Researchers at Moffitt Cancer Center and Duke University Medical Center have conducted a phase I trial of dasatinib, an oral SRC-family tyrosine kinase inhibitor, to determine the maximum tolerated dose when combined with paclitaxel and carboplatin to treat patients with advanced or recurrent ovarian cancer. They found that 150 mg daily in combination with the two other drugs was optimum.
The study appears in the October issue of Clinical Cancer Research, a publication of the American Association for Cancer Research.
Dasatinib has promising potential in treating advanced ovarian cancer because the SRC pathways play a role in the increased activation of cell migration, proliferation, survival, invasion and angiogenesis (tumor blood vessel growth). The SRC pathways have been found to be frequently disregulated in solid tumors and can increase chemotherapy resistance.
Previous laboratory studies have shown that SRC inhibition enhanced the cytotoxic efficacy of both paclitaxel and cisplatin in ovarian cancer cell lines. In vivo studies found that SRC inhibition resulted in decreased tumor growth.
"This is the first study to define the proper dose of dasatinib that, in combination with paclitaxel and carboplatin, can be moved forward into phase II or III studies," said study co-author Robert M. Wenham, M.D., M.S., F.A.C.O.G., F.A.C.S., member of the Center for Women's Oncology and Experimental Therapeutics Program at Moffitt. "Those additional trials may better help us understand not only the tolerability of the combination, but the efficacy in treating cancers."
The study found that administration of dasatinib with paclitaxel did not alter the effects of either drug and that dasatinib may be better used in combination with chemotherapy agents for a synergistic effect.
"It may also be better to combine dasatinib with only one cytotoxic therapy to improve tolerability," Wenham added.
The researchers concluded that finding biomarkers to direct the use of targeted therapies is of the utmost importance. Although SRC gene expression was not correlated with response, the research team found several differentially regulated genes between responders and those with stable disease.
"Unfortunately, a biomarker was unable to be identified to demonstrate which women are most likely to benefit from dasatinib," said study contributor Johnathan M. Lancaster, M.D., Ph.D., chair of Moffitt's Department of Women's Oncology, member of the Experimental Therapeutics Program and president of the Moffitt Medical Group. "Further study should explore relevant biomarkers and identify a patient population most likely to benefit from the addition of dasatinib."
- A. A. Secord, D. K. Teoh, W. T. Barry, M. Yu, G. Broadwater, L. J. Havrilesky, P. S. Lee, A. Berchuck, J. Lancaster, R. M. Wenham. A Phase I Trial of Dasatinib, an Src-Family Kinase Inhibitor, in Combination with Paclitaxel and Carboplatin in Patients with Advanced or Recurrent Ovarian Cancer. Clinical Cancer Research, 2012; 18 (19): 5489 DOI: 10.1158/1078-0432.CCR-12-0507
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