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(searched for: Generation and Characterization of A Carboplatin Resistant Ovarian Cancer Model)
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Noor Shakfa, Elizabeth Lightbody, Afrakoma Afriyie-Asante, Vinicius Kannen, Madhuri Koti
Poster Presentations - Proffered Abstracts, Volume 26; doi:10.1158/1557-3265.ovca19-b78

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Shalini N Swamy, Sandeep Kumar S, Devaraj Vr, Ramesh Gawari
Journal of Cancer Science and Clinical Therapeutics, Volume 4, pp 144-153; doi:10.26502/jcsct.5079060

Abstract:
Acquisition of drug resistance is one of the major hurdles in the treatment of several cancers including ovarian carcinoma. There exist very few models that aid in understanding the mechanism of drug resistance in cancer cells. Carboplatin is administered as a first line chemotherapeutic drug in the treatment of ovarian cancer. Majority of ovarian cancer patients respond well to chemotherapy in the initial stages, but 60-70% report recurrence post therapy. The underlying molecular mechanisms contributing to resistance to therapy remain elusive. Establishing a clinically relevant in vitro tumor model that could closely mimic the drug resistance pattern in the patient would provide an opportunity to understand drug resistance. The present study focuses on generating a clinically relevant drug resistant model of ovarian cancer.
Published: 15 December 2019
Abstract:
Purpose - There remains an unmet need for preclinical models to enable personalized therapy for ovarian cancer (OC) patients. Recently, patient-derived organoid (PDO) cultures of patients with OC have been established that faithfully represent the histopathological features and genomic landscape of the patient tumor. In this study, we evaluate the capacity of OC PDOs to predict clinical drug response and functional consequences of tumor heterogeneity. Experimental design - 36 genomically characterized PDOs from 23 patients with known clinical histories were exposed to chemotherapeutics and targeted drugs. Results - OC PDOs maintained genomic features of the original tumor lesion and recapitulated patient response to neoadjuvant carboplatin and paclitaxel combination treatment, according to distinct clinical outcomes (histopathological, biochemical and radiological). PDOs displayed inter- as well as intrapatient drug response heterogeneity, which could in part be explained by genetic aberrations. All PDOs were resistant to PARP-inhibitors, in accordance with homologous recombination pathway fidelity and genome-wide mutation context. KRAS, BRAF and NRAS mutation status predicted response to BRAF-inhibitor vemurafenib and pan-HER-inhibitor afatinib, and explained differential response among four PDOs derived from distinct tumor locations of an individual patient. Importantly, PDO drug screening identified sensitivity to at least one drug for the majority of patients (88%). Conclusions - OC PDOs are a valuable preclinical model system that can provide insights in drug response for individual patients with OC, complementary to genetic testing. Generating PDOs of multiple tumor locations can improve clinical decision making and increase our knowledge on genetic and drug response heterogeneity.
Yasuto Kinose, Dorothy Hallberg, Kai Doberstein, Gordon Mills, Tan Ince, Victor Velculescu, Fiona Simpkins, Ronny Drapkin
Tumor Biology, Volume 79, pp 1065-1065; doi:10.1158/1538-7445.sabcs18-1065

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Joseph I. Hoare, Jayeta Saxena, Helen Hockings, Jackie McDermott, Ashley Browne, Michelle Lockley
Abstracts: AACR Special Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; October 1-4, 2017; Pittsburgh, PA, Volume 24; doi:10.1158/1557-3265.ovca17-a54

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