MGMT

The role of MGMT

� A significant advance in determining which patients will benefit from Temodar was reported by the same research group that reported the definitive trial combining Temodar with radiation. Tumor specimens from the patients in that trial were tested for the level of activation of a specific gene involved in resistance to alkylating chemotherapy (which includes temozolomide and the nitrosoureas, BCNU, CCNU, and ACNU). More specifically, there is an enzyme produced by the MGMT gene that allows the damaged tumor cells to repair themselves, with the result that chemotherapy is less effective. Patients whose tumors have an inactivated MGMT gene through gene promoter methylation (which occurs in 35-45% of patients) have a significantly greater chance of responding to Temodar than those for whom the gene is still functional (5). For patients receiving both radiation and temozolomide, those with methylated MGMT hada two-year survival rate of 46%, compared to 14% for those with unmethylated MGMT. This implies that patients should have tumor tissue taken at the time of surgery tested for the methylation status of the MGMT gene.

The use of genetic markers to predict treatment outcome is an important advance, but so far it has not been routinely incorporated into clinical practice. Considerable controversy exists about the predictive validity of the MGMT marker, as several studies have failed to show a relationship between that marker and clinical outcome. This appears to be due primarily to different measurement procedures. A recent paper (6) compared the degree of MGMT protein expression by using commercial anti- MGMT antibody and an assessment of the methylation status of the promoter region of the MGMT gene. The

two measures correlated only weakly, and only the measure of gene promoter methylation correlated strongly with survival time. New methods for assessing methylation have recently been introduced (7) which may resolve the controversy.

The predictive validity of the methylation status of the MGMT gene promoter is an important issue to resolve because temozolomide appears to produce little survival improvement for those whose MGMT gene is active (i.e. the MGMT gene promoter is unmethylated). Thus, patients with unmethylated MGMT might be better served by use of a different chemotherapy agent. For example, a bi-functional alkyating agent known as VAL-083 or dianhydrogalactitol is currently being tested in phase 2 and 3 trials for recurrent glioblastoma. It damages DNA in a way that is not subject to repair by the MGMT enzyme and could therefore be more beneficial for patients with unmethylated MGMT status. Find more details on VAL-083 in Chapter 13.

In addition to changing the chemotherapy agent, there are other possible strategies for patients with unmethylated MGMT gene promoter. One involves the schedule of Temodar. An alternative to the standard 5 in 28 days schedule is a daily low-dose schedule. Previous studies using metronomic schedules have detected no effect of MGMT status on clinical outcome. The issue of the best schedule for Temodar will be discussed in a later section in Chapter 2. The second strategy is to utilize drugs that can inhibit MGMT expression (in preclinical studies). Two such drugs are Antabuse (disulfiram) and Keppra (levetiracetam) (10, 206), discussed in Chapter 6.