Parallel epigenomic and apoptotic profiling to identify targetable sensitivities in Multiple Myeloma

Objetivo

Multiple Myeloma (MM) is an incurable cancer caused by uncontrolled growth of the plasma cells. A major challenge is drug resistance, which is caused by increased reliance on the anti-apoptotic BCL-2 family proteins and altered epigenetic landscapes. Dependence is highly variable, with distinct dependencies on BCL-2 family members (MCL-1, BCL-2 & BCL-XL) across patient samples. It is currently not understood what causes heterogeneity of BCL2 dependence in MM, and thus exploiting this reliance for treatment has proved difficult. Epigenetic modifiers regulate apoptotic pathways and therefore represent a therapeutic avenue through which cells can be sensitized to BCL2-family inhibitor treatment. I will use the cutting-edge technology CUT&Tag to assess the epigenetic landscape of MM patient samples with diverse anti-apoptotic dependence. The key aim is to identify targetable epigenetic modifiers that can be combined with BCL2 inhibitors for more effective MM therapy. I have 3 main objectives for this proposal: 1) establish parallel CUT&Tag with BH3 profiling to understand the basal epigenetic profile of MCL-1/BCL-2/BCL-XL-dependent MM; 2) to identify inter- & intra-patient epigenetic profiles characteristic of sensitive/insensitive patient samples; 3) to assess MM sensitivity to epigenetic inhibitors, and I will apply this basic research to drug development during a 6-week secondment in Almac Discovery. This project will deliver vital information on mechanisms of drug insensitivity & therapeutic avenues to target epigenetic sensitivities in MM tumors. At this critical stage in my career, it is crucial that I further diversify my skillset and apply interdisciplinary tactics to my research questions. Winning the prestigious MSCA-PF will allow me to expand my skillset, gain inter-sectoral experience during secondment and foster key collaborations in clinical research. This is crucial to reach my ultimate career goal as an independent research expert in cancer epigenetics.