title: 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.affiliation: 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).
authors.forename: Angela
authors.initials: A
authors.lastname: Broggini-Tenzer
authors.affiliation: 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).
authors.forename: Ashish
authors.initials: A
authors.lastname: Sharma
authors.affiliation: 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).
authors.forename: Katarzyna J
authors.initials: KJ
authors.lastname: Nytko
authors.affiliation: 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).
authors.forename: Sabine
authors.initials: S
authors.lastname: Bender
authors.affiliation: 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).
authors.forename: Van
authors.initials: V
authors.lastname: Vuong
authors.affiliation: 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).
authors.forename: Katrin
authors.initials: K
authors.lastname: Orlowski
authors.affiliation: 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).
authors.forename: Daniel
authors.initials: D
authors.lastname: Hug
authors.affiliation: 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).
authors.forename: Terence
authors.initials: T
authors.lastname: O'Reilly
authors.affiliation: 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). martin.pruschy@usz.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Pruschy
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D034261:Epothilones / Q000008:administration & dosage; D000068338:Everolimus; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel / Q000008:administration & dosage; D012334:RNA, Neoplasm / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D050257:Tubulin Modulators / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D034261:Epothilones; D012334:RNA, Neoplasm; D050257:Tubulin Modulators; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel; C093788:epothilone B; D020123:Sirolimus