Gliomas are the third leading cause of cancer deaths in young adults. WHO grade II (low-grade) and grade III (anaplastic) gliomas comprise the majority of glial tumors affecting younger adults, with peak incidence between 35 and 45 years of age. Median survival ranges from 2 to more than 10 years, but the outcome is nearly uniformly fatal. Radiotherapy and alkylating agent-based chemotherapy are the main adjuvant treatments; however, response is highly variable and there are no predictive markers for the majority of grade II and III gliomas. There is pressing need to identify treatment-specific molecular markers that are prognostic of clinical response, in order to improve the efficacy of existing adjuvant therapies, to reduce treatment associated morbidity, to identify gliomas that are candidates for novel therapies and to prolong survival. ? ? This application addresses the hypothesis that apurinic endonuclease (Ap endo) activity, a DNA repair activity that processes cytotoxic abasic sites, is predictive of response to radiotherapy and to alkylating agent-based chemotherapy in grade II and grade III gliomas. Ap endo activity is a prime candidate as a predictive marker, based on fundamental mechanistic considerations and substantial supporting data. Importantly, our new pilot study indicates that there is a strong, inverse correlation of Ap endo activity with time to tumor progression (TTP) following either adjuvant radiotherapy or alkylator therapy. To address our hypothesis, we will [1] analyze the association of Ap endo activity with TTP following radiotherapy in larger, separate samples of grade II and of grade III gliomas; [2] analyze the association of Ap endo activity with TTP following alkylating agent therapy in a larger sample of grade III gliomas; and [3] evaluate sub-cellular localization of Apel/Ref-1, the major human Ap endo, as a histochemical surrogate for Ap endo activity. The ability to better manage individual tumors within existing radiation and alkylating agent protocols, or to direct tumors to alternative or novel treatment regimens, based on Ap endo activity, can be expected to improve overall outcome as well as quality of life. ? ?
| Bobola, Michael S; Kolstoe, Douglas D; Blank, A et al. (2012) Repair of 3-methyladenine and abasic sites by base excision repair mediates glioblastoma resistance to temozolomide. Front Oncol 2:176 |
