The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer
The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer
复制标题
DOI：
10.4161/15384047.2014.956605
复制
发表时间：
2014-01-01
影响因子：
3.6
通讯作者：
Kremmidiotis, Gabriel
中科院分区：
文献类型：
--
作者：
Inglis, Daniel J.;Lavranos, Tina C.;Kremmidiotis, Gabriel
BNC105 是一种微管蛋白靶向化合物，可选择性破坏实体瘤内的脉管系统。随后发生的严重肿瘤缺氧和坏死转化为短期肿瘤生长抑制。我们试图确定 BNC105 治疗后激活的分子和细胞事件，从而促进肿瘤恢复。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。发现 BNC105 强烈上调 HIF-1 α 和 GLUT-1，VEGF 信号轴也是如此。 mTOR、4E-BP-1 和 eF2 α 的磷酸化上调，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 信号传导的药物相结合的潜在治疗效用。贝伐珠单抗和帕唑帕尼靶向 VEGF 轴，已被批准用于肾癌的一线治疗。依维莫司以 mTOR 为靶点，目前已被批准用于肾癌和特定乳腺癌的二线治疗。我们将这些药物与 BNC105 结合，探索对肿瘤血管系统、肿瘤生长抑制和动物存活的影响。 BNC105 治疗后贝伐珠单抗阻碍肿瘤血管恢复，导致乳腺癌模型中肿瘤生长受到更大的抑制。与此一致的是，在帕唑帕尼治疗中添加 BNC105 导致原位肾癌模型的生存率显着增加。 BNC105 与依维莫司的联合治疗也增强了肿瘤生长抑制作用。 BNC105 目前正在一项随机 II 期临床试验中与依维莫司联合治疗肾癌进行评估。
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-1 alpha and GLUT-1 were found to be strongly upregulated by BNC105 as was the VEGF signaling axis. Phosphorylation of mTOR, 4E-BP-1 and elF2 alpha 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.