Abstract 2998: Targeting resistance mechanisms in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model

Abstract

Abstract Introduction: Non-metastatic muscle invasive urothelial bladder cancer (MIBC) has a poor prognosis and standard of care (SOC) consists of neoadjuvant cisplatin-based chemotherapy (NAC) combined with cystectomy. Patients receiving SOC have at best <10% improvement in five-year overall survival. Residual invasive cancer following NAC has no SOC and has high mortality risk. This major clinical problem underscores gaps in our understanding resistance mechanisms and a need for reliable pre-clinical models. The chicken embryo chorioallantoic membrane (CAM) represents a rapid, scalable, and cost-effective alternative in vivo patient-derived xenograft (PDX) platform. It leverages an easily accessible engraftment scaffold and vascular-rich, immunosuppressed environments for the engraftment of PDX tumors and subsequent functional studies. Our previous proteogenomic data on MIBCs with known chemo-resistant outcomes obtained prior to NAC (pre-NAC) suggests a benefit from treatment with kinase inhibitors (KI). Use of the CAM model in this study aims to address the MIBC pre-clinical model deficit and allow for the rapid screening of therapeutics against NAC-resistant PDXs using selected KI. Methods: We employed the CAM model to expand primary MIBC tumors and tested concordance between cisplatin-based chemotherapy response of patients to matching PDX tumors. We also tested selected KI response on chemotherapy-resistant bladder cancers. PDX growth was assessed by tumor surface area quantification following a week of growth with chemotherapy and KI treatment. Hematoxylin and eosin staining coupled with in situ hybridization, immunohistochemistry for Ki67, and cleaved PARP helped identify tumor cells on the CAM as well as their proliferative and apoptotic indexes. Results: Our initial results show pre-NAC primary MIBC tumors grown on the CAM phenocopy cisplatin-based chemotherapy resistance observed in parent tumor specimens. Histological analysis confirmed engraftment and growth of bladder tumors on the CAM. Patient tumor specimens acquired after chemotherapy treatment (post-NAC) and exhibiting NAC resistance were engrafted successfully on the CAM. Such CAM PDX tumors displayed decreased tumor growth size and proliferation in response to treatment with a dual EGFR and HER2 inhibitor, but had no significant response to either CDK4/6 or FGFR inhibition. Conclusion: Our data suggests concordance between Cisplatin-based chemotherapy resistance phenotypes in primary patient tumors and CAM PDX models. Further, proteogenomic informed KI use on MIBC CAM PDX models suggests a benefit from integration of rapid in vivo testing of novel therapeutics to inform more complex, pre-clinical mouse PDX experiments for more effective clinical trial design aimed at achieving optimal precision medicine for patients with limited treatment options. Citation Format: Hugo Villanueva, Patricia Castro, Andrew G. Sikora, Seth P. Lerner. Targeting resistance mechanisms in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2998.