Combined treatment strategies for microtubule stabilizing agent-resistant tumors.

Abstract

BACKGROUND:

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.

METHODS:

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

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Angela Broggini-Tenzer, Ashish Sharma, Katarzyna J Nytko, Sabine Bender, Van Vuong, Katrin Orlowski, Daniel Hug, Terence O'Reilly, Martin Pruschy
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 107 Issue 4 (Apr 2015) ISSN: 1460-2105 [Electronic] United States
• PMID: 25694444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal, Humanized
• Epothilones
• RNA, Neoplasm
• Tubulin Modulators
• Vascular Endothelial Growth Factor A
• Bevacizumab
• Everolimus
• TOR Serine-Threonine Kinases
• Paclitaxel
• epothilone B
• Sirolimus

Topics

• Adenocarcinoma (drug therapy)
• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Animals
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy)
• Drug Resistance, Neoplasm
• Epothilones (administration & dosage)
• Everolimus
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms (drug therapy)
• Mice
• Mice, Nude
• Microtubules (drug effects)
• Paclitaxel (administration & dosage)
• RNA, Neoplasm (analysis)
• Real-Time Polymerase Chain Reaction
• Sirolimus (administration & dosage, analogs & derivatives)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Tubulin Modulators (therapeutic use)
• Vascular Endothelial Growth Factor A (drug effects)
• Xenograft Model Antitumor Assays