title: The mTOR-targeting drug temsirolimus enhances the growth-inhibiting effects of the cetuximab-bevacizumab-irradiation combination on head and neck cancer xenografts.
abstract: We previously reported on head and neck tumor xenografts that the tumor regression induced by a triple combination of irradiation (RT), anti-EGFR and anti-angiogenic therapies was followed, after treatment arrest, by tumor re-growth characterized by activation of the AKT signaling pathway. Since mTOR is the main AKT-related messenger, the aim of this study was to add the mTOR inhibitor temsirolimus to a tri-therapy with RT plus anti-EGFR and anti-angiogenic drugs in order to improve anti-tumor effects. The human head and neck cancer cell line CAL33 (over-expressing EGFR and secreting VEGF-A) was xenografted in nude mice. Treatment (20 mice per treatment group) was administered for 2 weeks and consisted of either vehicle (control), temsirolimus (5mg/kg i.p. five times a week), tri-therapy with RT (6 Gy three times a week) combined with cetuximab (0.5mg/kg i.p. five times a week) and bevacizumab (5mg/kg i.p. five times a week) or the temsirolimus-tri-therapy association. The time to reach a tumor volume of 2000 mm(3) was significantly different between the four treatment groups (Log Rank p<0.0001), with a median of 29.5, 44.5, 67.0 and 70.0 days for control, temsirolimus, tri-therapy and combination groups, respectively. The combination of temsirolimus plus tri-therapy produced the longest growth-inhibiting effects (tri-therapy versus combination, p=0.01). No significant interaction was observed between temsirolimus and the tri-therapy, suggesting that temsirolimus, on the one hand, and RT-cetuximab-bevacizumab, on the other, exert additive effects on tumor growth inhibition. These decreases observed on tumor growth were corroborated by the parallel decreases observed on tumor proliferation (Ki67) and on anti-apoptotic markers (Bcl2). These results suggest that temsirolimus exhibits synergistic antiproliferative effects when administered in combination with irradiation, anti-EGFR and anti-angiogenic therapies in head and neck cancer patients.
authors.affiliation: Head and Neck Surgery Unit, Centre Antoine Lacassagne, 33 Av de Valombrose, 06189 Nice cedex, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bozec
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Fischel
authors.forename: Anne
authors.initials: A
authors.lastname: Sudaka
authors.forename: Nicolas
authors.initials: N
authors.lastname: Toussan
authors.forename: Patricia
authors.initials: P
authors.lastname: Formento
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003131:Combined Modality Therapy / Q000379:methods; D004357:Drug Synergism; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000068818:Cetuximab; D020123:Sirolimus