Glioblastomas are highly malignant brain tumors that are invariably fatal. Post-operative radiotherapy (RT) given concurrently with the methylating agent temozolomide (TMZ) is now the accepted standard of care for newly diagnosed glioblastoma. Yet response is highly heterogeneous and there is urgent need for markers of treatment outcome. Our objective is to develop predictive models, based on DNA repair-related markers, which stratify glioblastomas by risk for progression following concurrent RT-TMZ. DNA damage is largely responsible for the tumoricidal activity of RT and alkylators such as TMZ, and DNA repair plays a major role in determining clinical response. Our predictive models will include tumor Ap endonuclease (Ap endo) activity, which repairs treatment-induced abasic sites and single- strand breaks in DNA. Our published and preliminary work has shown a statistically significant inverse association between Ap endo activity and treatment outcome following RT or RT plus alkylating agent based-chemotherapy in diverse adult and pediatric brain tumors, including glioblastomas in an initial sample of males under the age of 50. Our models will also include CpG methylation status of the gene promoter, a previously developed marker, or the biochemical activity, of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT).
In Specific Aim 1, we will test the hypothesis that tumor Ap endo activity is inversely associated with progression-free survival (PFS) in adult glioblastomas receiving concurrent RT-TMZ.
In Specific Aim 2, we will test the hypothesis that inclusion of additional markers of DNA repair and resistance to cell death in multivariate models will strengthen the predictive power of Ap endo activity.
In Specific Aim 3, we will test the hypothesis that random mutation frequency, which has recently been shown to be elevated in human tumors, is a predictive marker of PFS. We will use Cox regression analysis to examine the association between Ap endo activity and PFS in multivariate models that include MGMT promoter methylation status and additional potential markers.
Glioblastomas are fatal brain tumors that strike 10,000 American adults each year, the average survival being between 9 and 15 months. A recent advance in post-surgical radiation and chemotherapy has improved survival for about half of patients, but the remaining half do not benefit and incur side effects for little or no gain. Our goal is to increase overall survival by developing tumor markers that predict response to the new therapy, in order to identify patients who will benefit and to direct others to alternative treatments while sparing them unnecessary side effects. ? ? ?
| Silber, John R; Bobola, Michael S; Blank, A et al. (2012) O(6)-methylguanine-DNA methyltransferase in glioma therapy: promise and problems. Biochim Biophys Acta 1826:71-82 |
| 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 |
| Bobola, Michael S; Jankowski, Pawel P; Gross, Mary E et al. (2011) Apurinic/apyrimidinic endonuclease is inversely associated with response to radiotherapy in pediatric ependymoma. Int J Cancer 129:2370-9 |
| Bobola, Michael S; Kolstoe, Douglas D; Blank, A et al. (2010) Minimally cytotoxic doses of temozolomide produce radiosensitization in human glioblastoma cells regardless of MGMT expression. Mol Cancer Ther 9:1208-18 |
