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Published on: October 27, 2014
Synergistic antitumor activity of ixabepilone (BMS-247550) plus bevacizumab in multiple in vivo tumor models
Francis Y F Lee1, Kelly L Covello, Stephen Castaneda
1Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. francis.lee@bms.com
Purpose:
Angiogenesis is a critical step in the establishment, growth, and metastasis of solid tumors, and combination of antiangiogenic agents with chemotherapy is an attractive therapeutic option. We investigated the potential of ixabepilone, the first in a new class of antineoplastic agents known as epothilones, to synergize with antiangiogenic agents to inhibit tumor growth.
Experimental Design:
In vitro and in vivo cytotoxicity of ixabepilone as single agent and in combination with two targeted antiangiogenic agents, bevacizumab or sunitinib, were examined in preclinical tumor models. Direct effects of the agents against endothelial cells was also examined and compared with the effects of paclitaxel as single agent and in combination with bevacizumab.
Results:
Ixabepilone showed robust synergistic antitumor activity in combination with bevacizumab and sunitinib in preclinical in vivo models derived from breast, colon, lung, and kidney cancers. The synergistic antitumor effect was greater with ixabepilone compared with paclitaxel. Furthermore, ixabepilone was more effective than paclitaxel at killing endothelial cells expressing P-glycoprotein in vitro and inhibiting endothelial cell proliferation and tumor angiogenesis in vivo.
Conclusions:
Ixabepilone may enhance the antitumor effects of antiangiogenic therapy by direct cytotoxicity and also indirectly via the killing of tumor-associated endothelial cells. Given that ixabepilone has reduced susceptibility to drug efflux pumps compared with taxanes, these data may explain the increased antiangiogenic and antitumor activity of ixabepilone in combination with antiangiogenic agents. Phase II studies to assess the efficacy and safety of ixabepilone plus bevacizumab in locally recurrent or metastatic breast cancer are planned.
Insights
Ixabepilone, a novel epothilone, synergizes with antiangiogenic agents like bevacizumab and sunitinib to inhibit tumor growth. This combination therapy shows greater efficacy than paclitaxel, offering a promising new strategy for cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Angiogenesis is crucial for solid tumor growth and metastasis.
- Combining antiangiogenic agents with chemotherapy is a promising therapeutic strategy.
- Epothilones represent a new class of antineoplastic agents.
Purpose of the Study:
- To investigate the synergistic potential of ixabepilone with antiangiogenic agents.
- To evaluate ixabepilone's efficacy in inhibiting tumor growth in preclinical models.
- To compare ixabepilone's activity with paclitaxel in combination therapies.
Main Methods:
- In vitro and in vivo cytotoxicity assays of ixabepilone alone and with bevacizumab or sunitinib.
- Assessment of direct effects on endothelial cells.
- Comparison with paclitaxel in combination with bevacizumab.
Main Results:
- Ixabepilone demonstrated robust synergistic antitumor activity with bevacizumab and sunitinib across various cancer types.
- The combination of ixabepilone showed greater synergistic antitumor effects than paclitaxel.
- Ixabepilone was more effective in inhibiting endothelial cell proliferation and tumor angiogenesis in vivo.
Conclusions:
- Ixabepilone enhances antiangiogenic therapy through direct cytotoxicity and by targeting tumor-associated endothelial cells.
- Reduced susceptibility to drug efflux pumps may contribute to ixabepilone's enhanced activity.
- Phase II studies are planned to evaluate ixabepilone plus bevacizumab in breast cancer.
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