to define the mechanistic basis of such therapeutic refractoriness and discover novel approaches to by-pass and defeat the acquired resistant state. This is the major goal of the current proposal. We envisage that our integrative approach using high-throughput RNA and DNA technologies at single-cell level in tumor and BM immune cells in both experimental and clinical samples will provide unprecedented results in field of MM acquired resistance to BCMA and GPRC5D targeted therapies. We expect that the proof-of-concept data generated will establish the scientific rationale to translating novel therapeutics overcoming the refractory state to the next clinical trials, which may eventually lead to the cure of MM.