Abstract 2807: Developing a variety of primary mouse tumor allograft models for evaluating efficacy of PARP inhibitor
Authors: Gavin Jiagui Qu, Davy Xuesong Ouyang, Li Chen, Likun Zhang, Annie Xiaoyu An, Jie Cai, Henry Q. X. Li
Journal: Cancer Research (2017)

Abstract Recent success of multiple poly (adenosine diphosphate [ADP]) ribose polymerase inhibitors (PARPi) in treating BRCA mutant ovarian cancers has fueled the development of PARPi in several areas, including expanding its use in other BRCA mutant or wildtype cancers; exploring resistant mechanisms and overcoming resistance; seeking for its combination with chemotherapy, radiotherapy and emerging immunotherapy to achieve persistent efficacy. Especially considering the mechanism of action of PARPi, its use can increase the mutational loads in tumors with defects in homologous recombination and DNA double strand break repair, which potentially would enhance the immunogenicity of the tumors. Therefore it would be very interesting to test the effectiveness of combining PARPi with anti-PD1/PD-L1 or anti-CTLA4. However, relevant animal models are lacking for such studies.Syngeneic mouse tumors offer about 30 viable in vivo models for proof of concept studies. However, these models suffer from several limitations: 1) only a few available and responsive to the current checkpoint inhibitors – for given strains of mouse, there are only very few choices of cells/disease types; 2) not mimicking patient tumors since they are in vitro immortalized cell lines; 3) not reflective of patient disease pathways thus unfit for common target agents, either in mono- or combination therapy. We have established allografts of spontaneous mouse tumors (MuPrime®) derived from genetically engineered mouse models (GEMMs) as a new type of immuno-oncology models with following advantages: 1) its primary nature of “stem cell diseases” and relevant tumor microenvironment; 2) its diverse cancer types/strains of mice; 3) engineered oncogenic drivers as seen in human diseases, deriving from a wide range of available GEMMs, suitable for targeted agents. Thus far, we have built a small library of allografts and are testing them to facilitate pharmacological investigation, particularly those of immuno-oncology.We have found a few models, including an APCmin/+ skin squamous cell carcinoma and a P53 null sarcoma responded well to PARPi Niraparib. Continuous treatment with Niraparib led to development of partial or complete resistance. We are now profiling the resistant models to find out their general mutation loads, as well as specific biomarkers render resistant mechanisms. We are also treating the tumors with mouse PD1 antibody to test whether presumably enhanced mutation loads would sensitize these tumors to immunotherapy. The data of these studies will be presented at the meeting. Citation Format: Gavin Jiagui Qu, Davy Xuesong Ouyang, Li Chen, Likun Zhang, Annie Xiaoyu An, Jie Cai, Henry Q. X. Li. Developing a variety of primary mouse tumor allograft models for evaluating efficacy of PARP inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2807. doi:10.1158/1538-7445.AM2017-2807