Computational Analysis of Drug Therapy Options for Glioblastoma

Abstract

Glioblastoma (GBM) is the most common primary brain tumor in the US and European countries and also the deadliest.  Glioblastoma cells exhibit a different gene expression profile from normal cells. There are 601 known mutations in GBM tumors. The aim of this study was to identify the most important proteins in the glioblastoma pathway that lack drug treatments. A total of 15 proteins were identified as pathway starters or driver proteins and 52 proteins were identified as passenger proteins using 3 databases. Protein-protein interaction maps and heatmaps were created and proteins were ranked based on the number of connections each protein exhibited. The top 9 proteins were identified that are important in GBM pathway. Then a protein-drug interaction map and heat map were created to find influential disease-causing proteins that currently lack drug treatments. Through this method, TERT, MDM2, and RB1 were found to be important proteins that lacked drug treatments. Drug development is needed to target these genes and a multiple target approach is needed since more than one pathway is involved in all GBMs. This could lead to new therapeutic options for glioblastoma.

Introduction

Glioblastoma Multiforme (GBM) is the most malignant form of brain tumor with a median survival of 15 months. 1 The annual incidence of GBM is 3.19 per 100,000 people in the USA.2  Glioblastoma is caused by over-expression of oncogenes, inactivation of tumor-suppressor genes, and dysregulation of signaling proteins. A number of abnormalities in protein pathways lead to the development and growth of this tumor. There are 601 known mutations in GBM tumors, some of which regulate the key steps that contribute to tumor development and growth.3  For this reason, I used a computational method to find the most important proteins in GBM for future drug research. The current treatment of GBM includes surgical resection of the tumor, followed by radiation and chemotherapy. Surgical treatment of cancerous tumors usually involves the removal of some normal tissue surrounding the tumor, in order to ensure that there are no microscopic remnants of the tumor. This helps in preventing recurrence of these tumors.  GBM is extremely hard to remove completely by surgery because of its ill-defined boundaries and location. An attempt to remove normal brain tissue surrounding the tumor can lead to serious neurological sequelae. Therefore, radiation and chemotherapy are given to kill the remaining tumor tissue. Radiation has similar limitation as surgery because it can destroy normal brain tissue also. Chemotherapy, given in the form of drugs, targets various proteins involved in the tumor development and growth pathway in order to prevent recurrence. The five-year survival rate with current treatment regimens is only 4-5% and the median survival is 15 months. 1 There is an unmet and urgent clinical need for new drug development in this area.

Objective

My objective is to identify the most influential disease-causing proteins that are overexpressed or dysregulated in the tumorigenesis pathways involved in the initiation and development of glioblastoma through protein-protein interaction maps and to find proteins that lack drug treatments through protein-drug interaction maps.

Methods

Creating a set of proteins whose protein-protein interactions should be examined

Three databases were studied to identify driver genes or pathway starters in glioblastoma. A starter or driver protein is the main protein that initiates a cellular pathway. A passenger protein is a protein that plays a minor role somewhere along the cellular pathway, but is not essential to it. These databases were KEGG (Kyoto Encyclopedia of Genes and genomes), COSMIC (Catalogue Of Somatic Mutations In Cancer), and TCGA (The Cancer Genome Atlas)4,5,6 A total of 15 pathway starter proteins were recorded using these databases. These 15 proteins are EGFR, PDGFRA, PTEN, PIK3CA, PIK3R1, H3F3A, TERT, RB1, MDM2, CHEK2, CDK4, CDKN2A, TP53, NF1, and IDH1. From these sources, 52 other proteins were also identified as important in glioblastoma pathways but were not pathway starters. These are the so called passenger proteins.