Despite advances in understanding cancer at the molecular level, timely and effective translation to clinical application of novel therapeutics in human cancer patients is lacking. Cancer drug failure is often a result of toxicity or inefficacy not predicted by preclinical models, emphasizing the need for alternative animal tumor models with improved biologic relevancy. Companion animals (dogs and cats) provide an opportunity to capitalize on an underutilized and biologically relevant translational research model which allows spontaneous disease modeling of human cancer. Head and neck squamous cell carcinoma (HNSCC) is a common cancer with a poor prognosis and limited clinical advancements in recent years. One potential novel spontaneous animal tumor model is feline oral squamous cell carcinoma (FOSCC). FOSCC and HNSCC share similar etiopathogenesis (tobacco and papillomavirus exposure) and molecular markers (EGFR, VEGF, and p53). Both human and feline SCCs share similar tumor biology, clinical outcome, treatment, and prognosis. Future clinical trials utilizing FOSCC as a tumor model may facilitate translation of preclinical cancer research for human cancer patients. 1. Introduction Advances in our understanding of cancer at the molecular level have outpaced clinical application of this information to human patients. It can take more than a decade and $800 million dollars to develop a new drug or diagnostic agent, yet less than 10% of promising drugs achieve FDA-approval [1, 2]. This discouraging drug failure rate is in part due to limited predictive value for drug toxicity and efficacy of accepted preclinical models [2]. The value of pre-clinical models to subsequently predict drug success is inherently based on the relevancy of animal models. Murine models provide crucial opportunities to investigate specific molecular and genetic pathways. These models often incorporate chemically induced cancer or xenografted human cancer cell lines in immunosuppressed animals. Thus, despite their importance these conventional murine models fail to adequately characterize the biologic variations inherent in spontaneously arising human cancer such as long latency period, genomic instability, tumor heterogeneity, and the complexity of the tumor microenvironment. While no single model can provide solutions to all drug-development questions, integration of information from multiple modeling systems can improve the successful translation of a novel drug into human patients. One approach is capitalization on biologically relevant companion animal translational research
References
[1]
E. L. Tobinick, “The value of drug repositioning in the current pharmaceutical market,” Drug News and Perspectives, vol. 22, no. 2, pp. 119–125, 2009.
[2]
I. Kola, “The state of innovation in drug development,” Clinical Pharmacology and Therapeutics, vol. 83, no. 2, pp. 227–230, 2008.
[3]
D. M. Vail and D. H. Thamm, “Spontaneous companion animal (pet) cancers,” in Tumor Models in Cancer Research: Cancer Drug Discovery and Development, B. A. Teicher, Ed., pp. 353–373, Humana Press, New Jersey, NJ, USA, 2nd edition, 2011.
[4]
I. K. Gordon and C. Khanna, “Modeling opportunities in comparative oncology for drug development,” ILAR Journal, vol. 51, no. 3, pp. 214–220, 2010.
[5]
M. Paoloni and C. Khanna, “Translation of new cancer treatments from pet dogs to humans,” Nature Reviews Cancer, vol. 8, no. 2, pp. 147–156, 2008.
[6]
K. Hansen and C. Khanna, “Spontaneous and genetically engineered animal models: use in preclinical cancer drug development,” European Journal of Cancer, vol. 40, no. 6, pp. 858–880, 2004.
[7]
S. Tannehill-Gregg, A. Levine, and T. Rosol, “Feline head and neck squamous cell carcinoma: a natural model for the human disease and development of a mouse model,” Veterinary and Comparative Oncology, vol. 4, no. 2, pp. 84–97, 2006.
[8]
C. Khanna, K. Lindblad-Toh, D. Vail et al., “The dog as a cancer model,” Nature Biotechnology, vol. 24, no. 9, pp. 1065–1066, 2006.
[9]
T. Voskoglou-Nomikos, J. L. Pater, and L. Seymour, “Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models,” Clinical Cancer Research, vol. 9, no. 11, pp. 4227–4239, 2003.
[10]
A. J. Shepherd, “Results of the 2006 AVMA survey of companion animal ownership in US pet-owning households,” Journal of the American Veterinary Medical Association, vol. 232, no. 5, pp. 695–696, 2008.
[11]
J. H. Elder, Y. Lin, E. Fink, and C. K. Grant, “Feline immunodeficiency virus (FIV) as a model for study of lentivirus infections: parallels with HIV,” Current HIV Research, vol. 8, no. 1, pp. 73–80, 2010.
[12]
J. C. Kenyon and A. M. L. Lever, “The molecular biology of feline immunodeficiency virus (FIV),” Viruses, vol. 3, no. 11, pp. 2192–2213, 2011.
[13]
M. S. Henson and T. D. O'Brien, “Feline models of type 2 diabetes mellitus,” ILAR Journal, vol. 47, no. 3, pp. 234–242, 2006.
[14]
M. Hoenig, “The cat as a model for human nutrition and disease,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 9, no. 5, pp. 584–588, 2006.
