By: Hanumantha Rao Madala and Surendra Reddy Punganuru
Primary glioblastoma multiforme (GBM) is one of the most heterogeneous, invasive, and infiltrative malignancies that arise in brain with a median survival of about 15 months. The standard treatment regimen includes maximal safe resection, followed by radiation and daily temozolomide (TMZ), which increased the overall survival about 2.5 months compared with radiation alone. Despite treatment, the invasive and infiltrative aspects are the ultimate cause of recurrence, drug resistance, and death. With minimal availability of Food and Drug Administration-approved weapons to combat this dreadful disease, effective treatment remains an unmet necessity.
“Tonight I’m launching a new precision medicine initiative to bring us closer to curing diseases like cancer and diabetes and to give all of us access to the personalized information we need to keep ourselves and our families healthier.”
President Barack Obama
“Precision medicine”—sometimes referred to as “individualized medicine,” “personalized medicine,” or “targeted therapy”—is, in basic terms, matching the right patients to the right medicines at the right time. This means gaining a deeper understanding of the specific molecular characteristics that are driving a patient’s tumor growth, and finding the right treatments to target those specific molecular abnormalities that are responsible for the disease. Because of the tumor heterogeneity and roles of a large number of oncogenic players in gliomagenesis, it is not likely that one treatment will be able to serve as a silver bullet for all GBM patients. However, there is one prominent molecular alteration—promoter methylation of a DNA repair protein called MGMT (Methyl Guanine Methyl Transferase)—that causes resistance to TMZ by removing the chemotherapy-induced alkyl moieties from guanine. Epigenetic silencing of the MGMT gene by promoter methylation in about 30% of GBM patients results in decreased MGMT protein expression, reduced DNA repair activity, and potential increased sensitivity to therapy. MGMT promoter methylation status has been most widely evaluated by methylation-specific polymerase chain reaction method, which is both sensitive and specific. The presence of MGMT promoter methylation has been shown to be an independent favorable prognostic factor and a strong predictor of responsiveness to alkylating chemotherapy (e.g., temozolomide). This is particularly relevant for elderly patients (older than 60–65 years), who usually have decreased tolerance for combined aggressive chemoradiation. Thus, in addition to the significant prognostic and predictive value, MGMT methylation status has emerged as a valuable biomarker to guide therapy decision making for newly diagnosed glioblastoma in elderly patients, preventing unnecessary treatment toxicities and costs.
MGMT is also an established target for improving the therapy for brain tumors. However, the strategy of creating MGMT protein deficiency in tumors using the inhibitor O6-benzylguanine and subsequent treatment with alkylating agents has run into trouble because, the function of bone marrow, a normal tissue, which replenishes the blood cells, becomes compromised. Another way is to shut off the MGMT expression at the gene level; this actually happens in a large number of lower grade gliomas due to mutations in a metabolic gene called isocitrate dehydrogenase 1, and these brain tumor patients respond much better to treatment. Further, the immunotherapy approaches for brain cancers are ongoing at the Duke University.
Yes, there is hope for more precise medicine. For example, efforts focusing on high energy ultrasound waves to disrupt the blood brain-barrier and allow more chemo-drugs into the brain, has been a new initiative. Altogether, these strategies will help to propel the precision medicine into doctors’ offices, help patients receive better, more individualized care, and ultimately extending the overall survival of patient with better quality of life.