Epigenetic personalized medicine in glioblastoma

Glioblastoma is a rare tumor that is responsible for 4% of all cancer deaths and is thus considered one of the deadliest human tumors. The new biologic drugs that have met success in many solid and hematologic malignancies constantly failed in glioblastoma, even though it harbors the same molecular alterations successfully hit in other tumors. The last advancement in glioblastoma therapy was in 2005, when it was shown that a subset of patients has a survival benefit from a multimodal combined therapy that includes irradiation and chemotherapy with the alkylating agent temozolomide. The patients who responded well to this regimen are those whose tumor presents hypermethylation of the CpG island at the promoter of the O⁶-methylguanine-DNA methyltransferase (MGMT) gene involved in the DNA repair mechanisms. Since then, many important discoveries on epigenetic modifications have shed light on physiologic and pathologic cell mechanisms and have contributed to the development of novel therapies for some cancers. Epigenetic modifications are likely one of the initial alterations in cancer development and a key mechanism that allows the transformed cells to continue to proliferate and invade the surrounding tissue, and because of their intrinsic reversibility, they are considered an important therapeutic opportunity. In recent years, we have witnessed the impressive advancement of the "omics" technologies that have allowed to identify genetic, proteomic, and epigenetic tumor characteristics that define unique subsets of patients that could likely benefit from specific therapeutic approaches operatively defined as "personalized." In this chapter, the basic concepts of personalized therapy will be described and how "epigenetic modifiers" could help in the future to build new standards of cure that are more specific and less toxic than those presently available.