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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.

Prostate Cancer (PCa) is the most frequently diagnosed cancer in men and remains one of the leading causes of cancer death worldwide. It is a highly heterogenous and complex disease, presenting serious challenges to preclinical drug development and biomedical research. The normal development, growth and function of the prostate and most of its malignancies are under androgen regulation. However, after initiation of androgen deprivation therapy (ADT), most patients progress to intractable castration-resistant PCa (CRPC) within 2 to 3 years. Therefore, understanding the mechanisms of resistance that cause PCa to progress to a castration-resistance stage is the key to developing future beneficial therapies. Patient Derived Xenografts (PDX) mouse models show greater fidelity to the disease than any other in vivo models in terms of histopathologic, genomic and metastatic features, facilitating the translation of preclinical results into the clinical setting. However, PCa PDXs have been challenging to develop and a major limitation in PCa research is the lack of relevant preclinical models. The development of PCa PDX models is a mandatory requirement to explore new treatments targeting castration-resistant tumor cells and to improve anti-androgen therapies. To overcome the limitations of the number of relevant available models, in the framework of the MATCH-R clinical trial, which enrolls patients with oncogene-driven cancer who had previously responded to targeted therapy and subsequently experienced disease progression, XenTech and Gustave Roussy Institute are collaborating to develop a panel of extensively characterized PCa PDX models. Using biopsy material from metastatic lesions implanted into the sub-renal capsule of NSG mice, we report the successful establishment of 8 advanced PCa PDX models. All PDX models are characterized at the molecular level by whole exome sequencing and RNA-sequencing. Their response to physical castration and to the androgen receptor inhibitor enzalutamide is compared to the response observed in patients. This collection of PCa PDX models will be a useful preclinical tool to identify pivotal mechanisms underlying acquired resistance to current targeted therapies and develop novel treatment strategies. Citation Format: Olivier Deas, Ludovic Bigot, Emilie Dassé, Fabrice André, Jean Charles Soria, Benjamin Besse, Stefano Cairo, Marie Tavernier, Katell Mevel, Enora Le Ven, Luc Friboulet, Jean Gabriel Judde, Yohan Loriot. Establishment, molecular and pharmacological profiling of novel prostate cancer-derived xenografts from patients with advanced, treatment-refractory, disease to identify resistance mechanisms and new therapeutic options [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1929.

The last 20 years have witnessed the identification of an increasing number of actionable oncogenic drivers and the development and clinical use of specific inhibitors against these targets. Unfortunately, patients treated with targeted therapies consistently develop resistance and progression under treatment. Hence, important scientific, pharmaceutical and medical research efforts are directed towards understanding the mechanisms of acquired resistance to explore new therapeutic pathways. The MATCH-R clinical trial enrolls patients with oncogene-driven cancer who have had previous clinical response to targeted therapy and subsequently experienced disease progression. In the framework of this project, Gustave Roussy and XenTech are joining forces to develop a panel of patient-derived xenografts (PDXs) derived from biopsies collected from these patients at the stage of acquired resistance. These PDX models will be fully characterized at molecular and pharmacological level and used to improve knowledge on the mechanisms underlying resistance to treatment and to evaluate response to new treatments. In this perspective, the development of 75 PDX-AR (Acquired Resistance) models is planned over 3 years. All the models are maintained under the same therapeutic pressure the parental tumor was submitted to at the time of biopsy, and will be subjected to extensive phenotypic and genotypic characterization. To favor successful xenograft establishment, the first two passages are performed without drug treatment, which is applied from the third passage on. When doing so, we observed 3 types of response: some models showed resistance from the first passage under treatment, some showed stabilization under treatment at the first passages and rapidly acquired resistance over passages, and others showed sensitivity to treatment, whereas the patient tumor showed progression under the same treatment. These different behaviors might be due to different mechanisms of resistance, irreversible for the former, reversible for the two latter, as well as to suboptimal correlation of the clinical dose with the one used in mice. An example of such discrepancies has been found in two models of NSCLC PDX obtained from two metastases from a patient treated by a ROS1 and ALK inhibitor. While LCx-MR135PD2-AR PDX does not respond to the treatment, the LCx-MR135PD1 model is highly sensitive. As both metastases were progressing under treatment in the patient, molecular and pharmacological comparative analysis of these two models will investigate these discrepancy and provide important insights into the mechanisms of resistance to such inhibitors. Overall, the MatchR PDX project will provide a unique preclinical platform to identify resistance mechanisms to current targeted therapies and to develop next generation therapeutic strategies. Citation Format: Olivier Déas, Ludovic Bigot, Emilie Dasse, Guillaume Lang, Yohann Loriot, Fabrice Andre, Jean-Charles Soria, Benjamin Besse, Stefano Cairo, Marie Tavernier, Katell Mevel, Enora Le Ven, Jean-Gabriel Judde, Luc Friboulet. Generation of a fully characterized preclinical PDX panel to accelerate the identification of next generation treatments for patients with acquired resistance to targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2122.

