The following is the project summary/abstract from the parent application. See Research Strategy for details on the administrative supplement activities. 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 adjuvant/neo- adjuvant 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 meth- ods to predict platinum responsiveness of EOCs, and for treatments that can be used either alone or in combi- nation 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 preclinical models (patient-derived xenografts and cell lines) pre- and post-treatment with platinum to add to and help pri- oritize 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 quan- tify potential predictive protein targets in tumor specimens obtained through NCI-funded trials, to test their asso- ciation 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 determine 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).
The following is the project narrative from the parent application. See Research Strategy for details on the ad- ministrative supplement activities. Ovarian cancer, the most lethal gynecological malignancy, is diagnosed in more than 225,000 women worldwide each year. Despite improvements in surgical and chemotherapy approaches, overall survival has not changed significantly for decades, due to the presence of drug-resistant cancer cells that enable tumor progression. Our project brings together an interdisciplinary team of ovarian cancer doctors and translational research experts to use novel approaches to understand how drug resistance develops in ovarian cancer, and to discover new ther- apies to overcome resistance.
| Whiteaker, Jeffrey R; Zhao, Lei; Ivey, Richard G et al. (2018) Targeted mass spectrometry enables robust quantification of FANCD2 mono-ubiquitination in response to DNA damage. DNA Repair (Amst) 65:47-53 |
| Collins, Christopher J; Chang, Irene J; Jung, Sunhee et al. (2018) Rapid Multiplexed Proteomic Screening for Primary Immunodeficiency Disorders From Dried Blood Spots. Front Immunol 9:2756 |
| Salter, Alexander I; Ivey, Richard G; Kennedy, Jacob J et al. (2018) Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. Sci Signal 11: |
| Whiteaker, Jeffrey R; Zhao, Lei; Saul, Rick et al. (2018) A Multiplexed Mass Spectrometry-Based Assay for Robust Quantification of Phosphosignaling in Response to DNA Damage. Radiat Res 189:505-518 |
