Abstract C4: Inhalational chemotherapy for malignant gliomas

Abstract

Abstract Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer, based on its mechanism of action as a ras inhibitor and a cell cycle inhibitor. Unfortunately, it had significant gastrointestinal side effects, and was never well received as an oral anticancer agent. Recently, POH has been administered intranasally in a Phase I/II trial for the treatment of recurrent malignant gliomas in Brazil. It is well tolerated when delivered intranasally, with a 50% progression free survival (PFS) of 6 months in patients with recurrent GBM, with radiographic reduction in size in some patients. Similar efficacy compared to bevacizumab (Avastin; Genentech) was obtained in recurrent GBM patients treated with intranasal POH alone. We have recently synthesized a pharmaceutical grade of POH with >98% purity. Synthesized POH inhibits vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and transforming growth factor-beta 2 (TGF-B2). Cytotoxicity, as measured by colony formation assay (CFA), demonstrated a IC50 of 0.5 mM. We have since conjugated POH to a number of different pharmaceutical agents, including temozolomide (TMZ). Data on these conjugates demonstrate increased cytotoxic activity compared to individual drugs alone or in combination. TMZ-POH is much more potent than POH alone (IC50 10–30 uM), and is effective in TMZ resistant glioma cells, inhibits glioma cancer stem cells, and is not toxic to normal astrocytes. Our goal is to use our synthesized POH and TMZ-POH in upcoming Phase I/II trials for recurrent malignant gliomas. Further definition of the perillyl alcohol derivatives will lead to a pipeline of new compounds which will enable further expansion of the intranasal delivery repertoire. Animal models demonstrating efficacy of intranasal delivery of POH and TMZ-POH is currently underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C4.