Inglis Daniel J, Lavranos Tina C, Beaumont Donna M, Leske Annabell F, Brown Chloe K, Hall Allison J, Kremmidiotis Gabriel
a Bionomics Ltd. ; Thebarton , South Australia , Australia.
Cancer Biol Ther. 2014;15(11):1552-60. doi: 10.4161/15384047.2014.956605.
BNC105 is a tubulin targeting compound that selectively disrupts vasculature within solid tumors. The severe tumor hypoxia and necrosis that ensues translates to short term tumor growth inhibition. We sought to identify the molecular and cellular events activated following BNC105 treatment that drives tumor recovery. We investigated tumor adaptation to BNC105-induced hypoxia in animal models of breast and renal cancer. HIF-1α and GLUT-1 were found to be strongly upregulated by BNC105 as was the VEGF signaling axis. Phosphorylation of mTOR, 4E-BP-1 and elF2α were upregulated, consistent with increased protein synthesis and increased expression of VEGF-A. We sought to investigate the potential therapeutic utility of combining BNC105 with agents targeting VEGF and mTOR signaling. Bevacizumab and pazopanib target the VEGF axis and have been approved for first line use in renal cancer. Everolimus targets mTOR and is currently approved in second line therapy of renal and particular breast cancers. We combined these agents with BNC105 to explore the effects on tumor vasculature, tumor growth inhibition and animal survival. Bevacizumab hindered tumor vascular recovery following BNC105 treatment leading to greater tumor growth inhibition in a breast cancer model. Consistent with this, addition of BNC105 to pazopanib treatment resulted in a significant increase in survival in an orthotopic renal cancer model. Combination treatment of BNC105 with everolimus also increased tumor growth inhibition. BNC105 is currently being evaluated in a randomized phase II clinical trial in combination with everolimus in renal cancer.
BNC105是一种靶向微管蛋白的化合物，可选择性破坏实体瘤内的脉管系统。随之而来的严重肿瘤缺氧和坏死导致短期肿瘤生长抑制。我们试图确定BNC105治疗后激活的驱动肿瘤恢复的分子和细胞事件。我们在乳腺癌和肾癌动物模型中研究了肿瘤对BNC105诱导的缺氧的适应性。发现BNC105可强烈上调HIF-1α和GLUT-1以及VEGF信号轴。mTOR、4E-BP-1和elF2α的磷酸化上调，这与蛋白质合成增加和VEGF-A表达增加一致。我们试图研究将BNC105与靶向VEGF和mTOR信号的药物联合使用的潜在治疗效用。贝伐单抗和帕唑帕尼靶向VEGF轴，已被批准用于肾癌一线治疗。依维莫司靶向mTOR，目前被批准用于肾癌尤其是乳腺癌的二线治疗。我们将这些药物与BNC105联合使用，以探索对肿瘤脉管系统、肿瘤生长抑制和动物生存的影响。在乳腺癌模型中，贝伐单抗阻碍了BNC105治疗后的肿瘤血管恢复，导致更大程度的肿瘤生长抑制。与此一致的是，在原位肾癌模型中，将BNC105添加到帕唑帕尼治疗中可显著提高生存率。BNC105与依维莫司联合治疗也增加了肿瘤生长抑制。目前正在一项随机II期临床试验中评估BNC105与依维莫司联合用于肾癌的疗效。
