Abstract 1928: Radiation response in preclinical orthotopic models of brain cancer

Abstract

Abstract Glioblastoma (GBM) is a fast-growing, aggressive type of central nervous system tumor that forms on the supportive tissue of the brain. Primary treatment options for patients with GBMs have not changed much in many years, and still include surgery, radiation and/or chemotherapy treatment with temozolomide (TMZ). GBM is an incurable disease where there is a desperate need for continued development of novel therapeutic options. A number of preclinical models exist to support the early work needed to develop these new drugs. Here we describe three different preclinical models of brain cancer, U87MG-Luc, GL261-Luc and BT142. Each model was evaluated following orthotopic implantation into the brain. As radiation therapy remains a steadfast approach to GBM, we evaluated each model for its response to radiation and tracked disease progression and response to treatment with either bioluminescence imaging (BLI) or magnetic resonance imaging (MRI) along with traditional survival (morbidity/mortality) analysis. U87MG-Luc is a human glioblastoma cell line that was developed from an astrocytoma. We found that orthotopic implant of U87MG-luc results in reliable growth with a tumor doubling time of 4 days and a median survival time of 45 days. We tested this model with radiation therapy (2.5Gy for 5 days on, 2 days off, for 2 cycles) and found a 70% partial response rate as measured by BLI. We also tested this model with TMZ therapy (33.3mg/kg; orally every day for 5 days) and found a significant delay in disease progression, resulting in a 93% increase in life span. GL261-Luc is a murine glioblastoma model that grows quite aggressively in the mouse brain. We find a tumor volume doubling time of 2 days and a median survival time of 14 days. As this model grows in a mouse strain with an intact immune system it allowed us to evaluate the tumor infiltrating immune cell populations. While we found a low number of CD45+ cells infiltrating into GL261-Luc tumors, immune population changes over time will be described. In this model we tested increasing doses of radiation and found that a single dose of 15Gy was curative whereas the tumors were more moderately responsive to a single dose of 7.5Gy (30% tumor regressions). We then combined 7.5Gy with the immune checkpoint inhibitor anti-PD-1 and saw an improved outcome with a 100% response rate. BT142 is a human anaplastic oligoastroytoma that is relatively unique due to its isocitrate dehydrogenase (IDH1/2) mutational status which results in an accumulation of the oncometabolite 2-hydroxygluarate (2-HG) in the tumor. This tumor line grows in the NOD SCID mouse strain and we found a tumor doubling time of 5 days, as measured by MRI. The BT142 model has proven to be sensitive to radiation following a single dose of 10Gy but less responsive when lower dosage levels were administered on a fractionated schedule. Thus, a variety of human and mouse GBM models exist to enable further drug discovery and development efforts for this intractable disease. Citation Format: Erin E. Trachet, Sumithra Urs, Alden Wong, Scott Wise, Maryland Rosenfeld Franklin. Radiation response in preclinical orthotopic models of brain cancer [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 1928.