October 20005, Vol. 12, No. 2

Authors: Nicholas Butowski, MD, Susan M. Chang, MD

Abstract

Background: The prognosis for most patients with primary brain tumors remains poor. Recent advances in molecular and cell biology have led to a greater understanding of molecular alterations in brain tumors. These advances are being translated into new therapies that will hopefully improve the prognosis for patients with brain tumors.
Methods: We reviewed the literature on small molecule targeted agents and monoclonal antibodies used in brain tumor research and brain tumor clinical trials for the past 20 years.
Results: Brain tumors commonly express molecular abnormalities. These alterations can lead to the activation of cell pathways involved in cell proliferation. This knowledge has led to interest in novel anti-brain-tumor therapies targeting key components of these pathways. Many drugs and monoclonal antibodies have been developed that modulate these pathways and are in various stages of testing.
Conclusions: The use of targeted therapies against brain tumors promises to improve the prognosis for patients with brain tumors. However, as the molecular pathogenesis of brain tumors has not been linked to a single genetic defect or target, molecular agents may need to be used in combinations or in tandem with cytotoxic agents. Further study of these agents in well-designed cooperative clinical trials is needed.

Introduction

Malignant gliomas are challenging to treat and are associated with a high degree of morbidity and mortality. Standard treatment usually consists of cytoreductive surgery followed by radiation therapy. Based on several meta-analyses, adjuvant chemotherapy appears to add some survival benefit, but its efficacy is limited.[1-4] Standard chemotherapy agents used to treat malignant glioma are non-cell-cycle specific and aimed at inducing cell death. Recent advances in molecular and cell biology have expanded our understanding of the genetic and cellular alterations that may lead to brain cancer.[5] For example, the transformation into cancer may involve amplification of oncogenes and/or loss of tumor suppressor genes. Such advances in the knowledge of these genetic and cellular alterations have been translated into new treatment agents that "target" these alterations in cell-signaling pathways and bring hope of improved prognosis for patients with brain tumors. However, this hope comes with the caution that new agents need to be studied in well-designed and properly conducted clinical trials before efficacy can be determined. This article reviews some of the molecular abnormalities found in malignant glial tumors and the related emerging molecularly targeted therapies.