[15]
C. K. Martin, W. P. Dirksen, S. T. Shu et al., “Characterization of bone resorption in novel in vitro and in vivo models of oral squamous cell carcinoma,” Oral Oncology, vol. 48, no. 6, pp. 491–499, 2012.
[16]
J. M. Wypij, T. M. Fan, R. L. Fredrickson, A. M. Barger, L. P. De Lorimier, and S. C. Charney, “In vivo and in vitro efficacy of zoledronate for treating oral squamous cell carcinoma in cats,” Journal of Veterinary Internal Medicine, vol. 22, no. 1, pp. 158–163, 2008.
[17]
S. Tannehill-Gregg, E. Kergosien, and T. J. Rosol, “Feline head and neck squamous cell carcinoma cell line: characterization, production of parathyroid hormone-related protein, and regulation by transforming growth factor-β,” In Vitro Cellular and Developmental Biology, vol. 37, no. 10, pp. 676–683, 2001.
[18]
B. Mognetti, F. Di Carlo, and G. N. Berta, “Animal models in oral cancer research,” Oral Oncology, vol. 42, no. 5, pp. 448–460, 2006.
[19]
American Cancer Society, Ed., Cancer Facts and Figures (2012), American Cancer Society, Atlanta, Ga, USA, 2012.
[20]
J. S. Cooper, K. Porter, K. Mallin et al., “National cancer database report on cancer of the head and neck: 10-year update,” Head and Neck, vol. 31, no. 6, pp. 748–758, 2009.
[21]
J. J. Marretta, L. D. Garrett, and S. M. Marretta, “Feline oral squamous cell carcinoma: an overview,” Veterinary Medicine, vol. 102, no. 6, pp. 392–406, 2007.
[22]
V. Poirier, B. K. Hotz, D. Vail, and R. Straw, “Efficacy and toxicity of an accelerated hypofractionated radiation therapy protocol in cats with oral squamous cell carcinoma,” Veterinary Radiology Ultrasound, vol. 54, no. 1, pp. 81–88, 2013.
[23]
K. E. Stebbins, C. C. Morse, and M. H. Goldschmidt, “Feline oral neoplasia: a ten-year survey,” Veterinary Pathology, vol. 26, no. 2, pp. 121–128, 1989.
[24]
C. K. Martin, S. H. Tannehill-Gregg, T. D. Wolfe, and T. J. Rosol, “Bone-invasive oral squamous cell carcinoma in cats: pathology and expression of parathyroid hormone-related protein,” Veterinary Pathology, vol. 48, no. 1, pp. 302–312, 2011.
[25]
D. G. Gardner, “Spontaneous squamous cell carcinomas of the oral region in domestic animals: a review and consideration of their relevance to human research,” Oral Diseases, vol. 2, no. 2, pp. 148–154, 1996.
[26]
D. E. Bostock, “The prognosis in cats bearing squamous cell carcinoma,” Journal of Small Animal Practice, vol. 13, no. 3, pp. 119–125, 1972.
[27]
R. L. Bradley, E. G. MacEwen, and A. S. Loar, “Mandibular resection for removal of oral tumors in 30 dogs and 6 cats,” Journal of the American Veterinary Medical Association, vol. 184, no. 4, pp. 460–463, 1984.
[28]
S. K. Salisbury, D. C. Richardson, and G. C. Lantz, “Partial maxillectomy and premaxillectomy in the treatment of oral neoplasia in the dog and cat,” Veterinary Surgery, vol. 15, no. 1, pp. 16–26, 1986.
[29]
N. C. P. Reeves, J. M. Turrel, and S. J. Withrow, “Oral squamous cell carcinoma in the cat,” Journal of the American Animal Hospital Association, vol. 29, no. 5, pp. 438–441, 1993.
[30]
N. C. Northrup, K. A. Selting, K. M. Rassnick et al., “Outcomes of cats with oral tumors treated with mandibulectomy: 42 cases,” Journal of the American Animal Hospital Association, vol. 42, no. 5, pp. 350–360, 2006.
[31]
C. A. Hutson, C. C. Willauer, E. J. Walder, J. L. Stone, and M. K. Klein, “Treatment of mandibular squamous cell carcinoma in cats by use of mandibulectomy and radiotherapy: seven cases (1987–1989),” Journal of the American Veterinary Medical Association, vol. 201, no. 5, pp. 777–781, 1992.
[32]
C. McDonald, J. Looper, and S. Greene, “Response rate and duration associated with a 4Gy 5 fraction palliative radiation protocol,” Veterinary Radiology Ultrasound, vol. 53, no. 3, pp. 358–364, 2012.
[33]
V. S. Bregazzi, S. M. LaRue, B. E. Powers, M. J. Fettman, G. K. Ogilvie, and S. J. Withrow, “Response of feline oral squamous cell carcinoma to palliative radiation therapy,” Veterinary Radiology and Ultrasound, vol. 42, no. 1, pp. 77–79, 2001.
