Abstract
Despite relevant progress obtained by multimodal treatment, glioblastoma (GBM), the most aggressive primary brain tumor, is still incurable. The most encouraging advancement of GBM drug research derives from the identification of cancer stem cells (CSCs), since these cells appear to represent the determinants of resistance to current standard therapies. The goal of most ongoing studies is to identify drugs able to affect CSCs biology, either inducing selective toxicity or differentiating this tumor cell population into nontumorigenic cells. Moreover, the therapeutic approach for GBM could be improved interfering with chemo- or radioresistance mechanisms, microenvironment signals, and the neoangiogenic process. During the last years, molecular targeted compounds such as sorafenib and old drugs, like metformin, displayed interesting efficacy in preclinical studies towards several tumors, including GBM, preferentially affecting CSC viability. In this review, the latest experimental results, controversies, and prospective application concerning these promising anticancer drugs will be discussed.
Highlights
Section of Pharmacology, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genova, Viale Benedetto XV, 2 16132 Genova, Italy
The most encouraging advancement of GBM drug research derives from the identification of cancer stem cells (CSCs), since these cells appear to represent the determinants of resistance to current standard therapies
The therapeutic strategy to improve the survival of GBM patients is based on a multimodal approach which includes maximal cytoreductive surgery followed by a combination of radiation and adjuvant chemotherapy with temozolomide (TMZ) [1]
Summary
Glioblastoma (GBM), classified by World Health Organization as grade IV astrocytoma, is the most common primary brain tumor in adults, accounting for more than 50% of all gliomas. The therapeutic strategy to improve the survival of GBM patients is based on a multimodal approach which includes maximal cytoreductive surgery followed by a combination of radiation and adjuvant chemotherapy with temozolomide (TMZ) [1]. RT prolongs survival of GBM patients compared to surgery alone, the responsiveness of GBM to RT is extremely variable, inducing a transitory phase of remission, characterized by stability or regression of neurologic deficits as well as reduction of the tumor size, followed by tumor recurrence, resulting in further fatal clinical decline within one year [3]. Preclinical and clinical studies are focused on (I) the identification of mechanisms to overcome TMZ resistance, (II) the development of molecular targeted and antiangiogenic agents, (III) immunotherapy, and (IV) drug combination. Only bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), was approved by the U.S FDA in 2009 as a single agent for recurrent GBM [8], a significant impact on overall survival was not observed [9]
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