Our trials of antiangiogenics in patients with newly diagnosed and recurrent glioblastoma supported this concept. Indeed, we demonstrated that judicious use of antiangiogenic agents-originally designed to starve tumors-could transiently normalize tumor vasculature, alleviate hypoxia, increase delivery of drugs and antitumor immune cells, and improve the outcome of various therapies.

We next hypothesized that agents that induce normalization of the microenvironment can improve treatment outcome. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells, and extracellular matrix associated with tumors are abnormal, which together create a hostile tumor microenvironment. Working on the hypothesis that the abnormal tumor microenvironment-characterized by hypoxia and high interstitial fluid pressure-fuels tumor progression and treatment resistance, we developed an array of sophisticated imaging technologies and animal models as well as mathematic models to unravel the complex biology of tumors. For almost four decades, my work has focused on one challenge: improving the delivery and efficacy of anticancer therapeutics.

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