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Vascular Normalization: Study Examines How Antiangiogenesis Therapies Work

Tracy Webb

It is a widely held belief that antiangiogenic therapy eradicates tumor vasculature, thus depriving the tumor of oxygen and nutrients necessary for survival. But this may not be the complete story. A new study published in December in Cancer Cell suggests that antiangiogenic therapy may also "normalize" the tumor vasculature for a short period of time, thereby providing a window of opportunity for improved drug delivery and enhanced sensitivity to radiation treatment.

Clinical trials have suggested a benefit to giving antiangiogenic agents in combination with other therapies to be effective; for example, a recent phase III clinical trial found that Avastin (bevacizumab), a vascular endothelial growth factor (VEGF) inhibitor, increased survival in colorectal cancer patients when given in combination with chemotherapy. Preclinical data also suggest that radiation therapy is more effective when given in combination with an antiangiogenic agent. But if antiangiogenic agents really produce hypoxia, how are they able to augment the response to radiation and to chemotherapy, which is delivered to the tumor via the vasculature?

"We are changing our thinking about antiangiogenic therapy by 180 degrees," said study author Rakesh Jain, Ph.D., professor of tumor biology at Harvard Medical School and director of the Steele Laboratory for Tumor Biology at Massachusetts General Hospital in Boston. "It was widely believed that antiangiogenesis therapy would starve the tumor to death by increasing hypoxia, but now we show that, if used properly, it can do the opposite—it can actually improve oxygenation and create a more ‘normalized’ environment. This will allow us to [use] antiangiogenic therapy differently."



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Rakesh Jain

 
Window of Normalization

Using gamma radiation and a VEGF receptor 2–specific monoclonal antibody, DC101, individually and in combination to treat mice containing human glioblastoma xenografts, Jain and colleagues found that giving radiation therapy 4 to 6 days after DC101 treatment delayed tumor doubling time by more than 21 days, which exceeded the expected additive effect. Upon further observation, tumor hypoxia decreased 2 days after DC101 treatment, was almost abolished by day 5, and increased again by day 8. This finding suggests that antiangiogenic therapy increases tumor oxygenation, thereby enhancing the tumor's response to radiation.



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Proposed normalization window

Rakesh Jain and colleagues developed the model above as the proposed effect of drug dose and schedule on tumor vascular normalization. During the "normalization" window, cancer cells may be more vulnerable to cytotoxic and targeted therapies. (Source: Science 2005;307:58–62.)

 
"I believe that the results are relevant to the use of VEGF blockade with any treatment that is oxygen- or delivery dependent," said Mark Dewhirst, D.V.M., Ph.D., professor of radiation oncology at Duke University Medical Center in Durham, N.C. "Radiotherapy is one example, but there are others. If there is normalization of perfusion, this could influence the uniformity of delivery of many small molecules, such as other drugs. So, this window of opportunity might extend to use with many chemotherapeutic drugs."

In addition to reducing hypoxia, DC101 treatment was associated with recruitment of pericytes—cells that help shore up vessel walls—to the tumor blood vessels, which stabilizes the leaky, dilated vasculature, common characteristics of these vessels. By day 8, pericyte-covered vessels had decreased in number. Vascular normalization thus occurred between days 2 and 5 after blocking VEGF.

"This appears to be contradictory to the standard theory of antiangiogenesis therapy, which is that it ‘chokes’ the tumor's blood supply. But vascular normalization and eradication may go on simultaneously and may be temporally related," said Lee Ellis, M.D., professor of surgery and cancer biology at the University of Texas M. D. Anderson Cancer Center in Houston. "This is probably the most important paper demonstrating just how complex angiogenesis and antiangiogenic therapy really is," he said.

Clinical Concerns

"This is very elegant work in mice. We now need to see how we can best apply this knowledge to humans. This is where the challenge lies, because humans are much more complex," said Ellis, who stressed that each tumor type is going to be different. In addition, he pointed out that solid tumors depend on more than VEGF for survival, and a combination of antiangiogenic agents would likely be needed to block all pathways.

Dewhirst said he is concerned about the relatively short time window over which the normalization effect occurs. If the window of opportunity is only a few days in human tumors, can researchers realistically take advantage of it?

"Normally, radiotherapy is given in multiple doses over several weeks," Dewhirst said. "One could increase the dose administered during a short period of reoxygenation, but I have a hard time believing that this would make much of a difference in improving the likelihood for local control. However, it might be that the time interval for improvement in oxygenation is longer in human tumors."

Jain and colleagues have begun the process of answering some of these questions in a clinical setting. Under the lead of Tracy Batchelor, M.D., at Massachusetts General Hospital, they will begin recruiting patients with glioblastoma multiforme and head and neck cancer for a clinical trial that was just approved by the National Cancer Institute, and that may begin as early as the end of this year. Using a number of VEGF blockers, they will address the question of whether, and when, vascular normalization occurs in humans.



             
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