Title: Exploiting recurrent chromosome copy number alteration (CNA)-driven defects in the treatment of Multiple Myeloma.
Funder: Cancer Research UK

Abstract: Background The genome of the incurable cancer multiple myeloma is characterised by recurrent copy number alterations (CNAs), indicating an underlying chromosome instability state. Certain CNAs confer poor outcomes in ‘high-risk’ patients (~20% cases), acting as more significant drivers than mutations; how they do this is largely unknown. Recurrence and clonal selection of particular CNAs in cancer indicate they harbour genes whose altered expression favours progression. Myeloma drugs cost a disproportionate fraction of cancer budgets. Currently, minimal precision targeting of combination therapies may means we over-treat some, but to date have failed to significantly improve outcomes for high-risk patients. Understanding the genetically-driven biological differences within this heterogeneous disease will enable better precision targeting of our increasing arsenal of therapies. This could not only support more sustainable therapeutic decision-making, but also improve outcomes in high-risk patients. I have previously identified and tracked CNAs that drive myeloma drug resistance. I have joined the Chapman group, who have identified that CNA 17q amplification imparts particular targetable vulnerabilities while also driving genome instability in cancer. My overarching aim is to identify such exploitable defects coupled to genome instability in myeloma, and how these may be tracked and targeted in patients. Aims: 1. To discover the responsible defect(s) that are synthetic lethal with centrosome depletion in myeloma, and identify the mechanistic basis for this effect. 2. To identify targetable vulnerabilities associated with 1q21 gain and the oncogenic properties it confers. 3. To track CNA-defined ‘high-risk’ subclones that expand with disease progression in patients, and determine associations with outcomes and subsequent genome instability. Methods 1. I will define myeloma responses to PLK4 inhibitor-mediated centrosome depletion. In myelomas hypersensitive to centrosome depletion, synergistic mitotic defects that propagate CIN will be identified by live cell imaging and CRISPR screening. 2. Genes specifically essential to 1q gain myelomas will be identified from published screens and validated using knockdowns +/-inhibitors. Targeted screens will identify which 1q gene(s) drive identified vulnerabilities. 3. Using 3 cohorts of sequential patient sample genetic sequencing data, I will perform computational analyses to track CNA-defined subclones, their genetic associations/dependencies, and their association with patient outcomes. How the results will be used Some CNAs drive high-risk myeloma. My results will define CNA-specific dysregulated biology that is associated with the poor outcomes we inadequately combat in high-risk myeloma. Concurrently developing strategies to track CNAs in patients will enable identification of groups who would benefit from therapies exploiting CNA-driven vulnerabilities.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS