2018 Recipient Sumegha Mitra, PhD

Sumegha Mitra, PhD

UCHL1 Regulates Oncogenic Signaling in Ovarian Cancer

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.

Bio

Dr. Sumegha Mitra is an Assistant Professor in the Department of Obstetrics and Gynecology at Indiana University Purdue University Indianapolis (IUPUI). Dr. Mitra completed her Ph.D. from University of Mumbai, India and was an Indian Council of Medical Research fellow. She joined the University of Chicago for her postdoctoral studies in Dr. Joe G. N. Garcia’s laboratory. She studied the mechanistic role of K63-specific ubiquitination in the activation of Akt signaling under mechanical stress. Subsequently, she completed her postdoctoral studies in Garcia lab at the University at Illinois (UIC) at Chicago. She was awarded with UIC Campus Research Board pilot grant. Currently, she studies the role ubiquitin signaling in ovarian cancer progression. Several components of ubiquitin proteasome system play a key role in mediating cancer signaling and are implicated as oncogenes or tumor suppressors. She also investigates the functional role of small-molecule inhibitors from ubiquitin proteasome system as adjuvant therapy for ovarian cancer. Her research is supported by Biomedical Research Grant from Indiana University School of Medicine and Ralph W. and Grace M. Showalter Research Trust.