Abstract
Abstract High-grade glioma is a devastating and uniformly fatal disease for which better therapy is urgently needed. In order to evaluate the potential of novel therapies, we have developed a set of glioma mouse models. These include LoxP conditional mouse models that form spontaneous high-grade gliomas following intracranial injection of lentiviral CMV-Cre vectors and high-grade glioma models that develop following intracranial injection of cell lines obtained from these spontaneous models and maintained as neurosphere cultures. Standard treatment of newly diagnosed high-grade glioma after surgical resection involves radiotherapy (RT) and chemotherapy (CT) with temozolomide. Both modalities are based on inflicting damage to the DNA of tumor cells but have only a limited effect on overall survival. A potential strategy to improve the efficacy of DNA damaging therapies is to combine these with agents that interfere with DNA damage repair. In this study we have concentrated on the inhibition of PARP by ABT-888 and the inhibition of Wee1 kinase by PD0166285 and MK-1775. Importantly, we have mimicked the therapy of patients as closely as possible by implementing μ-Image Guided Radiotherapy (μ-IGRT) using the X-Rad 225Cx (Precision X-Ray Inc). Through cone beam CT guidance this system offers precise delivery of high energy beams (225 KVp) of small field sizes (1 - 5 mm), minimizing the exposure of normal tissues and allowing the delivery of RT doses that can not be given by conventional whole body RT. Here RT was delivered using a fractionated schedule (5 Gy per day x 4) in combination with oral temozolomide (100 mg/kg/day x 4) alone or with ABT-888 (10 mg/kg/bid x 4), PD0166285 (0.25 mg/kg/bid x 4 or MK1775 (20 mg/kg/bid x 4). Treatment of orthotopically injected Ink4a/Arf;P53;K-Rasv12 neurosphere-cultured cells (GBM652457) by RT + CT was much more efficacious than by CT alone. In line with the expectations, the PARP inhibitor ABT-888 significantly improved the response (assessed by bioluminescence monitoring) nd survival. However, the same combination was not more efficacious against spontaneous Ink4a/Arf;P53;K-Rasv12 tumors relative to RT + CT alone. Addition of the Wee1 kinase inhibitors PD0166285 or MK1775 did not improve the efficacy of RT+CT against intracranially injected GBM652457 cells. We are currently investigating the underlying reason of these results. ABT-888, PD0166285 and MK1775 are all substrates of ABCB1 and ABCG2 and especially MK1775 has a very poor BBB penetration. In conclusion, μ-IGRT is an exciting new technique to mimic treatment of glioma patients in mouse models more closely. Since all novel therapies for treatment of high-grade glioma will be given in conjunction to the current chemoradiation therapy, this technique will allow more accurate preclinical evaluation of novel therapies in a clinically relevant setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5718. doi:1538-7445.AM2012-5718
Published Version
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