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Researchers find angiogenesis inhibitors effective in metastatic clear cell renal cell cancer treatment

American Association For Cancer Research (AACR) : 14 June, 2007  (Technical Article)
According to accumulating evidence, angiogenesis inhibitors can be far more effective in treating metastatic clear cell renal cell cancer, an aggressive form of the most common kind of kidney cancer that is also rich in blood supply, than traditional treatments. They can prolong life in about a third of patients, but researchers have not been able to identify the responding patients, prior to treatment.
A research team from the University of California, San Francisco and the Cleveland Clinic, has now found that patients whose tumors produce greater amounts of vascular endothelial growth factor and its receptor benefit most from these targeted treatments, because these proteins are the “targets” they are designed to go after.

“The more VEGF and VEGF receptor a patient’s tumor has, the better these treatments seem to work,” said the study’s lead author, Erich B. Jaeger, Ph.D., a postdoctoral researcher at the UCSF Comprehensive Cancer Center. “This is very exciting because, if validated, a fairly simple test could help oncologists direct these new treatments to patients who can benefit most from them.”

Results were presented at the first meeting on Molecular Diagnostics in Cancer Therapeutic Development, organized by the American Association for Cancer Research.

Clear cells RCCs often accumulate VEGF and other angiogenesis-related proteins due to mutation in the Von Hippel-Lindau tumor suppressor gene. This gene was identified as the cause of the rare and inherited Von Hippel-Lindau disease, which is characterized by frequent development of clear cell renal tumors.

About half of non-inherited clear cell renal cell cancer is believed to result from mutations in the VHL gene, Jaeger said. The mutations prevent proper degradation of specific VHL target proteins, which leads to over-expression of VEGF and other proteins associated with angiogenesis, he said. These proteins cause the tumor to become highly vascular, establishing a solid blood supply to feed the cancer. When functioning normally, VHL helps regulate the production of those proteins that might otherwise contribute to tumorigenesis.

But not all VHL mutations are alike, Jaeger says. Some cause substantial changes in the protein it encodes, leading to accumulation of VEGF, and others cause less functional difference.

In this study, the research team examined 43 tumor samples taken before patients were slated to receive angiogenesis inhibitors, and they found that 25 contained VHL mutations. Of these, 15 had mutations that led to severe disruption of the normal structure of the VHL protein.

They then correlated response to the drug with the level of VEGF and its receptor in the samples, and found that “patients who had the highest levels of expression of VEGF receptor had the best response to therapy,” Jaeger said. These patients experienced nearly a doubling in time to progression, gaining about six months, he said. “Because high levels of these proteins help drive the growth of tumors, it makes sense that if they are targeted and eliminated, the tumors don’t progress as fast.”

The researchers are preparing to test their mutational analyses on a set of renal tumor samples taken from 700 patients who were treated with Avastin, an angiogenesis inhibitor initially approved to treat advanced colon cancer. They also plan to improve the test by adding certain common mutations involving tumor suppressor genes, and the ability to look for these same mutations in paraffin-embedded tumors, which is how most samples are now prepared.
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