Title: Identification and therapeutic targeting of proteostatic and metabolic vulnerabilities in multiple myeloma
Funder: Cancer Research UK

Abstract: BACKGROUND. Multiple myeloma (MM) is one of the most common bone marrow cancers. Proteasome inhibitors (PIs), which disrupt controlled intracellular protein degradation, form the backbone of MM treatment regimens used at diagnosis and at relapse and have contributed to improved outcomes. However, PI resistance is a major clinical problem, and our understanding of underlying resistance mechanisms is limited, partly because the mechanisms of action of PIs are not well established. In particular, effects of PIs on intracellular amino acid (AA) pools and on MM cell metabolism remain remarkably under- researched. It also remains largely unknown how microenvironmental nutrient limitations and mechanical stroma-tumour cell interactions, well-established determinants of solid cancer biology, regulate how MM cells respond to MM drugs. Here, I will address these gaps in our understanding of MMC and PI biology, with the aim of developing therapeutic approaches that overcome PI resistance. AIMS. I propose to address three questions based on the hypothesis that AA homeostasis and metabolic rewiring are central to MM biology and PI resistance. (1) What are the mechanisms that allow MM cells to recover from PI-induced stress, and does recovery trigger vulnerabilities that can be exploited therapeutically? (2) Are MM cells addicted to pathways that sense and respond to AA pool alterations? (3) How does the mechanical and metabolic heterogeneity of MMC microenvironments regulate proteostatic and metabolic rewiring and drug sensitivity? METHODS. I will use a serial multiomics approach in PI-stressed MM cells to identify recovery-driven vulnerabilities and target those with genetic and pharmacological interventions. Additional metabolic and transcriptomic studies will be paired with conventional cell and molecular biology studies in cell lines and patient material, and computational approaches will be used to project experimental data onto clinical trial data sets. Moreover, I will use modifiable hydrogels and mouse xenografts as well as primary patient material to investigate environmental factors such as nutrient availability and mechanical signals on MM cells and PI effects. HOW THE RESULTS OF THE RESEARCH WILL BE USED. If successful, the studies will identify potential drugable vulnerabilities linked to PI-induced stress-recovery, redefine the mechanism of action of PIs, pave the way for the development of a new class of MM drugs, and advance our understanding of how MMC biology is shaped by their environment.

Lay abstract: BACKGROUND. Multiple myeloma (MM) is one of the most common bone marrow cancers. Proteasome inhibitors (PIs), which disrupt controlled intracellular protein degradation, form the backbone of MM treatment regimens used at diagnosis and at relapse and have contributed to improved outcomes. However, PI resistance is a major clinical problem, and our understanding of underlying resistance mechanisms is limited, partly because the mechanisms of action of PIs are not well established. In particular, effects of PIs on intracellular amino acid (AA) pools and on MM cell metabolism remain remarkably under- researched. It also remains largely unknown how microenvironmental nutrient limitations and mechanical stroma-tumour cell interactions, well-established determinants of solid cancer biology, regulate how MM cells respond to MM drugs. Here, I will address these gaps in our understanding of MMC and PI biology, with the aim of developing therapeutic approaches that overcome PI resistance. AIMS. I propose to address three questions based on the hypothesis that AA homeostasis and metabolic rewiring are central to MM biology and PI resistance. (1) What are the mechanisms that allow MM cells to recover from PI-induced stress, and does recovery trigger vulnerabilities that can be exploited therapeutically? (2) Are MM cells addicted to pathways that sense and respond to AA pool alterations? (3) How does the mechanical and metabolic heterogeneity of MMC microenvironments regulate proteostatic and metabolic rewiring and drug sensitivity? METHODS. I will use a serial multiomics approach in PI-stressed MM cells to identify recovery-driven vulnerabilities and target those with genetic and pharmacological interventions. Additional metabolic and transcriptomic studies will be paired with conventional cell and molecular biology studies in cell lines and patient material, and computational approaches will be used to project experimental data onto clinical trial data sets. Moreover, I will use modifiable hydrogels and mouse xenografts as well as primary patient material to investigate environmental factors such as nutrient availability and mechanical signals on MM cells and PI effects. HOW THE RESULTS OF THE RESEARCH WILL BE USED. If successful, the studies will identify potential drugable vulnerabilities linked to PI-induced stress-recovery, redefine the mechanism of action of PIs, pave the way for the development of a new class of MM drugs, and advance our understanding of how MMC biology is shaped by their environment.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS