Evolution of malignant glioma treatment: from chemotherapy to vaccines to viruses.

Malignant glioma is the most common type and most severe form of primary brain cancer. Each year, around 17,000 new patients are diagnosed in the United States, or about 5 cases in 100,000 people 1. The disease most commonly occurs in the sixth through eighth decades of life. The prevalence of the disease will increase with an aging populace. According to the World Health Organization classification system, grade III and IV gliomas are collectively termed malignant gliomas 2. Grade III gliomas are anaplastic high-grade gliomas and grade IV tumors are glioblastomas. Glioblastoma accounts for about 80% of malignant gliomas 1, 3. Glioblastoma carries a worse prognosis and is characterized histologically by vascular proliferation and necrosis. The median survival for a patient with glioblastoma is only about 14 months with a 5-year survival rate near zero 4. Median survival for grade III gliomas is two to five years 5. Glioblastomas are classified as either primary or secondary glioblastomas 6. Primary tumors (>90%) arise de novo without previous medical evidence of lower tumor grade formation, whereas secondary glioblastomas develop from a lower grade (II or III) glioma. Primary and secondary classification only refers to the progression pathway to glioblastoma development; the histopathology for the tumors is the same. Regardless of being a primary or secondary glioblastoma, the prognosis and current treatment is the same. Recent research has suggested differences in the tumors 6. These tumors develop at different ages and are comprised of different genetic mutations 7, 8. Each tumor type has different molecular signatures as well. Primary glioblastomas are characterized by the EGFR/PTEN/Akt/mTOR pathway 9. Amplification of EGFR occurs in 60% of these tumors, but is seldom seen in secondary tumors 10, 11. Secondary glioblastomas are primarily characterized by point mutations in the TP53 tumor suppressor pathway 11. Recently, isocitrate dehydrogenase 1 (IDH1) mutations have been discovered in secondary glioblastomas 12. Interestingly, presence of this mutation signifies a more favorable prognosis 13. The genetic signatures between primary and secondary tumors suggest underlying distinctions that may potentially guide targeted therapy in the future. Recent research has focused on further defining the genetics of malignant gliomas14. No unequivocal causal mutations of malignant gliomas have been discovered. Instead, the tumor appears to be induced by an accumulation of multiple mutations over time. As opposed to identifying specific mutations, identification of altered molecular pathways and how the pathways interact is much more informative. Integrated pathway analyses have determined important genetic pathways implicated in glioblastoma 15, 16. Genetic alterations in the RTK/RAS/PI(3)K pathway are most common, affecting 88% of glioblastomas. Signaling alterations in the p53 and RB pathways are second and third most frequent, altered in 87% and 78% of cases, respectively. Besides determining genes promoting gliomagenesis, other studies have shown how genes can serve as prognostic indicators. Several prognostic markers have been shown to correlate with glioblastoma survival. For instance, glioblastoma patients with IDH1 mutations survive longer compared to patients without mutations in this gene 12.