Experimental Drug Inhibits Ovarian Cancer by Blocking Two Critical Enzymes

An experimental drug that blocks two points of a crucial cancer cell signaling pathway has been shown to inhibit the growth of ovarian cancer cells, including those from cell lines that have developed resistance to conventional (cisplatin) platinum chemotherapy.

Investigators at the University of California, Los Angeles (UCLA; USA) worked with the experimental drug NVP-BEZ235. This drug is an imidazoquinoline derivative and PI3K (phosphoinositide 3-kinase) inhibitor that inhibits PI3K and mTOR (mammalian target of rapamycin) kinase activity by binding to the ATP-binding cleft of these enzymes. PI3K and mTOR are members of a molecular signaling pathway, which once activated promotes ovarian cancer growth. Tumors with this pathway are more aggressive and more likely metastasize.

In their paper published in the April 15, 2011, issue of the journal Clinical Cancer Research the investigators described the drug's effect on cell proliferation in 18 ovarian cancer cell lines, including four pairs of syngeneic cisplatin-sensitive and cisplatin-resistant cell lines. They also evaluated the in vivo effects of NVP-BEZ235 on established tumor growth using an immunocompetent, transgenic murine ovarian cancer model.

Results revealed that NVP-BEZ235 decreased cell proliferation in all ovarian cancer cell lines assayed and sensitized cisplatin-resistant cells to the cytotoxic effects of cisplatin. Oral administration of NVP-BEZ235 resulted in significantly longer survival of the mice with ovarian tumors compared to control animals that were not treated.

"Platinum-based chemotherapy drugs are effective in treating ovarian cancers as long as the cancer cells remain sensitive to platinum,” said senior author Dr. Oliver Dorigo, assistant professor of obstetrics and gynecology at the UCLA. "But once the tumor becomes resistant, treating the cancer becomes very challenging. This is a significant clinical problem, since the majority of ovarian cancer patients develop resistance at some point during treatment. Breaking chemotherapy resistance is a difficult challenge, but crucial if we want to improve long-term survival for our patients.”

"We were very encouraged to find that NPV-BEZ235 could resensitize the ovarian cancer cells to standard platinum treatment,” said Dr. Dorigo. "In addition, we found this drug to be more effective in inhibiting ovarian cancer cell growth than other drugs that target only one checkpoint, mTOR, in this pathway. We believe that NVP-BEZ235 has superior efficacy because of the dual effect on PI3Kinase and mTOR.”

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