MM_BH3_CutTag · Parallel epigenomic and apoptotic profiling to identify targetable sensitivities in Multiple Myeloma

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

Multiple Myeloma (MM) is an incurable disease with an extremely poor 10-year survival rate (~30%) (Cancer research UK, Survival for Myeloma). In 2022 in the EU alone, 22,000 people died of MM (European Cancer Information System Data Explorer). Over the last decade there have been several advances in MM treatment, such as the development of immunomodulators and proteasome inhibitors which have improved overall survival rates. However, MM remains incurable, as continuous treatment leads to the emergence of drug-resistant clones, eventually causing relapse. High levels of inter- and intra-patient genetic heterogeneity contribute to the failure of broadly targeted therapies. Therefore, it is imperative to generate novel, alternative strategies to treat this intractable disease that is specifically targeted at individual patients. BCL-2 is an anti-apoptotic protein that blocks cell death. Increased reliance on BCL-2 family proteins as well as altered epigenetic landscapes are mechanisms by which MM cells become resistant to drug treatment. Growing evidence across the field of oncology supports epigenetic regulation promoting cancer progression and treatment resistance. In fact, non-mutational epigenetic dysregulation is now considered an emerging hallmark of cancer. Therefore, a burgeoning opportunity for circumventing therapeutic resistance is through epigenetic drugs, particularly as there has been huge developments in the range of small molecule compounds targeting epigenetic regulatory proteins. The aims of this project are: 1) To establish a mechanism of epigenetic mapping (CUT&Tag), in combination with BH3 profiling (a technique to identify BCL-2 dependency profiles), that can be applied to primary MM patient samples in order to understand the basal epigenetic profile of BCL- 2 dependent MM. 2) Identify the basal landscape/distribution of inter- and intra-MM patient histone post-translational modifications (PTMs) using CUT&Tag 3) Assess sensitivity to epigenetic modifiers in patient MM samples, therefore identifying candidate drugs for future MM therapy. The significance of this project is to improve existing MM therapy (BCL-2 inhibition) by combining this treatment with epigenetic inhibitors that regulate different BCL-2 dependency profiles.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз