We hypothesize that tumor-immune microenvironment and macroenvironment alterations shape MM progression and treatment resistance. The problem is that the current understanding of immune resilience vs loss of function in MM is limited and, because of it, there are no immune biomarkers ready for primetime use in laboratory diagnostics. The consequence of this problem is that … Continued

The overarching objective of this proposal is to decipher the intricate molecular pathways, underlying myeloma-induced bone disease (MBD), a critical aspect of multiple myeloma pathogenesis. Employing state-of-the-art imaging, genomic and proteomic analyses, the proposal seeks to unravel the complex interplay between myeloma cells and the bone microenvironment. The objective of the proposal is to establish … Continued

Multiple Myeloma (MM) is marked by the clonal expansion of abnormal plasma cells (PCs) in the bone marrow. It is the second most common hematologic malignancy, predominantly affecting the elderly, men, and Non-Hispanic Black individuals. While current treatments often induce remission, MM remains incurable, relapsing and causing chronic organ damage and high healthcare costs. Thus, … Continued

Mitochondrial energetics and cellular metabolism play a central role in regulating T cell differentiation, fate and function. Heme (iron-protoporphyrin IX) is critical for maintaining mitochondrial electron transport chain (ETC) activity and oxidative phosphorylation (OXPHOS). Heme is taken up from the extrinsic environment in addition to being synthesized intracellularly. Our objective is to understand how heme … Continued

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 … Continued

This project aims to target the loss of the tumor suppressor TENT5C in multiple myeloma (MM). The primary goal is to investigate the effect of pathway-specific inhibitors in MM patients with biallelic TENT5C abnormalities. Additionally, the project seeks to identify novel synthetic lethality pathways associated with the loss of TENT5C in MM. Preliminary data suggest … Continued

This project aims to molecularly characterize and target Protein Kinase D2 (PRKD2) in t(4;14) multiple myeloma (MM), a high-risk subgroup of MM with poor outcomes. Specific aims include validating the functional role of PRKD2 in MM cells through transcriptomic and epigenomic studies, and evaluating the therapeutic potential of targeting PRKD2 and its downstream pathways using … Continued

This project aims to develop an optimized dual-targeted tandem VH-only fully-human CAR for the treatment of multiple myeloma, aiming to achieve durable remissions. Specific aims include analyzing factors associated with CAR T cell manufacturing success, predicting CAR T cell expansion post-infusion, correlating T cell composition with side effects, identifying markers for treatment response and resistance, … Continued

The project focuses on developing a novel CAR-T cell therapy aimed at treating multiple myeloma by utilizing advanced gene editing technologies to engineer a universal CAR-T cell product targeting SLAMF7 and BCMA. The approach involves strategic gene modifications to enhance the therapy’s compatibility and effectiveness while minimizing immune rejection and reducing the risk of adverse … Continued