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ONCOLOGY
Angiogenesis Inhibitors Revived, Revealed in Progress Against CancerThirty years ago, Judah Folkman proposed that cancers feed themselves by inducing their host to grow new blood vessels. Folkman, the Julia Dyckman Andrus professor of pediatric surgery at Children's Hospital and an HST faculty member, had the idea that if this process could be stopped, the tumors would lose their blood supply, wither, and die.
"TNP-470 was born here and is being improved here," said Judah Folkman, pictured above with scientists who have worked on the potent and newly promising angiogenesis inhibitor over the last two decades. From left are Donald Ingber, who discovered TNP-470 in the 1980s, Arin Greene, Ronit Satchi-Fainaro, Mark Puder, Folkman, and Gabriel Corfas. (Photos by Steve Gilbert) The concept has fueled a decades-long search for inhibitors of angiogenesis focused on therapies that kill or disable the specialized endothelial cells that form new vessels in tumors. Just last month, the first FDA-approved angiogenesis inhibitor, Avastin, hit the market after clinical tests showed it could prolong the life of colorectal cancer patients. Research from HMS continues to propel the field of anti-angiogenic therapy. Recent results from Folkman's lab are reviving interest in a powerful but previously discarded endothelial-cell inhibitor called TNP-470. And HST faculty member Rakesh Jain, the A. Werk Cook professor of radiation oncology (tumor biology) at Massachusetts General Hospital, and his colleagues report the first glimpse of how Avastin may work in concert with chemotherapy to deliver a double whammy to tumors in humans. Dusting Off TNP-470The story of TNP-470 started in the mid-1980's when Donald Ingber, HMS professor of pathology at Children's, was a postdoc in the Folkman lab and isolated the angiogenesis inhibitor from a fungus that had contaminated his endothelial cell cultures. Since then, more than 100 researchers have used TNP-470 to kill dozens of different types of tumors in animals, making it one of the most versatile antitumor compounds known. But despite early signs of antitumor activity in people, clinical trials foundered when the patients showed nervous-system toxicities like loss of balance and concentration.
The secret was to bulk up TNP-470 by conjugating it to a polymer that increased its weight 100 times. The large size seems to prevent the compound from passing through the blood-brain barrier. The researchers showed that unlike the parent, the conjugated TNP-470 did not enter the brain tissue in mice. To check for neurological toxicity, Satchi-Fainaro compared the ability of mice to balance on a rotating rod. Untreated mice balanced nearly 30 seconds before falling off while animals that had received TNP-470 fell off after only about 15 seconds. Mice treated with the conjugate TNP-470 performed as well as untreated mice, suggesting the conjugate did not affect their balance or motor skills. The new, weighty TNP-470 was as good or better at inhibiting tumor growth in mice as the original TNP-470, and according to Folkman, the conjugated TNP-470 is starting the long path back to the clinic amid interest from several pharmaceutical companies. Starve a Tumor, Feed a TumorProgress on understanding angiogenesis inhibition also has come from Jain and his colleagues, who for the first time directly observed what the drug Avastin can do to blood vessels in human tumors in the clinic. The results are a bit surprising. The researchers found that a single dose of Avastin caused the loss of a significant portion of a tumor's blood vessels. But rather than starve the tumor, the anti-angiogenesis treatment appeared to actually improve the function of the remaining vessels.That's good news, according to Jain, who explains that more efficient vascular function means that the chemotherapy agents used in conjunction with Avastin can be delivered to the tumor more efficiently.
Rakesh Jain and his colleagues got the first look at tumor blood vessels in patients treated with the angiogenesis inhibitor Avastin. Their results suggest that angiogenesis inhibitors can enhance the delivery of chemotherapy to tumors. Researchers working on the Avastin study include (above, front row, from left), Yves Boucher, Emmanuelle di Tomaso, Ricky Tong, and (rear) Dan Duda, Jain, Sergey Kozin, and Lance Munn. Inset: Christopher Willett. (Photo by Steve Gilbert) The apparently paradoxical result was no surprise to Jain, who has spent his career looking for ways to improve drug delivery to tumors. His studies have focused on the abnormal nature of the tumor vasculature as a barrier to drugs. Tumors have numerous blood vessels, but the network is chaotic and only permits sluggish blood flow. The vessels also are excessively leaky. As a result, the tumors fill with fluid and their internal pressure goes up, preventing drugs from getting inside. In Jain's clinical investigation, six patients with rectal tumors got a single dose of Avastin. Two weeks later, the research team, led by HMS professor of radiation oncology Christopher Willett, used several imaging techniques to determine the number and function of tumor blood vessels. CT scans showed the expected anti-angiogenic effect with a significant reduction in the quantity of tumor microvessels in five of the six patients. But the quality of the vessels was a different story. When the researchers looked at measures of vessel function, they found that the tumors had lower internal pressures, indicating the vessels were less leaky. Finally, they directly observed the ability of the vessels to deliver nutrients to the tumor by measuring uptake of a fluorescent glucose analog. "Kill half the blood vessels and the tumor is as lit up as it was before Avastin," said Jain. These results, published in February's Nature Medicine, support Jain's hypothesis that some angiogenesis inhibitors prune away a population of abnormal vessels, leaving a subset that function more like normal vessels. The normalization of vessels drops the internal pressure of the tumor and opens up what he calls a "window of opportunity" to deliver chemotherapy before the vessels are completely choked off by continued anti-angiogenic treatment. Folkman agrees. "Jain's article is very important, showing that angiogenesis inhibitors decrease intratumoral pressure in patients, " he said. "When the pressure goes down, you can get drugs in more easily." Now that angiogenesis blockers are becoming an accepted part of treating some well-advanced tumors in the clinic, Folkman has set his sights on a future goal of using the inhibitors to stop microscopic cancers before they grow a blood supply. "The availability of nontoxic angiogenic inhibitors may open a new era in cancer therapy," he said. By preventing tumors from initiating angiogenesis, Folkman believes that small cancers can be kept in check indefinitely. He will be well funded to test this idea over the next five years. He recently received a $5 million Breast Cancer Innovator Award from the U.S. Department of Defense for research on angiogenesis inhibitors in the early detection and treatment of breast cancer. --Pat McCaffrey |
