New Clues to Drug Resistance in Ovarian Cancer

Gil Mor, M.D.

Researchers at Yale School of Medicine report that a specific defense mechanism used by the immune system is imitated by cancer cells in order to fight off the effects of cancer drugs like paclitaxel.

Led by Gil Mor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences, the study suggests that two proteins, TLR-4 and MyD88, may indicate an increased risk for developing ovarian and other cancers, and could provide clues to a new drug target aimed at reversing chemoresistance to paclitaxel.

Published recently in Cancer Research, the work sheds light on the association between cancer and the active membrane receptor proteins TLR-4 and MyD88. TLR-4 belongs to a family of membrane receptors called Toll-like receptors (TLR) that play a role in the recognition processes of the immune response.

Mor and his colleagues assayed for TLR-4 in samples of ovarian cancer tissues and determined that it is produced in epithelial ovarian cancer cells. The TLR-4 and MyD88 proteins allow cancer cells to respond to bacterial stimuli by producing cytokines that stimulate tumor growth.

“We have also identified a sub-group of ovarian cancer patients who express MyD88 and are paclitaxel resistant,” said Mor. “In these patients, instead of inducing tumor death, paclitaxel induces tumor growth.”

“We are preparing a clinical trial to validate the expression of MyD88 as a marker for paclitaxel resistance. Preliminary studies indicate this is the case,” Mor added. “Our work provides new insight into a molecular mechanism that links inflammation and the development and progression of ovarian cancer.”

Chronic infection and inflammation are considered among the most important factors contributing to cancer development and growth. Individuals with ulcerative colitis, for example, have a 10-fold higher likelihood of developing colorectal cancer. Similarly, ovarian endometriosis, a condition that promotes a pro-inflammatory environment within the ovary on a cyclical basis, predisposes women to specific types of epithelial ovarian cancer. The drug paclitaxel, which is used to treat ovarian and other cancers, interferes with the growth of cancer cells, which are eventually destroyed.

Mor said animal studies have shown that surgical removal of a primary tumor is often followed by rapid growth and spread of previously dormant cancer. These findings may help pave the way to understanding this phenomenon.

Other participants on the study are Michael G. Kelly, M.D., Ayesha B. Alvero, Rui Chen, Dan-Arin Silasi, M.D., Vikki M. Abrahams, Serena Chan, Irene Visintin and Thomas Rutherford, M.D.

Citation: Cancer Research, 66: (7) (April 2006)

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