The prognosis of patients with malignant glioma remains dismal, with conventional treatment with surgery, radiotherapy and alkylnitrosourea-based chemotherapy failing to cure all patients with glioblastoma multiforme and the majority of patients with anaplastic astrocytoma. Review of clinical trials for treatment of malignant glioma indicate that a major impediment to further progress is the emergence of drug-resistant tumor cells. Methylating agents are one of the two """"""""gold"""""""" standards (the other being nitrosoureas) for the treatment of malignant glioma. Temodar (temozolomide) is an imidazole tetrazinone whose mechanism of action is similar to that of dacarbazine, specifically via metabolic conversion to a common active intermediate, the methylating agent MTIC. Clinical trials suggest that Temodar has activity in the treatment of patients with newly diagnosed and recurrent high-grade glioma. Nevertheless, it is clear that a cohort of patients with this tumor will fail Temodar. A series of studies conducted predominantly, but not exclusively, for non-CNS tumors has demonstrated that at least two mechanisms of resistance appear to be operational in mediating resistance to Temodar, O6-alkylguanine-DNA alkyltransferase (AGT) and DNA mismatch repair deficiency. The hypothesis of this proposal is that: mechanisms (discrete from AGT or DNA mismatch repair deficiency) involving DNA base excision repair and alterations in cell signaling mediate Temodar resistance in malignant glioma and medulloblastoma.
The specific aims of this proposal are: 1) to define the relative importance of novel mechanisms (per Specific Aims 2 & 3) of resistance to Temodar in human glioma and medulloblastoma cell lines, xenografts and clinical tumor samples by quantitating the role of AGT, AGT mutations, and DNA mismatch repair deficiency; 2) to define the role of adduct repair in mediating resistance to Temodar in human glioma and medulloblastoma cell lines, xenografts and clinical tumor samples; 3) to define the role of alterations in cell signaling following Temodar induced DNA methylation in mediating resistance to Temodar in human glioma and medulloblastoma cell lines, xenografls and clinical tumor samples; 4) to conduct Phase 1 and 2 trials of Temodar in combination with inhibitors of DNA repair in patients with malignant glioma and medulloblastoma.
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