Opinion statement
Head and neck squamous cell carcinomas (HNSCC) represent 6% of all cancers diagnosed each year in the United States, affecting approximately 43,000 new patients and resulting in approximately 12,000 deaths. Currently, three main rapalogs exist for the treatment of cancer: CCI-779 (temsirolimus), RAD001 (everolimus), and AP235373 (deforolimus). Clinicians managing HNSCC need to be aware of the three rapalogs. Extensive evidence has shown rapamycin-analogs to be effective agents in the treatment of a number of solid tumors. While extensive preclinical data suggests that HNSCC would be an appropriate tumor type to benefit from inhibition of the mTOR pathway, limited clinical data is yet available to support this. Numerous phase II trials evaluating mTOR inhibitors for use in HNSCC are currently recruiting patients.
Similar content being viewed by others
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;caac.20073.
Jemal A, Thun MJ, Ries LAG, et al. Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control 23 2008;1000.
Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12:9–22.
Amornphimoltham P, Sriuranpong V, Patel V, et al. Persistent activation of the Akt pathway in head and neck squamous cell carcinoma. Clin Cancer Res. 2004;10:4029–37.
Molinolo AA, Hewitt SM, Amornphimoltham P, et al. Dissecting the Akt/Mammalian target of Rapamycin signaling network: emerging results from head and neck cancer tissue array initiative. Clin Canc Res. 2007;17:4964–73.
Nathan CO, Amirghahari N, Abreo F, et al. Overexpressed eIF4E is functionally active in surgical margins of head and neck cancer patients via activation of the Akt/Mammalian target of Rapamycin pathway. Clin Cancer Res. 2004;10:5820–7.
Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol. 2005;16:525–37.
Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004;22:2954–63.
Zoncu R, Efeyan A, Sabatini D. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev. 2011;12:21–35.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex. Science. 2005;307:1098–101.
Gangloff Y-G, Mueller M, Dann SG, et al. Disruption of the mouse mTOR gene leads to early Postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol. 2004;24:9508–16.
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;123:471–84.
Raught B, Gingras A-C, Gygi SP, et al. Serum-stimulated, rapamycin-sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI. EMBO J. 1999;19:434–44.
Kouvaraki MA, Liakou C, Paraschi A, et al. Activation of mTOR signaling in medullary and aggressive papillary thyroid carcinomas. Surgery. 2011;150(6):1258–65.
Tang H, Hornstein E, Stolovich M, et al. Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinase-mediated signaling, is partially inhibited by Rapamycin, and is independent of S6K1 and rpS6 phosphorylation. Mol Cell Biol. 2001;21:8671–83.
Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged Rapamycin treatment Inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006;22:159–68.
Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6:1122–8.
Liu L, Li F, Cardelli J, Martin K, Blenis J, Huang S. Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene. 2006;25:7029–40.
Li B, Desai S, MacCorkle-Chosenek R, Fan L, Spencer D. A novel conditional AKT ‘survival switch’ reversibly protects cells from apoptosis. Gene Ther. 2002;9:233–44.
Castedo M. Sequential invovlemtn of CDK1, mtor and p53 in apoptosis induced by the HIV-1 envelope. EMBO J. 2002;21:4070–80.
Bjornsti M-A, Houghton PJ. The tor pathway: a target for cancer therapy. Nat Rev Cancer. 2004;4:335–48.
Raymond E, Alexandre J, Faivre S, et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a Novel mTOR inhibitor, in patients with cancer. J Clin Oncol. 2004;22:2336–47.
Hidalgo M, Rowinsky EK. The rapamycin-sensitive singal transduction as a target pathway as a target for cancer therapy. Oncogene. 2000;19:6680–6.
Zimmerman JJ, Patat A, Parks V, Moirand R, Matschke K. Pharmacokinetics of Sirolimus (Rapamycin) in subjects with severe hepatic impairment. J Clin Pharmacol. 2008;48:285–92.
Brattstrom C, Wilczek H, Tyden G, Bottiger Y, Sawe J, Groth CG. Hyperlipidemia in renal transplant recipients treated with Sirolimus(Rapamycin). Transplantation. 1998;65:1272–4.
Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of Rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004;22:909–18.
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, Interferon Alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–81.
Nathan C-AO, Amirghahari N, Sibley D, et al. In vivo and in vitro effect of CCI-779 a rapamycin analogue on HNSCC. AACR Meeting Abstracts. 2004;2004:850-c-1.
Tanaka C, O’Reilly T, Kovarik JM, et al. Identifying optimal biologic doses of Everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol. 2008;26:1596–602.
Tabernero J, Rojo F, Calvo E, et al. Dose- and schedule-dependent inhibition of the mammalian target of Rapamycin pathway with Everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol. 2008;26:1603–10.
Amato RJ, Jac J, Giessinger S, Saxena S, Willis JP. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer. 2009;115:2438–46.
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–56.
Khariwala SS, Kjaergaard J, Lorenz R, Van Lente F, Shu S, Strome M. Everolimus (RAD) inhibits in vivo growth of murine squamous cell carcinoma (SCC VII). Laryngoscope. 2006;116(5):814–20.
Patel V, Marsh CA, Dorsam RT, et al. Decreased Lyphangiogenesis and lymph node metastasis by mTOR inhibition in head and neck cancer. Cancer Research. 2011;71(22):7103–12.
Mita MM, Mita AC, Chu QS, et al. Phase I trial of the novel mammalian target of Rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 Days every 2 Weeks to patients with advanced malignancies. J Clin Oncol. 2008;26:361–7.
Hartford CM, Desai AA, Janisch L, et al. A phase I trial to determine the safety, tolerability, and maximum tolerated dose of Deforolimus in patients with advanced malignancies. Clin Cancer Res. 2009;15:1428–34.
Disclosure
S. Nguyen: none, D. Walker: none, M.B. Gillespie: none, J.S. Gutkind,T Day: received honoraria from Bristol-Myers and Eli Lilly.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nguyen, S.A., Walker, D., Gillespie, M.B. et al. mTOR Inhibitors and its Role in the Treatment of Head and Neck Squamous Cell Carcinoma. Curr. Treat. Options in Oncol. 13, 71–81 (2012). https://doi.org/10.1007/s11864-011-0180-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11864-011-0180-2