Molecular Therapeutic Agents

Signal transduction modulators. Advances in the molecular biology of brain tumors have led to the development of ''targeted therapeutics'', designed to exploit the signal transduction pathways mediating the malignant phenotype [193-197]. The pathways that have been most intensely studied include the epidermal growth factor and receptor (EGF, EGFR), platelet-derived growth factor and receptor (PDGF, PDGFR), Ras, phosphoinositide 30 kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), and p53, as well as the processes of tumor invasion, apoptosis, and the cell cycle [193-200]. The drugs that have been advanced the furthest in clinical testing include tyrosine kinase inhibitors of PDGFR (e.g., imatinib) and EGFR (e.g., geftinib, erlotinib), farnesyl-transferase inhibitors designed to reduce Ras activity (e.g., R115777), and mTOR inhibitors (e.g., CCI-779, RAD-001) [193,194]. Numerous other ''targeted agents'' are in development or early phases of clinical evaluation. Thus far, single-agent molecular therapeutic drugs have demonstrated minimal, if any, activity against malignant gliomas in clinical trials. Ongoing and new clinical trials will investigate the use of these drugs in combination with cytotoxic agents (e.g., temozolomide) and other molecular agents that target different pathways.

Angiogenesis inhibitors. For tumors to enlarge beyond 2-3 mm3 size (approximately one million cells), they must acquire the angiogenic phenotype and induce neovascularization [194,201]. The switch to the angiogenic phenotype involves up-regulation of the angiogenic factors (e.g., basic fibroblast growth factor, vascular endothelial growth factor (VEGF)) and down-regulation of angiogenesis inhibitors (e.g., thrombospondin-1) in the local environment. This process is important for the growth of PBT as

thalidomide figure 2.15

well as systemic neoplasms [202]. For example, there is a significant inverse correlation between the density of vessels in astrocytic gliomas and postoperative survival [203]. Patients with the highest microvessel density had the most malignant tumors and the shortest survivals. Several investigators have demonstrated extensive expression of VEGF and its receptors in gliomas and other PBT [204,205]. Bernsen and colleagues treated glioma xenografts in nude mice with TNP-470, a semisynthetic analog of fumagillin with antiangiogenic properties, but were unable to consistently demonstrate growth inhibition or alteration of vascular parameters [206]. In a phase II trial of the antiangiogenic agent thalidomide, Fine and coworkers treated 35 patients with recurrent high-grade gliomas (see Fig. 2.15) [207]. There were two minor responses noted among the first 10 evaluable patients. Other angiogenesis inhibitors, such as angiostatin, endostatin, and SU11248 are under consideration for clinical trials in brain tumor patients.

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