Abstract 5443: Modulating plasticity in aggressive variant prostate cancers

Abstract

Abstract Aggressive Variant Prostate Cancers (AVPC) are a clinically and molecularly distinct subset of prostate cancers with a poor prognosis characterized by androgen-indifference, platinum-sensitivity and combined defects in Tp53, RB1 and PTEN, for which novel therapeutic approaches are urgently needed. Defects observed in these tumor suppressor pathways have been linked to lineage plasticity in genetically engineered mouse models. We hypothesized that this plasticity can be identified in human tumor samples, and can be modulated to serve as the foundation for effective combination therapies for the AVPC subset. We previously defined a gene expression signature derived from mouse embryonic day 6.5 that is representative of extensive cellular plasticity (PMID:26123483). We determined the plasticity scores in 12 patient-derived xenograft (PDX) models representative of the spectrum of prostate cancer biology (using available RNA sequencing profiles), and in 26 macrodissected tumor biopsies obtained from patients who received platinum-based chemotherapy for aggressive prostate cancer (using ALMAC Affymetrix gene expression microarray). As expected, the AVPC PDX models exhibited high plasticity scores as did 11 (42.3%) of the patient samples, associated with patient progression free- and overall survival. We next treated a well characterized AVPC PDX model (144-4) with the anti-EMT drug (p38MAPK inhibitor) SB203580 at 10mg/kg, and observed a decrease in stem-cell and EMT factors associated with plasticity. These data confirm the association between plasticity and AVPC in human tumor samples, and suggest that changes in plasticity can be measured in tumor samples to determine the value of its modulation in clinical trials. Acknowledgments: ALMAC Diagnostics Services, UK, and UTMDACC ATGC Core Lab (CCSG-CA016672-ATGC) for RNA sequencing services; UTMDACC Prostate Cancer SPORE (RS, SAM, AA), UTMDACC IRG (RS), and the UTMDACC Prostate Cancer Moonshot Program (AA) for financial support. Citation Format: Rama Soundararajan, Petra den Hollander, Peter Shepherd, Nora Navone, Daniele Lorenzini, Caddie Laberiano-Fernandez, Wei Lu, Jianling Zhou, Jingjing Liu, Jianhua Zhang, Luisa Maren Solis-Soto, Sendurai A. Mani, Ana Aparicio. Modulating plasticity in aggressive variant prostate cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5443.