Abstract P005: Establishment and characterization of a panel of advanced prostate cancer patient-derived xenograft (PDX) models for cancer therapeutic evaluation

Abstract

Abstract Background: Prostate cancer is one of the most frequently diagnosed solid malignancies and is accountable for the second highest cancer-related deaths in males worldwide. Despite the success of targeting the androgen receptor signaling pathway with androgen deprivation therapy (ADT) and androgen receptor blockage (ARB), relapse and resistance to treatment leads to castration resistant prostate cancer (CRPC) or metastatic CRPC (mCRPC), resulting in poor clinical prognosis and therapeutic outcome. Prostate cancer is a highly heterogeneous disease, with different molecular pathways playing a role in the advanced disease, such as androgen receptor mutations, DNA repair gene deletions, P53 aberrations, RB1 function loss, as well as gene rearrangements, like TMPRSS2-ERG2. Preclinical models representing CRPC heterogeneity and clinically relevant responses to standard of care treatments are needed to better understand the biology and mechanisms of this malignancy. METHODS: CRPC PDX models derived from metastases of prostate cancer patients, which failed anti-androgen therapies, were established via subcutaneous engraftment in immunodeficient mice. Model classification and characterization were performed by histopathology and immunohistochemistry (IHC) with prostate-specific biomarkers. Genomic profiling of these models was performed by next generation sequencing (NGS). Chemotherapies such as docetaxel and target therapies, including anti-androgen, were evaluated in these prostate models. Tumor volume over time was used to determine growth rate and response to treatment in uncastrated and castrated mice. RESULTS: A series of CRPC PDX models derived from metastatic lesions in patients, including metastases from lymph nodes, bladder, ascites and rib/soft bone, were established and characterized. Histopathology by H&E staining presented distinct features of adenocarcinoma and the immunohistochemistry data indicated various expression levels of prostate-specific markers, such as prostate-specific antigen (PSA) and androgen receptor (AR). Most of the models showed loss of PTEN expression. Sequencing data also detected different gene aberrations such as TMPRSS2-ERG fusion, TP53 deletion and mutations, RB1 mutations, and AR alterations. In vivo modeling of these models presented tumor progression under castration. Docetaxel and enzalutamide, commonly used in mCRPC patients, presented varied responses. CONCLUSIONS: Prostate cancer presents high heterogenicity in clinical and molecular features, and treatment response. A panel of mCRPC PDX models have been established and characterized to provide clinically relevant preclinical models for prostate cancer therapeutic evaluation. Citation Format: Jessie Jingjing Wang, Leilei Chen, Xueying Yang, Likun Zhang, Wubin Qian, Henry Qixiang Li. Establishment and characterization of a panel of advanced prostate cancer patient-derived xenograft (PDX) models for cancer therapeutic evaluation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P005.