When children with neuroblastoma, a tumor originating in nerves, or Wilms tumor of the kidney come to Columbia-Presbyterian Medical Center for cancer treatment, doctors give the children chemotherapy and radiation therapy. But in aggressive cases, the cancers do not respond and the children die soon after the cancer is discovered.
To find more effective cures, Dr. Jessica Kandel, Irving Assistant Professor of Surgery, and Dr. Darrell Yamashiro, assistant professor of pediatrics, pathology, and surgery, teamed up to form the Pediatric Tumor Biology Laboratory to test anti-angiogenesis treatments in animal models of pediatric cancers.
Theoretically, anti-angiogenesis drugs should prevent new blood vessels from forming and fueling the growth of all types of tumors. But the researchers have found anti-angiogenesis drugs work on only certain tumors, and for a limited time, in some cases. All angiogenesis is not the same, Dr. Kandel says, so we need to test anti-angiogenesis drugs in each tumor-specific model.
Drs. Kandel and Yamashiro employ mice as models for certain common pediatric tumors, such as Wilms tumor and neuroblastoma. To make a mouse with a Wilms tumor, they inject millions of human Wilms tumor cancer cells into the mouses kidney. To make a mouse model of neuroblastoma, they inject human neuroblastoma cells into the mouse kidney. After a week, most of the mice have developed small tumors on the organ.
The two researchers tested the potential of anti-angiogenesis treatments to inhibit the growth of these small tumors. They injected the mice with anti-VEGF antibodies made by Genentech of South San Francisco, Calif., and currently in Phase III clinical trials in humans. The antibodies block the VEGF (vascular endothelial growth factor) that the tumor secretes to direct the growth of new blood vessels toward the cancer.
After six weeks of treatment, the researchers found that the Wilms tumors hardly grew at all, only reaching a size about 1 percent to 5 percent of the untreated control tumors, and didnt generate any metastases. Angiograms of control and treated tumors showed the expected effect: The untreated tumors were inundated with small blood vessels and the antibody-treated tumors had no vessels. But VEGF antibodies did not work as well in neuroblastoma. On average, neuroblastoma tumors grew to 40 percent of the size of the untreated tumors.
To determine if the anti-VEGF antibodies had failed to block new blood vessel growth in the neuroblastoma mouse model, the researchers postdoctoral fellow, Dr. Eugene Kim, looked at the microstructure of six-week-old tumors using a fluorescent dye. At first, he thought he did something wrong, since he did not see a fluorescent meshwork of blood vessels within the tumor. All he saw were glowing dots. The dots represented normal kidney blood vessels around which the tumor had grown.
Dr. Kims results suggested how the neuroblastoma resisted the anti-VEGF antibody: The antibodies could cut off the growth of new blood vessels to the tumor, but the tumor simply moved to pre-existing blood vessels in the kidney, particularly the glomeruli, and co-opted the blood supply for its own growth.
Longer-term studies with the Wilms tumor model also show that this tumor, which hardly grows at all in the first six weeks of treatment, starts to resist the anti-angiogenesis treatment after about two months of injections. But instead of using neuroblastomas strategy of moving to the site of existing vessels, the Wilms tumor stays put and widens existing vessels to increase the amount of oxygen delivered to the tumor.
Angiogenesis researchers initially believed cancers would not develop resistance to anti-angiogenic therapies because the therapies target genetically stable blood vessel cells and not the highly mutable cancer cells traditional therapies target. But the work of Drs. Kandel and Yamashiro, along with others who are testing anti-angiogenesis therapies, is providing evidence that at least some cancers employ clever strategies to survive. Adult tumors also are showing resistance to anti-angiogenesis factors.
Drs. Kandel and Yamashiro now are trying to understand the resistance strategies and are testing ways to overcome them in pediatric tumors. Combinations of anti-angiogenic drugs used simultaneously have a stronger effect on preventing tumor growth than each drug alone, they found. Their work was published in the March issue of the Journal of Pediatric Surgery. While a lot of children do well with current treatments, the ones that dont are the reason to look for better therapies, Dr. Kandel says. We see anti-angiogenic agents as another possible element in a multiple-drug approach.