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, O 6 -alkylguanine-DNA alkyltransferase (AGT) and DMA mismatch repair deficiency. The hypotheses of this proposal are 1) AGT and DNA mismatch repair deficiency play a role in mediating Temodar resistance in malignant glioma and medulloblastoma; 2) other mechanisms are also critical in mediating this resistance; and 3) inhibition of base excision repair can enhance Temodar activity.
The specific aims of this proposal are: 1) to define the role of AGT and AGT mutations in mediating resistance in tumors resected from patients with Temodar resistant malignant glioma; 2) to define the role of DNA mismatch repair deficiency in tumors resected from patients with Temodar resistant malignant glioma; and 3) to define the role of base excision repair (BER) in mediating resistance to tumors resected from patients with Temodar resistant malignant glioma and the role of inhibition of BER in enhancing Temodar activity in malignant glioma.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ONC-Q (01))
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Fountain, Jane W
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Duke University
Schools of Medicine
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Cui, B; Johnson, S P; Bullock, N et al. (2009) Bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea activates the ATR-Chk1 pathway independently of the mismatch repair pathway. Mol Pharmacol 75:1356-63
Bacolod, Manny D; Fehdrau, Randy; Johnson, Stewart P et al. (2009) BCNU-sequestration by metallothioneins may contribute to resistance in a medulloblastoma cell line. Cancer Chemother Pharmacol 63:753-8
Bacolod, M D; Lin, S M; Johnson, S P et al. (2008) The gene expression profiles of medulloblastoma cell lines resistant to preactivated cyclophosphamide. Curr Cancer Drug Targets 8:172-9
Maxwell, Jill A; Johnson, Stewart P; McLendon, Roger E et al. (2008) Mismatch repair deficiency does not mediate clinical resistance to temozolomide in malignant glioma. Clin Cancer Res 14:4859-68
Maxwell, Jill A; Johnson, Stewart P; Quinn, Jennifer A et al. (2006) Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma. Mol Cancer Ther 5:2531-9
Rich, Jeremy N; Sathornsumetee, Sith; Keir, Stephen T et al. (2005) ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors. Clin Cancer Res 11:8145-57
Quinn, Jennifer A; Desjardins, Annick; Weingart, Jon et al. (2005) Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J Clin Oncol 23:7178-87
Cheng, C Lynn; Johnson, Stewart P; Keir, Stephen T et al. (2005) Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft. Mol Cancer Ther 4:1364-8
Goudar, Ranjit K; Shi, Qing; Hjelmeland, Mark D et al. (2005) Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther 4:101-12
Bacolod, Manny D; Johnson, Stewart P; Pegg, Anthony E et al. (2004) Brain tumor cell lines resistant to O6-benzylguanine/1,3-bis(2-chloroethyl)-1-nitrosourea chemotherapy have O6-alkylguanine-DNA alkyltransferase mutations. Mol Cancer Ther 3:1127-35

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