Abstract 3327: G-quadruplex-stabilizer, Telomestatin, preferentially induces apoptosis of brain tumor stem cells with less effect on survival of normal stem cells

Abstract

Abstract Introduction: Recent studies have demonstrated the phenotypic and genetic similarities between brain tumor stem cells (BTSC) and their somatic counterparts in the brain, neural stem cells (NSC). To target the common pathways that play essential roles for survival of both BTSC and NSC, however, may eradicate both stem cell types. A better strategy would be to uncover the mechanisms that specifically regulate initiation of brain tumors and maintenance of the stem-like phenotype of BTSC. In this study, we hypothesized that formation of secondary DNA structure, G-quadruplex, is disrupted only in BTSC and targeting G-qudruplex results in eradication of BTSC without sacrificing the normal counterpart. Experimental procedures: The effect of the G-quadruplex stabilizer, telomestatin was investigated on survival and proliferation of 3 different cell types; patient-derived BTSC, non-stem tumor cells derived from the matched samples, and normal neural precursors derived from fetal brains. We then investigated the mechanism of telomestatin action in BTSC. Lastly, we performed xenotransplantation of tumor cells pretreated with telomestatin into immunodeficient mouse brains to verify the effect of telomestatin on in vivo tumor growth. Results: Treatment of patient-derived BTSC with telomestatin resulted in inhibition of proliferation and induction of apoptosis in vitro, and this phenotype was partially rescued by pretreatment with the PARP-1 inhibitor, suggesting that the action of telomestatin in BTSC is likely dependent on the PARP-1 pathway. In contrast, treatment of normal precursors with the same dose of telomestatin did not significantly affect their survival and proliferation. Growth of a glioma cell line in vivo was decreased by pretreatment with telomestatin. Conclusions: Differential susceptibility of BTSC, compared to the normal counterpart, to telomestatin treatment indicates the significance of G-quadruplex structure in malignant gliomas and their tumor stem cells. Currently, we are investigating the effect of telomestatin treatment on mouse brain tumors derived from patient BTSC. The novel strategy targeting molecular aberrations in BTSC may offer innovative therapeutic approaches for malignant gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3327.