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For the first time, an experimental drug designed to cut off a cancer’s blood supply has gone beyond stopping tumors from growing to actually shrinking them, according to new research from Drs. Jessica Kandel, Irving Assistant Professor of Surgery, and Darrell Yamashiro, Irving Assistant Professor of Pediatrics and Pathology.

“The drug, VEGF-Trap, offers hope to patients with large metastatic cancers that their tumors may indeed regress,” Dr. Kandel says. The study was published in the online issue of the Proceedings of the National Academy of Sciences on June 9 and in the print version on June 24.

The new agent blocks angiogenesis – the process by which vessels feed tumors with a new blood supply. If tumors can be starved of blood by drugs, tumor progression can theoretically be forestalled.

The researchers gave the drug to mice with large human cancers that had spread to the lungs. Within 24 hours the drug began to destroy blood vessels inside the tumors, and after five weeks the tumors and the metastases had shrunk by 80 percent compared with their pre-treatment sizes.

The new drug made by Regeneron Pharmaceuticals works similarly to Genentech’s Avastin, the first angiogenesis inhibitor found effective in a Phase III trial. Both drugs block VEGF (vascular endothelial growth factor), a substance that tumors release to promote vessel growth.

Unlike Avastin, VEGF-Trap consists of two VEGF receptors fused to one part of a human antibody. After the receptors bind VEGF, the body’s immune system destroys the drug and the attached VEGF. VEGF-Trap appears to be a stronger inhibitor of the growth factor than Avastin.

Because VEGF stimulates new blood vessel growth, drugs that work against VEGF were not expected to affect established blood vessels and thus shrink tumors. Drs. Kandel and Yamashiro found, though, that VEGF-Trap dismantles pre-existing blood vessels in the tumor, causing regression, while leaving vessels in normal tissues alone. “There are intrinsic abnormalities in tumor blood vessels and they probably need a constant supply of VEGF to keep the vessels intact,” Dr. Kandel says. “It’s like the difference between good plumbing, which rarely needs repair, and bad plumbing, which is constantly breaking down and leaking.”

The study was funded by the NCI, the Pediatric Cancer Foundation, and the Sorkin Fund.

—Susan Conova

Stroke is the third-leading cause of death in the United States and a significant percentage of those deaths can be attributed to clogged carotid arteries. For most patients with severe carotid blockages, surgeons open up the artery and scrape out the plaque, but P&S researchers are now investigating stents as an equally effective stroke prevention treatment.

Initial studies suggested that stenting is as safe as surgery in patients at high risk for surgical complications.

The risk of stroke from clogged carotid arteries comes mainly from plaque breaking off in the neck and lodging in smaller arteries in the brain, cutting off blood flow. Surgery removes the plaque and lowers stroke-risk from 29 percent to 9 percent in symptomatic patients. Stenting is less invasive – a balloon compresses the plaque and then a tiny tubular metal scaffold is placed in the artery. The stent is guided into position by threading a catheter into the carotid artery through a small leg incision.

An ongoing multi-center randomized trial is now comparing stenting to surgery in symptomatic patients. The NewYork-Presbyterian Division of Vascular Surgery and 60 other centers are participating in the 2,500-patient trial.

Columbia surgeons are also testing the safety and efficacy of stenting in patients who make poor surgical candidates. Both trials are testing stents that deploy a filter upstream of the plaque to catch any debris dislodged by the stent insertion. The filter – which looks like an umbrella with small holes or a windsock, depending on the manufacturer – catches debris while allowing blood to flow to the brain.

“In patients with a lower risk of surgical complications, such as stroke, surgery is still probably the best way to be treated,” says Dr. Daniel Clair, the division’s site chief. “But technologies that make the stents safer are changing so rapidly that interventional therapies may become the most common treatment in the future.”

This work is funded by the NIH and stent-makers Medtronic and Endotex.

—Susan Conova

The cell’s inability to efficiently repair double-strand DNA breaks leaves people prone to cancer and other diseases.

Now, for the first time, Columbia researchers have caught the repair process on video, a feat that will enable researchers to better understand the cell’s ability to fix DNA breaks. The research was published in the June issue of Nature Cell Biology.

The video shows that DNA double-strand breaks are repaired in only one, or a few, repair centers inside the nucleus of yeast cells. Double-strand break repair is similar in all eukaryotes, including humans.

The limited number of repair sites potentially benefits the cell in three different ways, say the paper’s authors, Dr. Rodney Rothstein, professor of genetics & development in the Institute for Cancer Genetics, and postdoctoral fellow Dr. Michael Lisby.

First, the sites concentrate the molecules needed for repair in a small region, which may increase repair rate. Second, because cells don’t divide until repair is complete, a limited number of sites could reduce the workload of the checkpoint molecules that determine when it’s safe to replicate. Finally, the centers may provide scaffolding for the broken ends of DNA to assure proper alignment during the repair.

See the video at http://rothsteinlab.hs.columbia.edu.

The research was funded by the NIH and the Danish Natural Science Research Council.

—Susan Conova


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