Next-Generation Sequencing in Glioblastoma Personalized Therapy

Abstract

The most common and aggressive form of intracranial tumors is glioblastoma (GBM). These tumors show significant amount of proliferation, invasion, angiogenesis and necrosis. The current treatment modality that includes surgery, radiotherapy and temozolomide chemotherapy fails to provide great benefit with the median survival remaining at a dismal 15–17 months. The response to standard therapy is highly variable which is primarily determined by the differences in the genetic makeup of the tumor. Hence, it is required that clinicians stratify the patients based on prognostic features such that appropriate therapy can be given as per aggressiveness of the tumor. However, it has been observed that almost all GBM tumors recur. This demands the necessity of alternative therapeutic options for the treatment of GBM. In recent times, Next Generation Sequencing (NGS) based techniques help us to interrogate the genome of cells in a comprehensive manner. Intensive studies have revealed various genetic alterations typical to GBM, e.g., TP53 mutation and loss, EGFR amplification and mutation, INK4a/ARF mutation, MDM2/4 amplification or overexpression, PTEN mutation and loss of heterozygosity (LOH) in chromosome 10p and 10q. Through the past few decades, many studies have been carried out to identify small molecule inhibitors and antibodies against various molecules deregulated in different cancers such that they can be used for targeted therapy. Moreover, each tumor harbors a spectrum of genetic alterations that are different from another tumor. Hence, personalized therapy, tailored to target tumor-specific alterations is the approach to be developed for improvement of survival of GBM patients. For identification of genetic alterations in each tumor, sequencing of the tumor DNA has to be carried out. For that purpose, NGS-based targeted sequencing of all known GBM-specific driver alterations is a lucrative option. In this chapter, we have discussed about how targeted sequencing can be used for identifying all driver genetic alterations in each GBM tumor such that those molecules can be targeted using small molecule inhibitors and antibodies against them.