Robert Rottapel, MD, FRCPC

My research program focuses on the translational aspects of the functional genetic landscape of high-grade ovarian cancer (HGSOC). We have performed extensive functional genetic “dropout” screens that use either shRNA or CRISPR-Cas9 technologies in 50 HGSOC cell line collection in our laboratory. These data provide a rich map that defines the set of essential genetic architecture of this tumour type. Identification of the essential genes required for survival and proliferation of cancer cell lines in competitive growth assays can identify new potential druggable targets. We have identified the tetraspan CD151 as an essential gene in HGSOC. CD151 is expressed in a high percentage of primary ovarian cancer tumors and is a biomarker of poor clinical outcome. We have demonstrated that HGSOC tumours are sensitive to the proteasome inhibitor bortezomib in tumours with excessive mTORC1 signaling as a result PTEN deletion. These studies pave the way for re-examination of the utility of proteasome inhibitors in PTEN-deficient HGSOC patients in clinical trials. We have identified a novel essential autocrine loop involving the Relaxin hormone and its cognate G-protein coupled receptor LGR7. Inhibition of Relaxin signaling synergizes potently with Cisplatin in in vitro and in vivo preclinical xenograft models of HGSOC. We have developed Relaxin-neutralizing antibodies which are directly cytotoxic to ovarian cancer cell lines and potentiate Cisplatin-induced cell death.