Abstract 4333: Difference in the synergistic effect of cytotoxicity in pediatric brain stem gliomas and adult glioblastomas to combination treatment with temozolomide and molecular target-specific agents

Abstract

Abstract Brain stem glioma (BSG) in children is comparable to adult glioblastoma (GBM) with regard to poor survival and resistance to chemo-radiation therapy. Temozolomide (TMZ) is an alkylating agent and rapidly penetrates the central nervous system (CNS), making it a standard chemotherapeutic agent for adults with malignant glioma. Despite some improvement of survival, radiation with TMZ monotherapy rarely provides long-term control. This study aimed to determine combination effect of conventional anticancer agent, TMZ and molecular target-specific agents such as Sunitinib, Tandutinib, Cediranib and Rapamycin in BSG and GBM. The drug combination effects were tested by cell proliferation inhibition in glioma cells from six children with BSG and five established GBM cell lines. The half-maximal inhibitory concentration (IC50) of each agent was estimated 48hr after treatment of agents by cell proliferation assay. The values of IC50 in brain stem gliomas were higher as much as 1.5 to 4 times than those of GBM cell lines in all of agents, suggesting that brain stem gliomas are more resistant to not only TMZ, but also to various molecular target specific agents. O6-methylguanine methyltransferase (MGMT) promoter methylation status was determined by methylation-specific PCR after bisulfite treatment. As a result, MGMT promoter methylation was detected in all of GBM cell lines, whereas incomplete methylated or unmethylated MGMT was shown in six brain stem gliomas from pediatric patients. For combination therapy, IC10 of each agent plus IC10 of TMZ was treated in each cell for 48hr to assess cytotoxicity. TMZ+Cediranib, +Rapamycin, +Sunitinib showed some tumor proliferation inhibition in 60%, 40%, 20% of 5 GBM cell line respectively. In BSGs, however TMZ-Sunitinib and TMZ-Cediranib presented considerable tumor growth inhibition in 2 (33%), 1 (16%) among 6 BSGs although most BSGs were unmethylated in MGMT promoter. BSGs in children showed different chemotherapeutic effect and MGMT promoter methylation status compared to GBM in adult. The combination therapy of TMZ and molecular target-specific agents showed more synergistic effects in cytotoxicity for BSG and GBM than TMZ only. Also children with BSG can be more effectively treated with TMZ with multiple molecular targeted agents such as Sunitinib than adult GBM. These results can be translated clinically to develop new chemotherapeutic trials for children with BSG. 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 4333. doi:1538-7445.AM2012-4333