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Invited Abstract (Plenary Session): Successes in Developing Tumor Determinants for Targeted Therapies: Lessons Learned

Case history: Lessons learned from the MGMT methylation experience

Spanish National Cancer Centre (CNIO), Madrid, Spain

Abstract

PL-03

Promoter CpG island hypermethylation can be used as predictor of response to different treatments. The case for this needs to be made for each gene separately. The most compelling evidence is provided by the methylation-associated silencing of the DNA repair MGMT in human cancer. The MGMT protein (O6-methylguanine DNA methyltransferase) is directly responsible for repairing the addition of alkyl groups to the guanine (G) base of the DNA. This base is the preferred point of attack in the DNA of several alkylating chemotherapeutic drugs, such as BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea), ACNU (1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea), procarbazine, streptozotocin, or temozolamide. Thus, our reasoning was that tumors that had lost MGMT due to hypermethylation would be more sensitive to the action of these alkylating agents since their DNA lesions could not be repaired in the cancer cell and so this would lead to cell death. We gave proof of principle for this hypothesis and effectively MGMT promoter hypermethylation predicts a good response to chemotherapy, greater overall survival, and longer time to progression in glioma patients treated with BCNU(carmustine). This study has been followed up by other groups, who have obtained similar results. It is important to note that MGMT hypermethylation alone, without treatment with an alkylating agent, is not a good prognostic factor per se. In fact, it is a poor prognostic factor, probably due to the finding that patients with epigenetic silencing of MGMT accumulate more mutations, as demonstrated for p53 and K-ras in colorectal, brain and lung tumors. The potential of MGMT to predict the chemoresponse of human tumors to alkylating agents is not limited to BCNU-like alkylating agents, but it also extends to other drugs such as cyclophosphamide. This has been demonstrated in diffuse large cell lymphomas treated with cyclophosphamide, where MGMT hypermethylation was the strongest predictor of overall survival and time to progression, and was far superior to classical clinical factors such as the International Prognostic Index. Finally, others and we have extended in gliomas the use of MGMT-methylation as a marker of good clinical response for another drug recently introduced, temozolomide.