Prof Adrian Mariño, UCD School of Medicine, St Vincent’s University Hospital

Genomic complexity as a therapeutic vulnerability in leiomyosarcoma

Leiomyosarcomas (LMS) are aggressive cancers with a median overall survival of ~2 years for metastatic patients. Most LMS have complex genomes with abundant copy number and structural genomic aberrations that result from chromosomal instability (CIN). To maintain cell viability, CIN and genotoxic damage must be constrained by DNA damage repair mechanisms, which include homologous recombination and non-homologous end joining (NHEJ). Overlapping defects in these partially redundant repair mechanisms result in cell death.

Mutational signature analyses demonstrate that homologous recombination defects (HRD) are very prevalent in LMS, while functional genomic screens confirm the extreme dependence of LMS cells on NHEJ. These genomic features provide compelling therapeutic opportunities with DNA damage repair-targeting compounds, such as PARPi and DNA PKi. Clinical trials based on our group’s work are ongoing to test the efficacy of these agents against LMS.

Biography

(opens in a new window) Dr Adrian Mariño is a physician-scientist with expertise in histopathology, molecular pathology, and genomics. His research is focused on discovering clinically useful diagnostic markers and therapeutic targets in sarcoma, using structural and functional genomic approaches. His clinical work involves the identification of clinically actionable molecular alterations to optimise management of cancer patients.