The last 20 years have witnessed the identification of an increasing number of druggable oncogenic drivers and the development and clinical use of specific inhibitors against these targets. Unfortunately, patients treated with targeted therapies consistently develop resistance and progression under treatment. Hence, important scientific, pharmaceutical and medical research efforts are directed towards understanding the mechanisms of acquired resistance to explore new therapeutic pathways. The MATCH-R clinical trial enrolls patients with oncogene-driven cancer who have had previous clinical response to targeted therapy and subsequently experienced disease progression. In the framework of this project, Gustave Roussy and XenTech are joining forces to develop a panel of patient-derived xenografts (PDXs) derived from biopsies collected from these patients at the stage of acquired resistance. These PDX models will be used to improve knowledge on the mechanisms underlying resistance to treatment and to evaluate response to new treatments. In this perspective, the development of 75 PDX-AR (Active Resistance) models is planned over 3 years. All the models are maintained under the same therapeutic pressure the parental tumor was submitted to at the time of biopsy, and will be subjected to extensive phenotypic and genotypic characterization. The following models have been established so far: • ENDx-MR-004-AR (endometrial): resistant to the combination of MEK and MDM2 inhibitors; • LCx-MR-007-AR: (NSCLC): resistant to third generation EGFR inhibitor (osimertinib); • UREx-MR-015A-AR (ureter) and VEx-MR-086A-AR (bladder): resistant to a FGFR inhibitor (erdafitinib); • PARx-MR-010-AR (parotid): resistant to a NOTCH Inhibitor; • TCx-MR-122-AR (colon): resistant to an ATR inhibitor. To favor successful xenograft establishment, the first two passages were performed without drug treatment, which was applied from the third passage on. When doing so, some models showed resistance from the first passage under treatment, whereas others showed stabilization under treatment at the first passages and rapidly acquired resistance over passages. These different behaviors might underlie different mechanisms of resistance, irreversible (monoclonal) for the former, reversible (polyclonal) for the latter. Parallel to the development of UREx-MR-015A-AR, we developed the UREx-MR-015B-SD (stable disease) model from a biopsy collected from a different metastasis in the same patient, but stabilized by the therapy. Comparative analysis of these two models will provide important insights into the mechanisms of resistance to FGFR inhibitors. The MATCH-R PDX project will provide a unique preclinical platform for identifying resistance mechanisms to current targeted therapies and developing next generation therapeutic strategies. Citation Format: Olivier Déas, Ludovic Bigot, Guillaume Lang, Yohann Loriot, Fabrice Andre, Jean Charles Soria, Benjamin Besse, Stefano Cairo, Marie Tavernier, Katell Mevel, Enora Le Ven, Jean-Gabriel Judde, Luc Friboulet. Development of preclinical models to accelerate the identification of next generation treatments for patients with acquired resistance to targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2147.

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Lung emphysema and fibrosis are severe complications of chronic obstructive pulmonary disease, and uncontrolled protease activation may be involved in the pathogenesis. Using experimental elastase-induced acute inflammation, we demonstrate here that inflammation and development of emphysema is IL-1R1 and Toll/IL-1R signal transduction adaptor MyD88 dependent; however, TLR recognition is dispensable in this model. Elastase induces IL-1β, TNF-α, keratinocyte-derived chemokine, and IL-6 secretion and neutrophil recruitment in the lung, which is drastically reduced in the absence of IL-1R1 or MyD88. Further, tissue destruction with emphysema and fibrosis is attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Specific blockade of IL-1 by IL-1R antagonist diminishes acute inflammation and emphysema. Finally, IL-1β production and inflammation are reduced in mice deficient for the NALP3 inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and we identified uric acid, which is produced upon elastase-induced lung injury, as an activator of the NALP3/ASC inflammasome. In conclusion, elastase-mediated lung pathology depends on inflammasome activation with IL-1β production. IL-1β therefore represents a critical mediator and a possible therapeutic target of lung inflammation leading to emphysema.