Drugs

, Volume 68, Issue 12, pp 1609–1619 | Cite as

Promising Newer Molecular-Targeted Therapies in Head and Neck Cancer

Leading Article

Abstract

Head and neck cancer (HNC) is the fifth most common cancer in the world. In the US alone, HNC accounts for 3–5% of all malignancies annually. Squamous cell carcinoma arising from the mucosa of the upper aerodigestive tract is the most common type of HNC and accounts for 90% of HNC diagnoses. Despite continued advances in the therapeutic options, the disease-free survival, functional outcome, toxicity of therapy and overall survival have remained less than optimal for patients with locally advanced, recurrent or metastatic disease. Therefore, new approaches for the treatment of patients with HNC, particularly patients with advanced stage, are clearly needed. Among the new therapies, molecular-targeted and biological therapies have gained special attention. While clinical trial data support the use of epidermal growth factor receptor (EGFR) inhibition in metastatic and locally advanced HNC, numerous trials are seeking to establish a clear role for new therapies targeting EGFR, the receptor for the type I insulin-like growth factor, as well as anti-angiogenesis agents.

Notes

Acknowledgements

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    Chin D, Boyle GM, Porceddu S, et al. Head and neck cancer: past, present and future. Expert Rev Anticancer Ther 2006; 6: 1111–8PubMedCrossRefGoogle Scholar
  2. 2.
    Agulnik M. Malignancies of the head and neck: the role for molecular targeted agents. Expert Opin Ther Targets 2007; 11: 207–17PubMedCrossRefGoogle Scholar
  3. 3.
    Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin 2007; 57: 43–66PubMedCrossRefGoogle Scholar
  4. 4.
    Monnerat C, Faivre S, Temam S, et al. End points for new agents in induction chemotherapy for locally advanced head and neck cancers. Ann Oncol 2002; 13: 995–1006PubMedCrossRefGoogle Scholar
  5. 5.
    Carvalho AL, Nishimoto IN, Califano JA, et al. Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer 2005; 114: 806–16PubMedCrossRefGoogle Scholar
  6. 6.
    Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2006; 24: 2644–52PubMedCrossRefGoogle Scholar
  7. 7.
    Cohen EE, Lingen MW, Vokes EE. The expanding role of systemic therapy in head and neck cancer. J Clin Oncol 2004; 22: 1743–52PubMedCrossRefGoogle Scholar
  8. 8.
    Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001; 37 Suppl. 4: S9–15PubMedCrossRefGoogle Scholar
  9. 9.
    Zimmermann M, Zouhair A, Azria D, et al. The epidermal growth factor receptor (EGFR) in head and neck cancer: its role and treatment implications. Radiat Oncol 2006; 1: 11PubMedCrossRefGoogle Scholar
  10. 10.
    Astsaturov I, Cohen RB, Harari P. EGFR-targeting monoclonal antibodies in head and neck cancer. Curr Cancer Drug Targets 2007; 7: 650–65PubMedCrossRefGoogle Scholar
  11. 11.
    Blick SK, Scott LJ. Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer. Drugs 2007; 67: 2585–607PubMedCrossRefGoogle Scholar
  12. 12.
    Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27–31PubMedCrossRefGoogle Scholar
  13. 13.
    Ranieri G, Patruno R, Ruggieri E, et al. Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem 2006; 13: 1845–57PubMedCrossRefGoogle Scholar
  14. 14.
    Fury MG, Zahalsky A, Wong R, et al. A Phase II study of SU5416 in patients with advanced or recurrent head and neck cancers. Invest New Drugs 2007; 25: 165–72PubMedCrossRefGoogle Scholar
  15. 15.
    Saba NF, Shin DM, Khuri FR. Targeting angiogenesis in head and neck cancer. Curr Cancer Drug Targets 2007; 7: 643–9PubMedCrossRefGoogle Scholar
  16. 16.
    Holbro T, Civenni G, Hynes NE. The ErbB receptors and their role in cancer progression. Exp Cell Res 2003; 284: 99–110PubMedCrossRefGoogle Scholar
  17. 17.
    Hynes NE, Horsch K, Olayioye MA, et al. The ErbB receptor tyrosine family as signal integrators. Endocr Relat Cancer 2001; 8: 151–9PubMedCrossRefGoogle Scholar
  18. 18.
    Rocha-Lima CM, Soares HP, Raez LE, et al. EGFR targeting of solid tumors. Cancer Control 2007; 14: 295–304PubMedGoogle Scholar
  19. 19.
    Ogiso H, Ishitani R, Nureki O, et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 2002; 110: 775–87PubMedCrossRefGoogle Scholar
  20. 20.
    Schlessinger J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell 2002; 110: 669–72PubMedCrossRefGoogle Scholar
