2018 Early Career Investigator Grant Recipient — Sumegha Mitra, PhD
Project Summary
High-grade serous ovarian cancer (HGSOC) affects about 70-80% of ovarian cancer patients and is the most lethal ovarian cancer subtype. More than 96% of HGSOC patients have p53 mutations, which orchestrate a distinct pro-tumorigenic signaling network and confer chemo-resistance. Knowledge of common mechanisms or mediators of oncogenic signaling among different p53 mutants are critical for a better understanding of recurrent disease and identifying novel therapeutic targets. Our studies have demonstrated a heterogeneity in the expression and function of the deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) in the context of p53 mutations. UCHL1 overexpression was a common event in HGSOC patients and ovarian cancer cell lines harboring different p53 mutants. High UCHL1 levels were significantly associated with poor progression free survival of HGSOC patients (PRECOG z-score 2.66). Response to chemotherapy and median survival was better (>19 months) in HGSOC patients with low UCHL1 levels compared to those with high UCHL1 expression (p=0.001; GSE9891). However, the role of UCHL1 in mutant p53-mediated oncogenic signaling remains unknown. This study will allow us to investigate the underlying mechanism of UCHL1-mutant p53 axis in HGSOC progression. It can potentially impact a significant unmet need of therapeutic agents targeting mutant p53 signaling and would test the therapeutic potential of UCHL1 inhibitor in HGSOC progression.