Application of signal transduction inhibition as a therapeutic strategy for central nervous system tumors.

During the last decade, rapid progress has been made in understanding the molecular pathways underlying the proliferation of both normal and neoplastic cells. The processes by which messages to initiate protein synthesis, cell cycle progression, and even cell death are transmitted from the cell surface or the cytoplasm to the nucleus are broadly referred to as 'signal transduction'. These multistep pathways involve a host of proteins that interact with other proteins in overlapping cascades that flow downstream in a stepwise fashion from the cell membrane to the nucleus. Inappropriate overactivation or underactivation of various components of such signaling pathways can contribute to pathological processes, such as neoplasia. Conversely, molecular and pharmacological interventions that target and attempt to reverse the aberrant state of activation can potentially be of therapeutic benefit. The present article provides a background for understanding the contribution of signal transduction pathways to the proliferation of normal and neoplastic cells and describes ways in which targetted inhibition of selected signaling pathway components has been exploited to inhibit tumor growth in vitro and in vivo. Because most studies to date involving central nervous system (CNS) tumors have focused on gliomas, in view of their frequency in both the pediatric and adult age groups, the discussion of therapeutic applications for CNS neoplasia will deal primarily with these lesions. However, the basic concepts presented are generalizable to most tumor types and have been successfully applied in vitro in medulloblastomas as well. Ultimately, the translation of such strategies to the treatment of patients with malignant brain tumors may provide novel approaches for improving the poor outlook associated with these neoplasms.