A large percentage of human cancers have high activity levels of an enzyme known as AKT. This enzyme controls a number of cell functions, including cell size, division and response to chemotherapy.

"The AKT signaling pathway is overly active in a wide variety of different cancers, including ovarian carcinoma, so we and others think that this pathway is an attractive target for cancer treatment at the molecular level," said Joseph Testa, Ph.D., director of the Human Genetics Program at Fox Chase. "However, because the AKT pathway is involved in so many cell processes, many of them beneficial, we were looking to control some of the proteins downstream from AKT so we didn't inhibit the good processes."

RAD001 is a derivative of rapamycin, a drug used as an immunosuppressant. RAD001 targets an enzyme known as mTOR (mammalian target of rapamycin). In mice injected with human ovarian cancer cells with high AKT activity, the researchers found that RAD001 arrested the cells so they couldn't divide (reproduce) or move to another location in the body (metastasize). The drug also reduced the cancer cells' ability to make blood vessels to nourish themselves (angiogenesis). In cancer cells with low levels of AKT activity, RAD001 had minimal effect.

Testa speculates that after being immobilized by RAD001, ovarian cancer cells could be vulnerable to chemotherapy that would kill the cells while their reproductive properties are weakened.

"Ovarian cancer is the leading cause of gynecologic cancer deaths," Testa said. "It usually isn't detected until it's quite advanced and is hard to treat. This is one drug that is well-tolerated and could be useful in ovarian cancer treatment."

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The researchers performed a blinded study and found that the one patient who experienced the only objective response to gefitinib during the 23-month trial had a mutation in the tyrosine kinase portion of the EGFR. Conversely, no mutations were observed in 23 of the cases that had no measurable response to gefitinib.

Given the apparent clustering of EGFR mutations found in previous studies of NSCLC, the researchers sequenced genes in an additional 32 ovarian tumor samples not treated with gefitinib. The majority of the tumors were late-stage serous adenocarcinomas. One additional sample was found to have a mutation (3.1%; 1 of 32).

Overall, the researchers detected mutations in the TK domain region in 2 of 56 (3.6%) of ovarian adenocarcinomas and observed that a patient on the clinical trial with a mutation in the catalytic domain of EGFR responded to gefitinib, suggesting a method to pre-select a subset of patients whose tumors may be more responsive to this EGF receptor-targeted therapy.

"This finding could have a dramatic impact on clinical care," indicated Schilder. "While this mutation is a relatively rare event, it could have a profound effect for some ovarian cancer patients," he says.

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