Abstract
Abstract Background There is a need to develop novel drugs that will improve survival in breast cancer patients. Angiogenesis is essential for breast tumour progression. To date, the most promising approach to inhibit angiogenesis in breast cancer patients has been the drug bevacizumab which targets the pro-angiogenic factor Vascular Endothelial Growth Factor (VEGF). Recently, there has been controversy regarding the efficacy of bevacizumab for breast cancer treatment. In clinical trials, bevacizumab failed to establish an overall-survival benefit and was associated with serious toxicities. This resulted in the FDA revoking approval for the drug for the first line treatment of advanced breast cancer. Due to this uncertainty surrounding the efficacy of bevacizumab for the treatment of breast cancer it is clear that there is a clinical need for more effective novel anti-angiogenic drugs with better toxicity profiles for the treatment of breast cancer. Aim This study aimed to identify novel small-molecule anti-angiogenic agents with therapeutic potential in human breast cancer. Methods Compounds with physiochemical properties consistent with drug-like compounds were screened for anti-angiogenic activity by high-throughput screening involving zebrafish larvae. Human breast tumour explants were treated with the lead compound and secretion of angiogenic factors was assessed by ELISA. Results We have identified a novel small-molecule agent ‘SMG1’ that significantly inhibited inter-segmental blood-vessel development in zebrafish and showed no toxicity. Treatment of breast tumour explants with SMG1 significantly inhibited secretion of the potent pro-angiogenic cytokine VEGF (p = 0.01). Furthermore, SMG1 inhibited VEGF secretion more than the standard targeted breast cancer therapies tamoxifen and Herceptin® which have been reported to inhibit angiogenesis. Conclusion Continuing pre-clinical work will determine if SMG1 has potential as a therapeutic agent for human breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-16.
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