Supervisor View Full Details 2nd

• cancer/oncology

• Medicine

• Haematology
• Oncology

Multiple Myeloma (MM) is characterised by the clonal proliferation of plasma cells and excess production of non-functional immunoglobulins, making this malignancy particularly vulnerable to interference with protein handling pathways. The ubiquitin proteasome pathway (UPP) is at the core of cellular protein homeostasis and strategies targeting both specific and bulk protein degradation through this pathway, using IMiDs and proteasome inhibitors, form the backbone of MM therapy. While these therapies have contributed to improved survival rates, emergence of resistance to all currently available therapies is a major clinical challenge. The major focus of our lab is to explore the molecular mechanisms involved in dysregulation of the ubiquitin proteasome system in MM, particularly E3 ligases, and apply this knowledge to identify novel therapeutic opportunities to augment the efficacy or overcome resistance to current therapies. Using a combination of genomic and proteomic approaches, we are currently investigating the role of two E3 ligases in promoting increased genomic instability in MM and exploring strategies to therapeutically exploit related vulnerabilities in specific patient subgroups.

HUWE1 is a large HECT domain E3 ligase that regulates a number of proteins involved in oncogenic transformation, including MYC and MCL-1. We and others have identified dysregulated expression of HUWE1 in MM, with a significant increase in expression observed across plasma cell dyscrasias and mutations identified in a proportion of patients with the t(11;14) translocation. Our group has demonstrated that inhibition of HUWE1 is effective at blocking MM cell growth in vitro and in vivo, and shown that HUWE1 depletion induces MYC degradation in cell line models and patient-derived MM cells. Genomic instability is a key feature of MM, linked to both development and progression of the disease. HUWE1 and MYC are both implicated in the regulation of genomic stability through their involvement in replicative stress and DNA damage responses and preliminary studies in our lab demonstrate that MM patients and cell lines expressing HUWE1 mutations exhibit increased genomic instability. Using state-of-the-art proteomics and genomics and in vitro models reflecting the spectrum of clinical mutations observed, this project seeks to further delineate the role of HUWE1 in regulating genomic stability, to understand the functional consequences of HUWE1 mutations in MM and to explore the potential of therapeutically targeting associated vulnerabilities to overcome resistance and enhance existing therapies.