Abstract 1114: Novel preclinical models of aggressive variants of castration-resistant prostate cancer
Authors: Bigot Ludovic , Sabio Jonathan , Ibrahim Tony , Menssouri Naoual , poiraudeau Loic , Helissey Carole , Scoazec Jean-Yves , Merabet Zahira , De Baere Thierry , Deschamps Frederic , Ngocamus Maud , Nicotra Claudio , Rouleau Etienne , Lacroix Ludovic , Deas Olivier , Friboulet Luc , Vassal Gilles , Solary Eric , Soria Jean-Charles , Fizazi Karim , André Fabrice , Massard Christophe , Besse Benjamin , Loriot Yohann 
Published: September 2020

Abstract
Background: Recent advances in the biology of prostate cancer have identified aggressive variants of metastatic castration-resistant prostate cancer [mCRPC] (e.g, CRPC with neuroendocrine (NE) features, or microsatellite instability [MSI], or BRCA2 mutations). However, few preclinical models have been successfully established to study these aggressive mCRPC variants owing to their historically low establishment success and to the difficulty in accessing such clinical samples
Methods: Fresh tumor biopsy specimens were obtained prospectively from patients with mCRPC through a prospective single-institution clinical trial (MATCH-R, NCT02517892). Patient-derived xenografts (PDX) in NOD Scid Gamma mice were developed and characterized as well as PDX-derived organoids derived from the same PDX (PDXO). Whole-exome sequencing, RNA sequencing and immunohistochemistry were performed on human samples and their corresponding PDX and PDXO. The primary aim was to successfully derive PDX and PDXO models reproducing the clinical features of mCRPC aggressive variants.
Results: As of November 2019, 83 tumor biopsies were obtained from 61 mCRPC patients, 16 biopsies from 13 patients were successfully engrafted with an overall success rate of 26% (16/61). In addition, 16 PDXO were developed with a success rate of 100%. Overall, we developed 4 PDX and 4 PDXO from 2 patients with germline BRCA2 mutation, 2 PDX and 2 PDXO from 1 patient with MSI-high CPRC, 10 PDX and 6 PDXO from 10 patients with NE mCPRC. Molecular profiling revealed a high concordance between PDX, PDXO and human tumor samples for histological phenotype, driver mutations and transcriptomic phenotypes. The two models harbouring BRCA2 mutation were highly sensitive to both carboplatin and olaparib (in PDX and PDXO) reflecting the clinical scenario observed in the patients. BRCA2-mutated PDX models were treated in vivo to derive olaparib-resistant mCRPC models. Genetic analysis identified secondary mutations restoring the reading-frame of the gene which reversed the sensitivity of the PDX to carboplatin and olaparib. Preclinical models derived from mCRPC with NE features (including the case of small cell carcinoma) globally reproduced the clinical patterns seen in human samples. Results from high-throughput organoid drug screening suggest good concordance with patients clinical response
Conclusion: The study demonstrated the feasibility of establishing preclinical models (PDX and PDXO) derived from aggressive mCRPC variants. Overall, our models reproduce the phenotypic, molecular and pharmacological characteristics of their initial human samples and may represent a unique preclinical platform modeling BRCA2 mutated, MSI and neuroendocrine prostate cancers.
Citation Format: Ludovic Bigot, Jonathan Sabio, Tony Ibrahim, Naoual Menssouri, Loic poiraudeau, Carole Helissey, Jean-Yves Scoazec, Zahira Merabet, Thierry De Baere, Frederic Deschamps, Maud Ngocamus, Claudio Nicotra, Etienne Rouleau, Ludovic Lacroix, Olivier Deas, Luc Friboulet, Gilles Vassal, Eric Solary, Jean-Charles Soria, Karim Fizazi, Fabrice André, Christophe Massard, Benjamin Besse, Yohann Loriot. Novel preclinical models of aggressive variants of castration-resistant prostate cancer [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 1114.