Abstract and Introduction
Glioblastoma (GBM) is the most common malignant primary brain tumor, which despite combined modality treatment, recurs and is invariably fatal. New therapies for GBM represent an unmet need in neuro-oncology. This review provides an overview of the epidemiology and molecular biology of GBM and focuses, in particular, on integrins, which are heterodimeric transmembrane surface proteins that, when activated, signal through several GBM-relevant pathways, including proliferation, motility, cytoskeleton organization, survival and angiogenesis pathways. Consequently, the potential effects of anti-integrin strategies in anti-GBM therapeutics are threefold: antiangiogenesis; anti-invasion; and anti-tumor. Trials of anti-integrins are most mature in GBM, and this review summarizes the completed and future trials of integrin inhibitors in the treatment of both newly diagnosed and recurrent GBM.
Glioblastoma (GBM) is the most common malignant primary brain tumor and is associated with a poor prognosis (median survival is approximately 15–20 months in protocol-eligible patients with newly diagnosed GBM). Approximately 15,000 individuals in the USA are diagnosed with GBM each year. Despite extensive research efforts, there have been few therapeutic advancements and consequently only incremental improvements in patient survival. The new standard of care for newly diagnosed GBM, introduced in 2005, is temozolomide (TMZ), an oral alkylating agent given concurrently with radiotherapy and for 6 months post-radiotherapy. This management strategy has resulted in some improvement; however, the prognosis for the majority of patients with GBM nonetheless remains discouraging. The juncture has nearly been reached where basic research in GBM is producing exciting new data that are defining the molecular basis for tumor development and suggesting biomarkers that are both predictive and prognostic. This new information is increasingly being used to design drugs and drug trials that target specific steps in the aberrant molecular biology of this aggressive and ultimately fatal cancer. Integrins are a family of cell surface receptor proteins that are involved in many critical pathways that contribute to the malignant phenotype of GBM. Integrins therefore represent potential anti-GBM targets for specific anti-integrin inhibitors. Accordingly, anti-integrins and integrin inhibitors are currently in advanced trials as novel agents to treat GBM. This article provides an overview of GBM pathophysiology, reviews the interplay between cancer cells and their environment, and highlights the involvement of integrins in this relationship. In addition, specific anti-integrin agents in development are described, along with current clinical trials suggesting that integrin inhibitors are valid and novel anti-GBM therapeutic agents. Constraints associated with targeted therapies are considered and the future outlook summarized as the pursuit of targeted therapies for GBM continues.
Expert Rev Neurother. 2012;12(4):421-435. © 2012 Expert Reviews Ltd.