Turning off a protein that helps grow blood vessels that feed tumors actually makes cancers get bigger, not smaller, according to two new studies. These studies raise questions about why certain drugs that try to decrease blood vessel growth around tumors to starve them of oxygen and nutrients have been disappointing when used by themselves—and why they may need to be combined with traditional chemotherapy.

Scientists at the University of California, San Diego knocked out genes for vascular endothelial growth factor (VEGF), a protein key to angiogenesis — the development of new blood vessels. These mice were then bred with a strain that develops mammary tumors. In those offspring, blood vessels didn't grow as much as they would have otherwise, but the remaining vessels were organized better than expected. At the same time, the tumor itself grew larger and was more likely to move on to a more advanced stage of the disease, according to the research in today's issue of Nature.

"Common dogma predicts that reducing VEGF makes the tumor smaller, but the tumor got larger," says David Cheresh, a co-author on the studies who is professor and vice chair of the department of pathology at UCSD's Moores Cancer Center.

But Cheresh says the findings don’t mean that blocking VEGF is a bad idea. Anti-VEGF drugs might be given to cancer patients before chemotherapy to keep intact the blood vessel network that feeds the tumors, making it more efficient at delivering medicine.

"When you reduce VEGF, the tumors grow bigger, but are more sensitive to drugs because the vessels grow bigger," Cheresh says.

The development of VEGF inhibitors is a hot area of cancer drug development, and the angiogenesis concept has been hyped in the popular press for a decade. A few  anti-angiogenesis drugs are approved: Sutent for kidney cancer, Gleevec for stomach cancer and Avastin for breast cancer. But Avastin prolongs life for only a few months when it's combined with chemotherapy, and other candidates, such as PTK/ZK didn’t slow colorectal cancer, PharmaDD notes in a review of the angiogenesis concept.

The Nature papers may explain the mechanism by which Avastin works, Cheresh says. "It's hard to say" if the findings explain why other anti-angiogenesis drugs haven’t been more successful, he says.

"The Nature papers are interesting in terms of the detailed mechanistic insights they provide, and support much of what is known about how VEGF works, but this information doesn’t change our understanding of how to administer Avastin or its clinical benefit," Genentech said in a statement.

Cheresh is scientific founder of San Diego-based TargeGen, which he said is working on drugs unrelated to the newly published research. His team at UCSD is developing chemical compounds that target another blood vessel growth receptor that may ultimately be used as anti-cancer medication.

(Updated at 11:40 a.m. Nov. 10 with Genentech comment.)

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