Molecularly targeted therapies for recurrent glioblastoma: current and future targets

Abstract

Object: Glioblastoma is the most aggressive and diffusely infiltrative primary brain tumor. Recurrence is expected and is extremely difficult to treat. Over the past decade, the accumulation of knowledge regarding the molecular and genetic profile of glioblastoma has led to numerous molecularly targeted therapies. This article aims to review the literature and highlight the mechanisms and efficacies of molecularly targeted therapies for recurrent glioblastoma.

Methods: A systematic search was performed with the phrase "(name of particular agent) and glioblastoma" as a search term in PubMed to identify all articles published up until 2014 that included this phrase in the title and/or abstract. The references of systematic reviews were also reviewed for additional sources. The review included clinical studies that comprised at least 20 patients and reported results for the treatment of recurrent glioblastoma with molecular targeted therapies.

Results: A total of 42 articles were included in this review. In the treatment of recurrent glioblastoma, various targeted therapies have been tested over the past 10-15 years. The targets of interest include epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Ras pathway, protein kinase C, mammalian target of rapamycin, histone acetylation, and integrins. Unfortunately, the clinical responses to most available targeted therapies are modest at best. Radiographic responses generally range in the realm of 5%-20%. Progression-free survival at 6 months and overall survival were also modest with the majority of studies reporting a 10%-20% 6-month progression-free survival and 5- to 8-month overall survival. There have been several clinical trials evaluating the use of combination therapy for molecularly targeted treatments. In general, the outcomes for combination therapy tend to be superior to single-agent therapy, regardless of the specific agent studied.

Conclusions: Recurrent glioblastoma remains very difficult to treat, even with molecular targeted therapies and anticancer agents. The currently available targeted therapy regimens have poor to modest activity against recurrent glioblastoma. As newer agents are actively being developed, combination regimens have provided the most promising results for improving outcomes. Targeted therapies matched to molecular profiles of individual tumors are predicted to be a critical component necessary for improving efficacy in future trials.

Keywords: BBB = blood-brain barrier; CR = complete response; EGFR = epidermal growth factor receptor; MGMT = methyguanine DNA methyltransferase; OS = overall survival; PD = progressive disease; PDGFR = platelet-derived growth factor receptor; PFS = progression-free survival; PKC = protein kinase C; PR = partial response; RTK = receptor tyrosine kinase; RTKI = RTK inhibitor; SD = stable disease; TCGA = The Cancer Genome Atlas; VEGF = vascular endothelial growth factor; VEGFR = VEGF receptor; combination treatment; glioblastoma; mTOR = mammalian target of rapamycin; molecular therapy; overall survival; progression-free survival; recurrent.

Fig. 1

Combination bevacizumab, erlotinib, and temozolomide for glioblastoma. Left: Axial T1-weighted MR image with contrast showing a ring-enhancing lesion in the left temporal lobe, pathology proven glioblastoma. The patient underwent gross-total resection and adjuvant triple therapy with bevacizumab, erlotinib, and temozolomide for 1 year and observation off therapy. Right: Axial T1-weighted MRI with contrast showing no evidence of recurrent disease 3.5 years after initial surgery.