Abstract 4677: A preclinical platform of breast cancer PDX and derived cellular models as a tool for pharmacological screening and functional studies

Abstract

Abstract Despite considerable progress in understanding the biology and genetics of breast cancer, the development of effective therapies needs physiological and predictive preclinical models. In this context, breast cancer (BC) patient-derived xenograft (PDX) models have become a standard tool as they reproduce the biology of tumors of origin, in term of histology, genotype and response to chemotherapy. They have proven their relevance in the study of pathways leading to the development and progression of cancer, to the mechanisms linked to tumor resistance and to the identification of novel effective therapies. We present a preclinical platform of over 60 fully characterized BC PDX models and their in vitro cell derivatives for preclinical evaluation of new treatment modalities. Our platform consists of a PDX collection of 43 TNBC, 6 ER+, 4 HER2+, 6 Luminal B models (ER+ HER2+) and 14 cellular models derived from these PDXs, representing the variety of BC. PDX models were obtained by transplantation of post-surgery tumor specimens either by grafting of tumor fragments in the interscapular region of nude mice or by injection of tumor cells into the fat pad of NOD-Scid mice. Molecular analyses were done included gene expression, gene copy number, whole exome sequencing and IHC markers staining. In vivo drug efficacy assays were performed with standards of care as single agent or in combinations. This PDX panel mostly reflects the molecular heterogeneity of breast cancer and reproduce accurately the molecular and drug response profile of human tumors. It provides an invaluable tool for translational research. It is widely used to performed standard drug evaluation but also “Mouse Clinical Trials” (MCT) in vivo screens to provide more predictive preclinical data on single-agent or combination drug efficacy. Engrafted on highly immunodeficient mice humanized with human PBMCs or CD34+ cells, these PDX models allow bispecific T-Cell engager antibody testing or immune-checkpoint inhibitors evaluation. In addition to these PDX panel, we derived cellular models (PDXDCs) to offer a time- and cost-effective preclinical screening tool. PDXDCs were obtained from dissociated PDX tumors cultured under different media and matrix conditions. They were characterized by comparison with the parental PDX by Short Tandem Repeat (STR) profiling before performing a master bank. WES and RNASeq molecular analyses were done and in vitro drug sensitivity was compared with their parental PDX in vivo drug response. Overall, the results show that this PDXDC panel reproduced in vitro the in vivo drug response profile of the original PDXs with various therapies. This BC PDX panel and in vitro cell derivatives provide a powerful preclinical platform to improve our knowledge on BC biology and to rapidly evaluate response to new treatments and translate this knowledge to the clinic. Citation Format: Delphine Nicolle, Aurore Gorce, Marie Tavernier, Elisabetta Marangoni, Didier Decaudin, Christophe Ginestier, Emmanuelle Charafe-Jaufret, Judith Passildas, Nina Robin, Robert Clarke, Erwan Corcuff, Anaïs Joachim, Bernard Malissen, Ana Zarubica, Hervé Luche, Jean-Gabriel Judde, Olivier Déas. A preclinical platform of breast cancer PDX and derived cellular models as a tool for pharmacological screening and functional studies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4677.