  21. 21.
    Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2: 127–37PubMedCrossRefGoogle Scholar
  22. 22.
    Kruger JS, Reddy KB. Distinct mechanisms mediate the initial and sustained phases of cell migration in epidermal growth factor receptor-overexpressing cells. Mol Cancer Res 2003; 1: 801–9PubMedGoogle Scholar
  23. 23.
    Masuda M, Toh S, Koike K, et al. The roles of JNK1 and Stat3 in the response of head and neck cancer cell lines to combined treatment with all-trans-retinoic acid and 5-fluorouracil. Jpn J Cancer Res 2002; 93: 329–39PubMedCrossRefGoogle Scholar
  24. 24.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489–501PubMedCrossRefGoogle Scholar
  25. 25.
    Ellerbroek SM, Halbleib JM, Benavidez M, et al. Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association. Cancer Res 2001; 61: 1855–61PubMedGoogle Scholar
  26. 26.
    Shtiegman K, Yarden Y. The role of ubiquitylation in signaling by growth factors: implications to cancer. Semin Cancer Biol 2003; 13: 29–40PubMedCrossRefGoogle Scholar
  27. 27.
    Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 2002; 7 Suppl. 4: 31–9PubMedCrossRefGoogle Scholar
  28. 28.
    Cruz JJ, Ocana A, Del Barco E, et al. Targeting receptor tyrosine kinases and their signal transduction routes in head and neck cancer. Ann Oncol 2007; 18: 421–30PubMedCrossRefGoogle Scholar
  29. 29.
    Harari PM, Allen GW, Bonner JA. Biology of interactions: antiepidermal growth factor receptor agents. J Clin Oncol 2007; 25: 4057–65PubMedCrossRefGoogle Scholar
  30. 30.
    Masui H, Kawamoto T, Sato JD, et al. Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 1984; 44: 1002–7PubMedGoogle Scholar
  31. 31.
    Harari PM, Huang SM. Head and neck cancer as a clinical model for molecular targeting of therapy: combining EGFR blockade with radiation. Int J Radiat Oncol Biol Phys 2001; 49: 427–33PubMedCrossRefGoogle Scholar
  32. 32.
    Milas L, Mason K, Hunter N, et al. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 2000; 6: 701–8PubMedGoogle Scholar
  33. 33.
    Baselga J, Pfister D, Cooper MR, et al. Phase I studies of antiepidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 2000; 18: 904–14PubMedGoogle Scholar
  34. 34.
    Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–78PubMedCrossRefGoogle Scholar
  35. 35.
    Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006; 24: 1072–8PubMedCrossRefGoogle Scholar
  36. 36.
    Merlano MC, Numico G, Russi EG, et al. Cetuximab (C-mab) and chemo-radiation (CT-RT) for loco-regional advanced squamous cell carcinoma of the head and neck (HNC): a phase II study [abstract]. J Clin Oncol 2007; 25: 6043Google Scholar
  37. 37.
    Wanebo HJ, Ghebremichael M, Burtness B, et al. Phase II evaluation of cetuximab (C225) combined with induction paclitaxel and carboplatin followed by C225, paclitaxel, carboplatin, and radiation for stage III/IV operable squamous cancer of the head and neck (ECOG, E2303) [abstract]. J Clin Oncol 2007; 25: 6015Google Scholar
  38. 38.
    Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005; 23: 8646–54PubMedCrossRefGoogle Scholar
  39. 39.
    Vermorken J, Mesia R, Vega V, et al. Cetuximab extends survival of patients with recurrent or metastatic SCCHN when added to first line platinum based therapy: results of a randomized phase III (Extreme) study [abstract]. J Clin Oncol 2007; 25: 6091CrossRefGoogle Scholar
  40. 40.
    Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007; 25: 2171–7PubMedCrossRefGoogle Scholar
  41. 41.
    Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2005; 23: 5568–77PubMedCrossRefGoogle Scholar
  42. 42.
    Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 2005; 23: 5578–87PubMedCrossRefGoogle Scholar
  43. 43.
    Kies MS, Garden AS, Holsinger C, et al. Induction chemotherapy (CT) with weekly paclitaxel, carboplatin, and cetuximab for squamous cell carcinoma of the head and neck (HN) [abstract]. J Clin Oncol 2006; 24: 5520Google Scholar
  44. 44.
    Yang XD, Jia XC, Corvalan JR, et al. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 2001; 38: 17–23PubMedCrossRefGoogle Scholar
  45. 45.
    Foon KA, Yang XD, Weiner LM, et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 2004; 58: 984–90PubMedCrossRefGoogle Scholar
  46. 46.
