Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT).
High level of DNA repair protein, O<sup>6</sup>-methylguanine-DNA-methyltransferase (MGMT) and occurrence of glioma stem-like cells contribute to GBM resistance to the drug.
The DNA repair protein O6-Methylguanine-DNA methyltransferase (MGMT) is suggested to be associated with resistance to alkylating agents such as Temozolomide which is being used in treatment of patients with glioblastoma (GBM).
We show that nanoparticle-mediated knockdown of the DNA repair protein apurinic endonuclease 1 (Ape1) sensitizes GBM cells to radiotherapy and extend survival in a genetic mouse model of GBM.
Synthesis of PET probe O<sup>6</sup>-[(3-[<sup>11</sup>C]methyl)benzyl]guanine by Pd<sup>0</sup>-mediated rapid C-[<sup>11</sup>C]methylation toward imaging DNA repair protein O<sup>6</sup>-methylguanine-DNA methyltransferase in glioblastoma.
To understand the mechanistic basis for this effect and its potential utility as a TMZ response biomarker, we compared the response of isogenic GBM cell populations differing only in expression of the DNA repair protein methyltransferase (MGMT), a TMZ-sensitivity determinant, after exposure to TMZ in vitro and in vivo.
Hypermethylation in the promoter region of the MGMT gene encoding the DNA repair protein O(6)-methylguanine-DNA methyltransferase is among the most important prognostic factors for patients with glioblastoma and predicts response to treatment with alkylating agents like temozolomide.
We also demonstrated that the Holliday Junction Recognizing Protein, a novel DNA repair protein over expressed in lung cancer, is extremely over-expressed in glioblastoma, with a median change of about 134 fold.