Pd14-04 Bladder Cancer CTC-PDX Model Systems Platform for Discovering Druggable Molecular Pathways to Overcome Cisplatin-Based Therapy Resistance

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II (PD14)1 May 2024PD14-04 BLADDER CANCER CTC-PDX MODEL SYSTEMS PLATFORM FOR DISCOVERING DRUGGABLE MOLECULAR PATHWAYS TO OVERCOME CISPLATIN-BASED THERAPY RESISTANCE Spyridon P. Basourakos, Vijayakumar Jawalagatti, Grant Henning, Kirthika Perumalraja, Abhinav Khanna, Vidit Sharma, Matthew Tollefson, Paras Shah, Jeffrey Karnes, Veronica Rodriguez-Bravo, Stephen Boorjian, and Josep Doming-Domenech Spyridon P. BasourakosSpyridon P. Basourakos , Vijayakumar JawalagattiVijayakumar Jawalagatti , Grant HenningGrant Henning , Kirthika PerumalrajaKirthika Perumalraja , Abhinav KhannaAbhinav Khanna , Vidit SharmaVidit Sharma , Matthew TollefsonMatthew Tollefson , Paras ShahParas Shah , Jeffrey KarnesJeffrey Karnes , Veronica Rodriguez-BravoVeronica Rodriguez-Bravo , Stephen BoorjianStephen Boorjian , and Josep Doming-DomenechJosep Doming-Domenech View All Author Informationhttps://doi.org/10.1097/01.JU.0001009472.76470.8c.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cisplatin-based chemotherapy represents a mainstay of treatment for advanced bladder cancer (BCa). However, most patients progress, and prognosis remains guarded. Enhanced understanding of the pathogenesis of disease, in particular through human model systems, may recapitulate the evolution of the progression and thereby assist with the identification of targetable pathways for novel therapies. METHODS: We developed a disease platform to elucidate molecular mechanisms of cisplatin resistance which included 5 paired patient-derived xenograft (PDX) models from circulating tumor cells (CTC) isolated from peripheral blood of patients with metastatic BCa before cisplatin-based chemotherapy and after treatment progression. The CTC-PDX models were characterized by comprehensive genomic and molecular analysis. RESULTS: CTCs were successfully engrafted in immunocompromised mice, with an ∼30% engraftment rate for the initial passage and >90% when passaged serially. Notably, genomic and molecular characterization identified CTC-PDX models as luminal or basal sub-types, confirming maintained integrity of the molecular characteristics of human BCa. CTC-PDX models from pre-treatment and progressing tumors, respectively, recapitulated their sensitivity and resistance to cisplatin-based therapy. Through transcriptome profiling, we identified a consensus signature of cisplatin progression genes. Gene ontology analysis demonstrated that cellular proliferation, differentiation, and immune effector processes were the most deregulated categories after BCa progression on cisplatin-based therapy. Importantly, GSEA revealed that the cisplatin progression gene signature in BCa is significantly enriched in DNA damage and cell cycle progression signalling pathways (Figure 1). CONCLUSIONS: We generated a cohort of paired cisplatin sensitive and resistant CTC-PDX models displaying human BCa characteristics and identified a subset of biological processes that may contribute to cisplatin resistance. These model systems may serve as a powerful tool in discovering and evaluating novel targetable molecular pathways for BCa treatment. Download PPT Source of Funding: NIH/NCI © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e354 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Spyridon P. Basourakos More articles by this author Vijayakumar Jawalagatti More articles by this author Grant Henning More articles by this author Kirthika Perumalraja More articles by this author Abhinav Khanna More articles by this author Vidit Sharma More articles by this author Matthew Tollefson More articles by this author Paras Shah More articles by this author Jeffrey Karnes More articles by this author Veronica Rodriguez-Bravo More articles by this author Stephen Boorjian More articles by this author Josep Doming-Domenech More articles by this author Expand All Advertisement PDF downloadLoading ...