Abstract
The WHO grading based on a comprehensive evaluation of morphology, cell biology, genetics and immunological characteristics of primary brain tumors has been widely used as it is also a good indicator of clinical outcomes. The molecular pathology of gliomas not only serves as an adjunct to histological diagnosis but may also hold the key to developing new prognostic classifications with therapeutic implications. Despite aggressive treatment, the prognosis of malignant gliomas remains dismal. Extensive research on the genetics and epigenetics of gliomas has been carried out in order to gain a better understanding of the molecular biology of tumors. Understanding the molecular factors associated with glioma is essential for the development of an effective anti-glioma chemotherapy. Several studies report characteristic genetic factors, such as O6-methylguanine DNA-methyltransferase (MGMT), chromosome 1p19q, epidermal growth factor receptor (EGFR), TP53, and isocitrate dehydrogenase (IDH) 1 & IDH2, and suggest their potential role in the clinical prognosis of the tumor by determining the efficacy of anti-tumor chemotherapy. Reports on the major determinants of resistance to anti-glioma therapy, namely the existence of MGMT, sustained angiogenesis, and the blood-brain barrier, call for novel strategies to overcome these barriers if the fight against malignant glioma is to be won. The standard therapy for malignant gliomas is maximal resection followed by the Stupp regimen of radiation and temozolomide (TMZ) chemotherapy. TMZ, a second generation alkylating agent, has high blood-brain barrier permeability but almost half of the tumors show TMZ resistance. Various clinical trials, using TMZ as the main trunk, have tried modifying TMZ administration and combining TMZ with other anti-tumor agents in order to overcome the limits of the standard TMZ based anti-glioma therapy. Basic research and clinical trials continue to contribute to developing novel molecular-targeting agents and novel strategies to overcome the above mentioned shortcomings.
In this paper, we review the important factors in understanding the molecular pathology of glioma and drug resistance and report on the main barriers that need to be overcome in the current standard therapy. We summarize recent clinical trials of Avastin (BEV), AVAGlio study and RTOG 0825, aimed at overcoming the barrier of angiogenesis by targeting VEGF. We also report our results on the efficacy of Interferon-β on animal models and its clinical trial—INTEGRA study. We also review the potential of local interstitial chemotherapy such as Gliadel (Carmustine, BCNU) wafers as an approach to overcome the blood-brain barrier.
