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. This failure is due almost exclusively to de novo or acquired resistance to chemotherapy resulting in subsequent tumor growth and patient death. Temodar is a methylating agent recently shown to be active in the treatment of malignant glioma. The FDA approved Temodar in 1999 for the treatment of patients with recurrent anaplastic astrocytoma. Temodar is now being used as a standard of care for many, albeit not all, patients with glioblastoma multiforme and anaplastic astrocytoma. Unfortunately, the majority of patients with malignant glioma treated with Temodar demonstrate de novo or acquired resistance with subsequent tumor progression. A series of studies conducted predominantly, but not exclusively, for non-CNS tumors has demonstrated that two mechanisms of resistance appear to be operational in mediating resistance to Temodar. The first of these mechanisms which involves removal of the methyl adduct on the O6-position of guanine via O6-alkylguanine-DNA alkyltransferase (AGT) has been shown in both cell culture and xenografts studies to produce resistance to Temodar. AGT depletion by the substrate analog O6-benzylguanine (BG) have been found to increase the cytotoxicity of Temodar in vitro and in vivo. Similarly, a deficiency to DNA mismatch repair has recently been shown to confer resistance to Temodar in vitro and in vivo. The Brain Tumor Center at Duke has conducted four clinical trials using BG alone (1 trial), BG plus BCNU (2 trials), or BG plus Temodar (1 trial) for adults with recurrent malignant glioma (presented in more detail in Section 3: Preliminary Data). These results demonstrate that BG: 1) is non-toxic; 2) can be administered safely with appropriate dose modifications of BCNU or Temodar; and 3) in preliminary phase 1 results can restore sensitivity to Temodar in Temodar-resistant malignant glioma. The hypotheses of this proposal are that: 1) AGT is the major mechanism of resistance to Temodar in malignant glioma; 2) BG-mediated depletion of AGT can restore sensitivity to Temodar in patients with Temodar -resistant malignant glioma.
The specific aims of this proposal are: 1) To define the role of BG in restoring Temodar sensitivity in patients with Temodar-resistant malignant glioma; 2) To further define the toxicity of combination therapy using Temodar plus BG.
| Quinn, Jennifer A; Jiang, Sara Xiaoyin; Reardon, David A et al. (2009) Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol 27:1262-7 |
