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A two-drug combination that disrupts critical signaling circuits in cancer cells has produced an observable benefit in patients with recurrent high-grade serous ovarian cancer (HGSC) or triple-negative breast cancer (TNBC). These results, from a phase I clinical trial of the regimen, will be reported by Dana-Farber Cancer Institute investigators at the annual meeting of the American Society of Clinical Oncology (ASCO) on Saturday, May 31, 2014.
The study, which tested successively higher doses of the targeted drugs BKM120 and olaparib in 46 patients, focused on the safety of the treatment, the optimal dosage, how the drugs are metabolized, and their anti-cancer activity. At each dose level tested,
there was evidence of clinical benefit — tumors either shrank or stopped expanding. Side effects were similar to those associated with BKM120 or olaparib alone.
“These are very promising results and should be investigated further in both women with relapsed high-grade serous ovarian cancer and triple-negative breast cancer,” said the study’s lead author, Ursula Matulonis, MD,
medical director of Gynecologic Oncology at the Susan F. Smith Center for Women’s Cancers at Dana-Farber. The senior author is Eric Winer, MD,
director of Breast Oncology at the Susan F. Smith Center for Women’s Cancers at Dana-Farber.
BKM120, which inhibits the PI3K signaling pathway in cells, and olaparib, which blocks the PARP-1 protein, had previously been shown to enhance each other’s effectiveness in mice with TNBC or with breast cancer linked to mutations in the BRCA1 gene (triple-negative breast tumors lack estrogen and progesterone receptors as well as the human epidermal growth factor receptor 2). Other studies had found olaparib to be active in HGSC and in ovarian and breast cancers linked to inherited BRCA mutations. These and other findings led researchers to test the drugs in tandem in patients with recurrent HGSC or TNBC.
Although the two drugs attack different survival mechanisms within tumor cells, they appear to reinforce each other. The PI3K pathway obstructed by BKM120 is often switched on in cancer cells. The PARP-1 protein targeted by olaparib helps cancer cells
repair DNA damage; shutting down the protein allows DNA damage to accumulate to the point where cancer cells begin to die.
The phase 1 study was supported fully by a Stand Up To Cancer Dream Team Translational Cancer Research Grant.
Posted on May 29, 2014
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