Tamoxifen plus angiogenesis inhibitor could maximize therapeutic efficacy
MedWire News: Combining tamoxifen with a low-dose angiogenesis inhibitor is as effective at controlling tumor growth as less tolerable doses of either drug used alone, US research shows.
“Tamoxifen, a selective estrogen receptor modulator (SERM), and brivanib alaninate, a vascular endothelial growth factor receptor (VEGFR)-2 inhibitor, are two target specific agents that result in a substantial decrease in tumor growth when given alone,” explain Craig Jordan (Lombardi Comprehensive Cancer Center, Washington, DC) and colleagues.
Jordan and team hypothesized that combining tamoxifen with a sub-therapeutic dose of brivanib alaninate would be a beneficial strategy for long-term therapy in the treatment of breast cancer, and may reduce the side-effects observed when the drugs are given alone.
To test their hypothesis, the researchers evaluated doses of 125 µg of tamoxifen and 0.05 mg/g of brivanib alaninate for efficacy, and minimal effects on tumor growth in mice with SERM-sensitive, estrogen-stimulated tumor xenografts. They also evaluated the response of SERM-stimulated breast and endometrial tumors to demonstrate the activity of brivanib alaninate in SERM resistant models.
As reported in the European Journal of Cancer, brivanib alaninate effectively inhibited tumor growth in SERM-sensitive and SERM-stimulated models. Furthermore, the combination of tamoxifen and brivanib alaninate resulted in a significant reduction in the size of SERM-sensitive tumors, compared with each drug alone.
In established tumors, the combined treatment successfully decreased tumor growth over a 2-week period, whereas neither agent alone was effective.
Molecular analysis revealed that treatment of established tumors with tamoxifen alone increased phosphorylation of VEGFR-2, and this increase in phosphorylation was inhibited when brivanib alaninate was combined with tamoxifen.
“Based on an increasing laboratory database that implicates an elevation in angiogenic factors in endocrine resistant breast cancer in the presence of tamoxifen, we have provided evidence that a combination of tamoxifen plus a low dose dual inhibitor of VEGFR-2 and fibroblast growth factor receptor-1, brivanib alaninate, effectively controlled tumor growth,” write Jordan and co-authors.
“Indeed, the strategy of inhibiting angiogenesis, might in fact, improve responsiveness of those estrogen receptor positive tumors that are refractory to tamoxifen alone. We believe this issue should be addressed in clinical trial,” they conclude.
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By Laura Dean