    Kettleborough CA, Saldanha J, Heath VJ, et al. Humanization of a mouse monoclonal antibody by CDR-grafting: the importance of framework residues on loop conformation. Protein Eng 1991; 4: 773–83PubMedCrossRefGoogle Scholar
  47. 47.
    Hoffend J, Mohammed A, Eisenhut M, et al. Uptake of the anti-epidermal growth factor receptor (EGFR) antibody EMD 72000 in tumors of subjects with head and neck squamous cell carcinoma (HNSCC) [abstract]. J Clin Oncol 2004; 22: 3043Google Scholar
  48. 48.
    Crombet T, Osorio M, Cruz T, et al. Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. J Clin Oncol 2004; 22: 1646–54PubMedCrossRefGoogle Scholar
  49. 49.
    ClinicalTrials.gov. Phase II study of nimotuzumab and cisplatin/radiotherapy for locally advanced head and neck squamous cell cancer [online]. Available from URL: http://www.clinicaltrials.gov/ct2/show/NCT00702481 [Accessed 2008 Jul 10]
  50. 50.
    Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 2004; 22: 77–85PubMedCrossRefGoogle Scholar
  51. 51.
    Pollack VA, Savage DM, Baker DA, et al. Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 1999; 291: 739–48PubMedGoogle Scholar
  52. 52.
    Siu LL, Soulieres D, Chen EX, et al. Phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Princess Margaret Hospital phase II consortium and National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol 2007; 25: 2178–83PubMedCrossRefGoogle Scholar
  53. 53.
    Agulnik M, da Cunha Santos G, Hedley D, et al. Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with erlotinib. J Clin Oncol 2007; 25: 2184–90PubMedCrossRefGoogle Scholar
  54. 54.
    Kim ES, Kies MS, Glisson BS, et al. Final results of a phase II study of erlotinib, docetaxel and cisplatin in patients with recurrent/metastatic head and neck cancer [abstract]. J Clin Onc 2007; 25: 6013Google Scholar
  55. 55.
    Goss G, Hirte H, Miller Jr WH, et al. A phase I study of oral ZD 1839 given daily in patients with solid tumors: IND.122, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group. Invest New Drugs 2005; 23: 147–55PubMedCrossRefGoogle Scholar
  56. 56.
    Wolf M, Swaisland H, Averbuch S. Development of the novel biologically targeted anticancer agent gefitinib: determining the optimum dose for clinical efficacy. Clin Cancer Res 2004; 10: 4607–13PubMedCrossRefGoogle Scholar
  57. 57.
    Chen C, Kane M, Song J, et al. Phase I trial of gefitinib in combination with radiation or chemoradiation for patients with locally advanced squamous cell head and neck cancer. J Clin Oncol 2007; 25: 4880–6PubMedCrossRefGoogle Scholar
  58. 58.
    Cohen EE, Rosen F, Stadler WM, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003; 21: 1980–7PubMedCrossRefGoogle Scholar
  59. 59.
    Cohen EE, Kane MA, List MA, et al. Phase II trial of gefitinib 250mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2005; 11: 8418–24PubMedCrossRefGoogle Scholar
  60. 60.
    Wheeler RH, Jones D, Sharma P, et al. Clinical and molecular phase II study of gefitinib in patients (pts) with recurrent squamous cell cancer of the head and neck (H & N Ca) [abstract]. J Clin Oncol 2005; 23: 5531Google Scholar
  61. 61.
    Belón J, Irigoyen A, Rodríguez I, et al. Preliminary results of a phase II study to evaluate gefitinib combined with docetaxel and cisplatin in patients with recurrent and/or metastatic squamous-cell carcinoma of the head and neck [abstract]. J Clin Oncol 2005; 23: 5563CrossRefGoogle Scholar
  62. 62.
    Agulnik M, Cohen EW, Cohen RB, et al. Phase II study of lapatinib in recurrent or metastatic epidermal growth factor receptor and/or erbB2 expressing adenoid cystic carcinoma and non adenoid cystic carcinoma malignant tumors of the salivary glands. J Clin Oncol 2007; 25: 3978–84PubMedCrossRefGoogle Scholar
  63. 63.
    Abidoye OO, Cohen EE, Wong SJ, et al. A phase II study of lapatinib (GW572016) in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) [abstract]. J Clin Oncol 2006; 24: 5568Google Scholar
  64. 64.
    Bourhis J, Harrington K, Rosine D, et al. A phase I, open label study (EGF 100262) of lapatinib plus chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) [abstract]. Ann Oncol 2006; 17(9s): 180Google Scholar
  65. 65.
    ClinicalTrials.gov. Lapatinib versus placebo given concurrently with cisplatin and radiotherapy in patients with head and neck cancer [online]. Available from URL: http://www.clinicaltrials.gov/ct2/show/NCT00387127 [Accessed 2008 Jul 10]
  66. 66.
