Developing genetically modified homograft models of mouse prostate cancer for efficacy evaluation of combinatory immunotherapies

Despite the early approval of Sipuleucel-T for metastatic castration-resistant prostate cancer, which often perceived as a milestone achievement in cancer immunotherapy, subsequent progress in prostate cancer immunotherapy development has been limited by disappointing results with tumor vaccines and its resistance to immune checkpoint inhibitors, such as PD1 & PD-L1. It is now generally accepted that we need to tackle prostate cancer by combinatorial approaches of chemo-, targeted- and immuno-therapies. Highly relevant preclinical models are very much needed for proof of principle efficacy evaluation. Genetically engineered mouse models (GEMM) recapitulate key aspects of human prostate cancer in both histo- & molecular- pathology. Among those, PTEN loss of function (LOF) in prostate epithelium is one of the central events in human prostate cancer. PTEN haploinsufficiency in mice is sufficient to drive mouse prostatic intraepithelial neoplasia (PIN) formation, while loss of both alleles of PTEN in mouse prostate leads to hyperplasia at 4 weeks, PIN at 6 weeks, and fully invasive adenocarcinoma from 12 weeks of age. PTEN null tumors are also resistant to androgen depletion. In the meantime, although KRAS mutation are not often seen in human prostate cancer, activation of MAPK pathway often happens in advanced tumor. Mutant KRAS or BRAF can robustly promote mouse prostate cancer progression. Prostate specific Pten null and Kras G12D; Pten null mouse prostate cancer models have been well characterized by a number of labs. However, parental GEMM models are difficult to be used for pharmacological studies due to the spontaneous nature of tumor onset and progression. The compound mutant mice are also costly to breed. Here we report generation of transplantable mouse prostate cancer homograft models by passaging the primary tumor subcutaneously in the C57BL/6 mice. These mouse tumors featuring Pbsn-Cre;LSL-Kras G12D/+ ;Pten flox/flox or Pbsn-Cre;Pten flox/flox retain morphological similarity to moderate to poorly differentiated human prostate cancer. These homograft tumors show high levels of M2 macrophage infiltration. Growth of these mouse prostate tumors are resistant to androgen depletion. They are also resistant to the treatment of AR inhibitor enzalutamide, only marginally responsive to docetaxel, but sensitive to treatments with mTOR inhibitor everolimus. When treated with immune checkpoint antibodies, i.e. PD1 and CTLA4, these tumors showed increased T-cell infiltration, but very modest growth inhibition. We are now testing a variety of combinatory therapies with chemotherapies, immune modulators and immune checkpoint antibodies. The results will be presented at the meeting. Citation Format: Jessie Jingjing Wang, Yanrui Song, Annie Xiaoyu An, Likun Zhang, Henry Qixiang Li, Davy Xuesong Ouyang. Developing genetically modified homograft models of mouse prostate cancer for efficacy evaluation of combinatory immunotherapies [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 4621.