Beyond maximum tolerated doses: COMBATing poor prognosis pediatric cancer.

Although the past 30 years have seen remarkable progress in the treatment of childhood malignancies, not all types of cancer have achieved this improvement in prognosis. The outcome for children with metastatic sarcomas, and some other high risk, or relapsed malignancies continues to be poor despite the use of dose-intensified chemotherapy and/or high dose chemotherapy. Intensification of therapy by dose escalation beyond the standard, MTD chemotherapy regimes has not yielded definitive evidence of increased activity so far, and additional treatment strategies are needed. Novel treatment approaches are being evaluated, including immunotherapy, radionuclide therapy, and the use of novel apoptosis and/or differentiation inducers. Among novel cancer treatment strategies is the inhibition of angiogenesis one of the most promising. Angiogenesis is fundamental in many biological processes, and it is tightly regulated under normal condition. In cancer tissues, compelling data suggest that inhibition of angiogenesis cannot only prevent tumor-associated neovascularization but also affects tumor growth and spread. An anticancer approach in which the tumor-induced new blood vessels are targeted is particularly appealing for several reasons. First, despite the extreme molecular and phenotypic heterogeneity of human cancer, it is likely that most, if not all, tumor types require neovascularization to achieve their full malignant phenotype. Second, the endothelial cells, although rapidly proliferating, are inherently normal with a very low rate of mutation. Therefore, they are unlikely to evolve an angiogenesis inhibitor-insensitive phenotype. This is in distinction to the rapidly proliferating tumor cells that do undergo a high rate of spontaneous mutation and therefore can readily generate drug-resistant clones…

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