Optimal dose of dasatinib determined for advanced, recurrent ovarian cancer
A phase I trial determined that dasatinib 150 mg daily is the optimum dose when dasatinib is combined with paclitaxel and carboplatin to treat patients with advanced or recurrent ovarian cancer.
Dasatinib is an oral SRC-family tyrosine kinase inhibitor. It has promising potential to treat advanced ovarian cancer because the SRC families play a role in the increased activation of cell migration, proliferation, survival, invasion, and angiogenesis. The SRC pathways are frequently dysregulated in solid tumors and can increase chemotherapy resistance.
Previous laboratory studies with ovarian cancer cell lines found that SRC inhibition enhanced the cytotoxic efficacy of both paclitaxel and cisplatin. Studies done in vivo found decreased tumor growth with SRC inhibition. This study sought to determine the maximum tolerated dose of dasatinib when it was combined with paclitaxel and cisplatin.
Administering dasatinib with paclitaxel did not alter the effects of either drug, according to the study's results. Further, 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,” study co-author Robert M. Wenham, MD, of the Moffitt Cancer Center explained.
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, MD, PhD, also of Moffitt Cancer Center. “Further study should explore relevant biomarkers and identify a patient population most likely to benefit from the addition of dasatinib.”This study was published in Clinical Cancer Research (2012; doi:10.1158/1078-0432.CCR-12-0507).