Towards Tailored Therapy of Glioblastoma Multiforme

Abstract

Gliobastoma multiform (GBM) is the most common and aggressive brain tumor, which is characterized by its infiltrative nature. Current standard therapy for GBMs consists of surgery followed by radiotherapy combined with the alkylating agent temozolomide (TMZ). Recent clinical trials have demonstrated that this chemo-irradiation approach results in a significant increase in survival compared to radiotherapy alone. Nevertheless, due to tumor recurrence, the median survival time is still limited to approximately 15 months. Recently, several studies have focused on aberrant signal transduction in GBM, resistance mechanisms of GBM to TMZ and to radiotherapy. Attention has been focused on molecular targets including phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, protein kinase C (pKC) pathway, Ras/mitogen-activated protein kinase pathway (MAPK), Wnt pathway and intrinsic or extrinsic apoptosis pathways. In addition, research has been directed to radiotherapy and radiosensitizing agents, and cancer gene therapy as well. This article will address several resistance mechanisms of GBM to chemotherapy and radiotherapy and the recent preclinical and clinical studies on targeted therapy.

Glioblastomas: are individual therapies required for individual tumors?

“…Since IDH-1 mutations are related to a better prognosis and might help to differentiate between primary and secondary glioblastoma, they have a valuable diagnostic potential, however, therapeutic approaches using the IDH-1 pathway are not described [4,7,16]. In primary tumors, manifesting themselves as highgrade tumors from the beginning, phosphatase and tensin homologue (PTEN) mutations are a common, however, not general finding [8,16].…”

“…By Stupp and coworkers, it was shown in a randomized study that treatment with oral Temozolomide, a cytostatic drug, acting as an alkylating agent, leads to a limited, yet significant prolongation of survival with acceptable toxicity. Previously, for example a large clinical study examining combined Procarbacin, CCNU (Lomustin) and Vincristin (PCV), had reported a very modest gain of survival with radiotherapy plus PCV versus 13 months with radiotherapy alone; however, the toxicity connected with such a therapy approach led to a significant debate regarding the actual benefit for the patient [1,3,7,8]. In children, systemic approaches have already been standard in therapy back from the nineties, however, here, the cure rate was also dismal -although in general, it is slightly better than in adults [9].…”

“…Thus they dictate the behaviour of the cells -including processes of differentiation, cell cycle progress, proliferation, migration, or apoptosis [8,16,19]. Therefore, the relevance of growth factor receptor alterations in glioblastomas is evident.…”

“…Particularly common genetic factors in high grade gliomas include classical oncogenetic alterations like mutations in p53 or PTEN [7,8,16], which are very frequent in glioblastomas, while microsatellite instability is only observed in a small subgroup [16]. Loss of heterozygosity in numerous chromosomes may also lead to functional alterations of tumor suppressor genes [16].…”

“…Many new concepts have been developed after the work of Stupp et al, and an enormous lot of different systemic therapy approaches have been developed in the last years -besides cytostatic chemotherapy, multiple agents with molecular targets, agents inducing differentiation or cell cycle arrest, anti-angiogenetic approaches, or immunotherapy, nanoparticles, oncolytic viruses, and others [1,7,8]. But, there still is a large gap between optimistic concepts and final results: in each of these therapies, clinical studies, although initiated with much enthusiasm, ended up with disappointing results -none of the new targeted substances, for example, could, as monotherapy, improve significantly the prognosis of glioblastomas in a larger number of patients.…”