Glioblastoma Multiforme; Drug Resistance & Combination Therapy

Brain tumors are most aggressive lethal types of cancer and have been reported to have poor prognosis. Patients diagnosed with glioblastoma multiforme (GBM) have an aggressive, tough and resistant brain tumor with average survival 12 to 16 months. The most common age for diagnosis of GBM is reported to be in between 45 and 70 years. GBM arises from glial cells which are glue like supportive cells of the brain that help to maintain and protect the neurons of central and peripheral nervous system from any damage. GBM is usually treated with surgery and radiation followed by chemotherapy where temozolomide (TMZ) is a part of therapy. TMZ is an alkaline agent that destroys the glioblastoma cells by forming O6-methylgunine in DNA. TMZ is an anticancer drug popularly used sometimes along with ionizing radiation. However, one of the downsides of chemotherapy is the development of resistance against the drug which results in the failure of the treatment and hence poor prognosis. The alternate treatment strategies are being explored to prolong the survival of GBM. The treatment of GBM by using HDACi (histone deacetylase inhibitors), MGMT (O6-methylguanine DNA methyltransferase) inhibitors, beta blockers, statins, antimetabolites, and some phytotherapeutics in synergistic combinations may be beneficial for outcome. A number of drugs are being investigated in synergistic combination and will offer a substantial survival advantage in GBM patients. The present chapter discusses the synergistic combinations of mainly TMZ with various other anti-cancer or FDA approved drugs for other indications that can enhance different molecular mechanisms, increase cell death, reduce drug resistance or decrease the drug toxicity in glioblastomas.

Keywords: Bcl-2, Cancer Stem Cells, Chemotherapeutics, Combination, GBM, Hypoxia, MGMT, Resistance, Temozolomide, Therapy.