Proteogenomic studies aimed at understanding ovarian tumor responses to agents targeting the DNA damage response and translating this knowledge into clinical benefit

项目总结/文摘

Project Summary/Abstract Epithelial ovarian cancer (EOC), the most lethal gynecological malignancy, is diagnosed in more than 225,000 women worldwide each year, with most patients presenting with advanced-stage, high-grade serous ovarian cancers (HGSOC). Despite improvements in surgical and chemotherapeutic approaches, overall mor- tality has not changed significantly for decades. Standard of care involves surgical debulking plus adju- vant/neoadjuvant combination chemotherapy with platinum compounds and taxanes. Platinum compounds damage DNA by inducing intra- and inter-strand cross-links (ICL) between purine ba- ses. ICL repair depends on both Fanconi anemia and BRCA proteins, which are required for homologous re- combination. EOC is one of the most chemo-sensitive epithelial tumors, with initial response rates of ~75% to platinum-based chemotherapy. The striking platinum sensitivity of EOC tumors is thought to be related to their HRD. Unfortunately, 80-90% of patients suffer relapse and develop drug-resistant disease. Moreover, ~20% of patients have platinum-refractory disease at diagnosis. Thus, there are crucial unmet clinical needs for methods to predict platinum responsiveness of EOCs, and for treatments that can be used either alone or in combination with platinum compounds to overcome resistance. The goals of our PTRC are to enhance our ability to predict which EOCs will respond to DNA-damaging platinum therapy, to understand mechanisms of resistance, and to identify potential new drug targets in resistant disease to point to desperately-needed new therapeutic approaches for these patients. Our Proteogenomic Translational Research Center will perform proteo-genomic analyses of EOC preclini- cal models (patient-derived xenografts and cell lines) pre- and post-treatment with platinum to add to and help prioritize potential predictive protein targets of platinum response that have been implicated in the literature. In our Clinical Arm, we will use targeted multiple reaction monitoring (MRM) mass spectrometry-based assays to quantify potential predictive protein targets in tumor specimens obtained through NCI-funded trials, to test their association with response to therapy. In addition, there is an imperfect and incompletely understood overlap in tumor responses between platinum and PARP inhibitors (PARPi); thus, in an exploratory sub-aim, we will de- termine which proteogenomic correlates of platinum response are also associated with response to PARPi (e.g. based on underlying defects in homologous recombination (HR)-mediated DNA repair).