    Bahr C, Groner B. The IGF-1 receptor and its contributions to metastatic tumor growth-novel approaches to the inhibition of IGF-1R function. Growth Factors 2005; 23: 1–14PubMedCrossRefGoogle Scholar
  67. 67.
    Adams TE, Epa VC, Garrett TP, et al. Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol Life Sci 2000; 57: 1050–93PubMedCrossRefGoogle Scholar
  68. 68.
    Barnes CJ, Ohshiro K, Rayala SK, et al. Insulin-like growth factor receptor as a therapeutic target in head and neck cancer. Clin Cancer Res 2007; 13: 4291–9PubMedCrossRefGoogle Scholar
  69. 69.
    Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004; 4: 505–18PubMedCrossRefGoogle Scholar
  70. 70.
    Mitsiades CS, Mitsiades N. Treatment of hematologic malignancies and solid tumors by inhibiting IGF receptor signaling. Expert Rev Anticancer Ther 2005; 5: 487–99PubMedCrossRefGoogle Scholar
  71. 71.
    Larsson O, Girnita A, Girnita L. Role of insulin-like growth factor 1 receptor signalling in cancer. Br J Cancer 2007; 96 Suppl.: R2–6PubMedGoogle Scholar
  72. 72.
    ClinicalTrials.gov. Phase 1 study of BIIB022 (anti-IGF-1R monoclonal antibody) in relapsed/refractory solid tumors [online]. Available from URL: http://www.clinicaltrials.gov/ct2/show/NCT00555724 [Accessed 2008 Jul 10]
  73. 73.
    Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990; 82: 4–6PubMedCrossRefGoogle Scholar
  74. 74.
    Zhong H, Bowen JP. Molecular design and clinical development of VEGFR kinase inhibitors. Curr Top Med Chem 2007; 7: 1379–93PubMedCrossRefGoogle Scholar
  75. 75.
    Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995; 376: 62–6PubMedCrossRefGoogle Scholar
  76. 76.
    Kyzas PA, Cunha IW, Ioannidis JP. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res 2005; 11: 1434–40PubMedCrossRefGoogle Scholar
  77. 77.
    Kyzas PA, Stefanou D, Batistatou A, et al. Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2. Mod Pathol 2005; 18: 485–94PubMedCrossRefGoogle Scholar
  78. 78.
    Choong NW, Haraf DJ, Cohen EE, et al. Randomized phase II study of concomitant chemoradiotherapy with 5-fluorouracil-hydroxyurea (FHX) compared to FHX and bevazicumab (BFHX) in intermediate stage head and neck cancer (HNC) [abstract]. J Clin Oncol 2007; 25: 6043Google Scholar
  79. 79.
    Savvides P, Greskovich J, Bokar J, et al. Phase II study of bevacizumab in combination with docetaxel and radiation in locally advanced squamous cell cancer of the head and neck (SCCHN) [abstract]. J Clin Oncol 2007; 25: 6068Google Scholar
  80. 80.
    Karamouzis MV, Friedland D, Johnson R, et al. Phase II trial of pemetrexed (P) and bevacizumab (B) in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC): an interim analysis [abstract]. J Clin Oncol 2007; 25: 6049Google Scholar
  81. 81.
    Seiwert TY, Davis DW, Yan D, et al. pKDR/KDR ratio predicts response in a phase I/II pharmacodynamic study of erlotinib and bevacizumab for recurrent or metastatic head and neck cancer (HNC) [abstract]. J Clin Oncol 2007; 25: 6021Google Scholar
  82. 82.
    Williamson SK, Moon J, Huang CH, et al. A phase II trial of sorafenib in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC): a Southwest Oncology Group (SWOG) trial [abstract]. J Clin Oncol 2007; 25: 6044Google Scholar
  83. 83.
    Elser C, Siu LL, Winquist E, et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol 2007; 25: 3766–73PubMedCrossRefGoogle Scholar
  84. 84.
    Bozec A, Formento P, Lassalle S, et al. Dual inhibition of EGFR and VEGFR pathways in combination with irradiation: antitumour supra-additive effects on human head and neck cancer xenografts. Br J Cancer 2007; 97: 65–72PubMedCrossRefGoogle Scholar
  85. 85.
    ClinicalTrials.gov. The effects of AZD2171 & gefitinib in patients with non-small cell lung cancer or head & neck cancer [online]. Available from URL: http://www.clinicaltrials.gov/ct2/show/NCT00243347 [Accessed 2008 Jul 10]
  86. 86.
    Bianco C, Giovannetti E, Ciardiello F, et al. Synergistic antitumor activity of ZD6474, an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, with gemcitabine and ionizing radiation against pancreatic cancer. Clin Cancer Res 2006; 12: 7099–107PubMedCrossRefGoogle Scholar
  87. 87.
    Sano D, Kawakami M, Fujita K, et al. Antitumor effects of ZD6474 on head and neck squamous cell carcinoma. Oncol Rep 2007; 17: 289–95PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicagoUSA

Personalised recommendations