Laboratory for Molecular Radiobiology, Radiation Oncology, University Hospital Zurich, Zurich, Switzerland (ABT, AS, KJN, SB, VV, KO, DH, TOR, MP); Department of Dermatology, University Hospital Zurich, Zurich, Switzerland (DH); Clinical Research Priority Program Tumor Oxygenation, University Hospital Zurich, Zurich, Switzerland (KJN, MP).Current affiliation: Novartis Pharma Switzerland (KO).
J Natl Cancer Inst. 2015 Feb 17;107(4). doi: 10.1093/jnci/dju504. Print 2015 Apr.
Resistance to microtubule-stabilizing agents is a major hurdle for successful cancer therapy. We investigated combined treatment of microtubule-stabilizing agents (MSAs) with inhibitors of angiogenesis to overcome MSA resistance.
Treatment regimens of clinically relevant MSAs (patupilone and paclitaxel) and antiangiogenic agents (everolimus and bevacizumab) were investigated in genetically defined MSA-resistant lung (A549EpoB40) and colon adenocarcinoma (SW480) tumor xenografts in nude mice (CD1-Foxn1
Inhibition of mTOR-kinase by everolimus only minimally reduced the proliferative activity of β tubulin-mutated lung adenocarcinoma cells alone and in combination with the MSA patupilone, but everolimus inhibited expression and secretion of vascular endothelial growth factor (VEGF) from these cells. mTOR-kinase inhibition strongly sensitized tumor xenografts derived from these otherwise MSA-resistant tumor cells to patupilone. Tumors treated with the combined modality of everolimus and patupilone had statistically significantly reduced tumor volume and stronger tumor growth delay (16.2 ± 1.01 days) than control- (7.7 ± 0.3 days, P = .004), patupilone- (10 ± 0.97 days, P = .009), and everolimus-treated (10.6 ± 1.4 days, P = .014) tumors. A combined treatment modality with bevacizumab also resensitized this MSA-refractory tumor model to patupilone. Treatment combination also strongly reduced microvessel density, corroborating the relevance of VEGF targeting for the known antivasculature-directed potency of MSA alone in MSA-sensitive tumor models. Resensitization to MSAs was also probed in P glycoprotein-overexpressing SW480-derived tumor xenografts. Different bevacizumab regimens also sensitized this otherwise-resistant tumor model to clinically relevant MSA paclitaxel.
A treatment combination of MSAs with antiangiogenic agents is potent to overcome tumor cell-linked MSA resistance and should be considered as strategy for MSA-refractory tumor entities.
对微管稳定剂的耐药性是癌症治疗成功的主要障碍。我们研究了将微管稳定剂（MSA）与血管生成抑制剂联合治疗以克服 MSA 耐药性。
在裸鼠（CD1-Foxn1
依维莫司抑制 mTOR-激酶仅轻微降低了β微管突变肺腺癌细胞的增殖活性，并且与 MSA 帕图皮隆联合使用，但依维莫司抑制了这些细胞中血管内皮生长因子（VEGF）的表达和分泌。mTOR-激酶抑制强烈敏化了源自这些 otherwise MSA 耐药肿瘤细胞的肿瘤异种移植物对帕图皮隆的敏感性。与对照组（7.7 ± 0.3 天，P =.004）、帕图皮隆组（10 ± 0.97 天，P =.009）和依维莫司组（10.6 ± 1.4 天，P =.014）相比，用依维莫司和帕图皮隆联合治疗的肿瘤体积明显减小，肿瘤生长延迟时间明显延长（16.2 ± 1.01 天）。贝伐单抗的联合治疗也使这种 MSA 难治性肿瘤模型对帕图皮隆敏感。联合治疗还强烈降低了微血管密度，这证实了 VEGF 靶向在 MSA 敏感肿瘤模型中对 MSA 单独的已知抗血管生成作用的相关性。还在 P 糖蛋白过表达的 SW480 衍生的肿瘤异种移植中探测了对 MSA 的重新敏感性。不同的贝伐单抗方案也使这种 otherwise 耐药的肿瘤模型对临床相关 MSA 紫杉醇敏感。
MSA 与抗血管生成剂的联合治疗是克服肿瘤细胞相关 MSA 耐药性的有效方法，应被视为 MSA 难治性肿瘤实体的一种治疗策略。
