MGMT Trial:

Genome wide expression profiling to determine the molecular basis of sensitivity to Temozolomide in patients with Glioblastoma multiforme

Objectives:

To understand the molecular basis of temozolomide (TMZ) sensitivity by comparing the expression profile of GBM tumour tissues with the overall survival following treatment with TMZ

Back Ground::

Glioblastoma multiforme (GBM) constitutes the most common primary brain tumour in adults. In Tata Memorial Centre, we see 50-70 cases per year. Unfortunately, despite major advances in cancer diagnostic and treatment modalities, these tumours are still incurable with long-term survivor rates being less than 5. One of the most exciting agents which have generated a considerable amount of interest recently in CNS tumours is Temozolomide (TMZ). TMZ is an alkylating agent that causes DNA damage of tumor cells.

Among the lesions produced in DNA after treatment of cells with temozolomide, the most common is methylation at the N7 position of guanine, followed by methylation at the O3 of position of adenine and the O6 position of guanine. The cytotoxicity of TMZ has been attributed primarily to the methylation of the O6 position of guanine. During replication, the O6 methylguanine incorrectly pairs with thymine, triggering the mismatch repair system. The repair of the mismatched bases leads to preferential reinsertion of thymine, which may result in repetitive and futile attempts at repair. This process leads to the generation of DNA strand breaks and eventually growth arrest and apoptosis.

Epigenetic silencing of the MGMT (O6 methylguanine DNA methyl transferase) gene by promoter methylation has been shown to be associated with longer overall survival in GBM patients treated with TMZ.There are few phase 2 trials showing benefit of MGMT silencing. But randomized trial is lacking.

Research Plan:

Twenty five adult patients with histologically confirmed diagnosis of GBM will be screened for eligibility in the study. Fresh tissue specimens will be procured after informed consent for the MGMT promoter methylation status and global gene expression profiling by microarray.
Patients will be treated with TMZ and radiotherapy.

Study design:

Twenty children presenting with clinical and radiological features characteristic of a brain stem glioma accrued and is under followup.

Inclusion criteria

• 1. Adults of either sex
• 2. Age 18-70
• 3. Histologically confirmed WHO grade IV astrocytoma (Glioblastoma multiforme).
• 4. Patient’s informed consent
• 5. KPS >60
• 6. Patient suitable for radical radiotherapy and Temozolomide
• 7. Adequate haematological parameters, namely Haemoglobin > 11 grams, total leukocyte count of at least 4000 per mm3 with absolute neutrophil count (ANC) > 1500 per mm3 and platelets > 100,000 per mm3
• 8. Normal hepatic and renal functions, i.e. aspartate aminotransferase or alanine aminotransferase less than 2.5 times the upper limit of normal and serum creatinine < or equal to 1.5 mg

Exclusion criteria

• 1. No severe underlying disease (HIV and chronic hepatitis B or C infection).
• 2. Patients with recurrent tumours either after previous surgery and/or radiotherapy
• 3. Prior cranial radiotherapy or chemotherapy
• 4. Concurrent malignant disease

Endpoint criteria :

Overall survival (OS) and Progression free survival (PFS).

Status :

Trial proposal submitted.