Abstract LB-031: A novel model of prostate cancer suggests enzalutamide functions through the immune system to diminish metastatic growth

Abstract

Purpose: There is tremendous need for improved prostate cancer models. The murine prostate is anatomically and developmentally different from the human prostate, and unlike the human prostate, does not form sporadic tumors, limiting relevance of genetically engineered model systems. Furthermore, engineered models lack the heterogeneity of human disease, rarely (if ever) establish metastatic growth, and tend to be driven in a contrived manner, not at all related to human disease or the human drivers of disease progression. Human xenografts represent alternative models, but they rely on tumor growth in an immunocompromised murine host, preventing the study of tumor-immune interactions and immunotherapy interventions. Consequently, translational progress in prostate cancer research is hampered by the lack of human-derived models that can recapitulate the natural history of the disease—from initiation to metastatic spread—that will respond appropriately to the standard of care hormonal therapies. Accordingly, we generated a prostate cancer xenograft model in a murine system with an intact human immune system to test the hypothesis that humanizing tumor-immune interactions would improve modeling of metastatic prostate cancer, and further-enable improved modeling of hormonal and immune therapies. Procedure: Male huNOG mice were produced at Taconic Biosciences by engrafting juvenile NOG mice with human CD34+ hematopoietic stem cells. These mice stably develop and maintain multiple human cell lineages, including functional human T-cells. HuNOG and NOG control mice were surgically castrated. One week following castration, castrated and intact control mice were injected subcutaneously with luciferase-transduced 22Rv1 human prostate cancer cells to assay organ-specific metastatic growth. After tumors reached 100mm 3 , half of the castrated mice were treated with enzalutamide, and then tumor growth was monitored to endpoint. At sacrifice, organs were ex-vivo analyzed for metastatic growth, tumor infiltrating lymphocytes, and splenic immune reconstitution. Results: Primary tumor size was not significantly altered across conditions; however, the extent and growth at the secondary sites differed markedly in castrate huNOG vs conventional NOG mice treated with enzalutamide. Furthermore, enzalutamide responses in huNOG and NOG mice were distinct, and associated with increased CD3+ T-cells within tumors of enzalutamide treated huNOG mice, and increased CD3+ T-cell activation, accessed by intracellular interferon-γ. These results illustrate, to the best of our knowledge, the first model of human prostate cancer with metastases to clinically relevant locations, an intact human immune system, that responds appropriately to standard-of-care hormonal therapies. Citation Format: Steven Kregel, Jae Eun Choi, Kristen Juckette, Brooke Mccollum, Stephanie Simko, Parth Desi, Yuanyuan Qiao, Paul A. Volden, Arul M. Chinnaiyan. A novel model of prostate cancer suggests enzalutamide functions through the immune system to diminish metastatic growth [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 LB-031.