Bevacizumab-Dasatinib Combination Shows Promise in Treating Brain Cancer

Volume 2, Issue 2, 2013

Summary

Using bevacizumab and dasatinib together may shrink tumors and block them from spreading.

Panagiotis Z. Anastasiadis, Ph.D., chair of the Department of Cancer Biology at Mayo Clinic in Florida and co-leader of the Mayo Clinic Cancer Center Cell Biology Program

Panagiotis Z. Anastasiadis, Ph.D.

The drug bevacizumab (Avastin) shrinks tumors briefly in patients with an aggressive brain cancer known as glioblastoma multiforme. But then the tumor often grows again and spreads throughout the brain for reasons not previously understood.

Now, Mayo Clinic Cancer Center researchers have found out why this can happen. They have also discovered that pairing bevacizumab with dasatinib (Sprycel), another cancer drug, can stop that lethal brain tumor spread.

The findings, based on an animal study, were published in an article in the Feb. 14, 2013, online issue of the journal PLOS ONE.

Based on those results, Mayo Clinic Cancer Center researchers have already conducted a phase I clinical trial testing a combination of bevacizumab and dasatinib in glioblastoma patients whose other therapies didn't work.

Mayo Clinic is now conducting a randomized phase II study of 100 patients through the Alliance for Clinical Trials in Oncology, a clinical trials network supported by the National Cancer Institute.

"We are very encouraged. This finding could potentially benefit many cancer patients," said article co-author Panagiotis Z. Anastasiadis, Ph.D., chair of the Department of Cancer Biology at Mayo Clinic in Florida and co-leader of the Mayo Clinic Cancer Center Cell Biology Program. Working with him were researchers and oncologists from Mayo Clinic Cancer Center campuses in Florida and Minnesota.

The research began after Dr. Anastasiadis, a basic research scientist who studies cell adhesion and migration, gave a seminar to a group of oncologists who treat brain tumors. The issue of bevacizumab-induced invasion was brought up, and a collaboration to study it was quickly created and funded by the Mayo Clinic Specialized Program of Research Excellence (SPORE) grant for brain cancer, one of only four in the country.

The issue of bevacizumab's induced aggressiveness is not limited to brain cancer.

"While Avastin offers clear benefit in some patients, oncologists have noted that when cancers of many types recur after use of Avastin, they become aggressive and invasive," Dr. Anastasiadis said.

The team discovered that as brain tumors become more aggressive after use of bevacizumab in mice, the cancers begin inducing a family of kinases known as Src, which then activate proteins found at the edge of brain tumors. These proteins essentially give the tumor cells legs upon which to crawl away and find a new source of nutrition.

"Anti-angiogenesis drugs like Avastin deprive tumor cells of blood nutrients, so the tumors shrink initially, but we believe that this deprivation acts like a switch to turn on proteins that help the cancer cells migrate to other parts of the brain in search of blood," Dr. Anastasiadis said. "In short, if Avastin does not allow a tumor to make new blood vessels to feed it, the tumor will move to other existing blood vessels."

The researchers then tested dasatinib, a drug that inhibits Src kinases. They found that while use of bevacizumab or dasatinib alone did not provide much benefit in mouse models of human glioblastoma, use of both together shrank tumors and blocked any subsequent spread.

"If you block that migration, the cells are forced to stick together and hopefully die by lack of nutrition," Dr. Anastasiadis said.

Researchers next will work to identify which patients benefit the most from this new treatment, which do not, and why. The study was funded by National Institutes of Health grants R01CA100467 and R01NS069753.