Normalization of tumor vasculature and microenvironment

Solid tumors require blood vessels for growth, and many new cancer therapies are targeted against the tumor vasculature. The widely held view is that these antiangiogenic therapies destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. Indeed, that is the ultimate goal of antiangiogenic therapies. However, emerging preclinical and clinical evidence support an alternative hypothesis, that judicious application of agents that block angiogenesis directly (e.g., bevacizumab, AZD2171) and indirectly (e.g., trastuzumab) can also transiently normalize the abnormal structure and function of tumor vasculature. In addition to being more efficient for oxygen and drug delivery, the normalized vessels are fortified with pericytes, which can hinder intravasation of cancer cells, a necessary step in hematogenous metastasis. Drugs that induce vascular normalization can also normalize the tumor microenvironment-reduce hypoxia and interstitial fluid pressure-and thus increase the efficacy of many conventional therapies if both are carefully scheduled. Reduced interstitial fluid pressure can decrease tumor-associated edema as well as the probability of lymphatic dissemination. Independent of these effects, alleviation of hypoxia can decrease the selection pressure for a more malignant phenotype. Finally, the increase in proliferation of cancer cells during the vascular normalization window can potentially sensitize tumors to cytotoxic agents. Our recent Phase II clinical trial in glioblastoma patients shows that the normalization window-identified using advanced magnetic resonance imaging (MRI) techniques-can last one to four months, and the resulting changes in tumor vasculature correlate with circulating molecular and cellular biomarkers in these patients.