Combined treatment strategies for microtubule stabilizing agent-resistant tumors

• Published in: JNCI : Journal of the National Cancer Institute 2015-04, Vol.107 (4), p.1
• Main Authors: Broggini-Tenzer, Angela, Sharma, Ashish, Nytko, Katarzyna J, Bender, Sabine, Vuong, Van, Orlowski, Katrin, Hug, Daniel, O'Reilly, Terence, Pruschy, Martin
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Angiogenesis; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animals; Antibodies, Monoclonal, Humanized - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Blotting, Western; Cancer therapies; Cell Line, Tumor; Cell Proliferation - drug effects; Colonic Neoplasms - drug therapy; Drug resistance; Drug Resistance, Neoplasm; Epothilones - administration & dosage; Everolimus; Humans; Kaplan-Meier Estimate; Lung Neoplasms - drug therapy; Mice; Mice, Nude; Microtubules - drug effects; Oncology; Paclitaxel - administration & dosage; Real-Time Polymerase Chain Reaction; RNA, Neoplasm - analysis; Rodents; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; TOR Serine-Threonine Kinases - antagonists & inhibitors; Tubulin Modulators - therapeutic use; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/dju504

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, ICRnu; 5-14 per group). Tumor growth delays were calculated by Kaplan-Meier analysis with Holm-Sidak tests. All statistical tests were two-sided. 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.