[34]
J. Fidel, J. Lyons, C. Tripp, R. Houston, B. Wheeler, and A. Ruiz, “Treatment of oral squamous cell carcinoma with accelerated radiation therapy and concomitant carboplatin in cats,” Journal of Veterinary Internal Medicine, vol. 25, no. 3, pp. 504–510, 2011.
[35]
S. M. Evans, F. LaCreta, S. Helfand et al., “Technique, pharmacokinetics, toxicity, and efficacy of intratumoral etanidazole and radiotherapy for treatment of spontaneous feline oral squamous cell carcinoma,” International Journal of Radiation Oncology Biology Physics, vol. 20, no. 4, pp. 703–708, 1991.
[36]
A. M. Hayes, V. J. Adams, T. J. Scase, and S. Murphy, “Survival of 54 cats with oral squamous cell carcinoma in United Kingdom general practice,” Journal of Small Animal Practice, vol. 48, no. 7, pp. 394–399, 2007.
[37]
L. G. Marcu and E. Yeoh, “A review of risk factors and genetic alterations in head and neck carcinogenesis and implications for current and future approaches to treatment,” Journal of Cancer Research and Clinical Oncology, vol. 135, no. 10, pp. 1303–1314, 2009.
[38]
J. Rautava and S. Syrjanen, “Biology of human papillomavirus infections in head and neck carcinogenesis,” Head and Neck Pathology, vol. 6, supplement 1, pp. S3–S15, 2012.
[39]
J. S. Munday, L. Howe, A. French, R. A. Squires, and H. Sugiarto, “Detection of papillomaviral DNA sequences in a feline oral squamous cell carcinoma,” Research in Veterinary Science, vol. 86, no. 2, pp. 359–361, 2009.
[40]
S. H. O'Neill, K. M. Newkirk, E. A. Anis, R. Brahmbhatt, L. A. Frank, and S. A. Kania, “Detection of human papillomavirus DNA in feline premalignant and invasive squamous cell carcinoma,” Veterinary Dermatology, vol. 22, no. 1, pp. 68–74, 2011.
[41]
J. S. Munday, C. G. Knight, and A. F. French, “Evaluation of feline oral squamous cell carcinomas for p16CDKN2A protein immunoreactivity and the presence of papillomaviral DNA,” Research in Veterinary Science, vol. 90, no. 2, pp. 280–283, 2011.
[42]
J. S. Munday, M. Kiupel, A. F. French, and L. Howe, “Amplification of papillomaviral DNA sequences from a high proportion of feline cutaneous in situ and invasive squamous cell carcinomas using a nested polymerase chain reaction,” Veterinary Dermatology, vol. 19, no. 5, pp. 259–263, 2008.
[43]
E. R. Bertone, L. A. Snyder, and A. S. Moore, “Environmental and lifestyle risk factors for oral squamous cell carcinoma in domestic cats,” Journal of Veterinary Internal Medicine, vol. 17, no. 4, pp. 557–562, 2003.
[44]
L. A. Snyder, E. R. Bertone, R. M. Jakowski, M. S. Dooner, J. Jennings-Ritchie, and A. S. Moore, “p53 expression and environmental tobacco smoke exposure in feline oral squamous cell carcinoma,” Veterinary Pathology, vol. 41, no. 3, pp. 209–214, 2004.
[45]
S. Kalyankrishna and J. R. Grandis, “Epidermal growth factor receptor biology in head and neck cancer,” Journal of Clinical Oncology, vol. 24, no. 17, pp. 2666–2672, 2006.
[46]
J. Looper, D. Malarkey, D. Ruslander, D. Proulx, and D. Thrall, “Epidermal growth factor receptor expression in feline oral squamous cell carcinomas,” Veterinary and Comparative Oncology, vol. 4, no. 1, pp. 33–40, 2006.
[47]
H. Yoshikawa, E. J. Ehrhart, J. Charles, D. Thamm, and S. Larue, “Immunohistochemical characterization of feline oral squamous cell carcinoma,” American Journal of Veterinary Research, vol. 73, no. 11, pp. 1801–1806, 2012.
[48]
G. T. Bergkvist, D. J. Argyle, L. Morrison, N. Macintyre, A. Hayes, and D. A. Yool, “Expression of epidermal growth factor receptor (EGFR) and Ki67 in feline oral squamous cell carcinomas (FOSCC),” Veterinary and Comparative Oncology, vol. 9, no. 2, pp. 106–117, 2011.
[49]
G. T. Bergkvist, D. J. Argyle, L. Y. Pang, R. Muirhead, and D. A. Yool, “Studies on the inhibition of feline EGFR in squamous cell carcinoma: enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors,” Cancer Biology and Therapy, vol. 11, no. 11, pp. 927–937, 2011.
[50]
L. Y. Pang, G. T. Bergkvist, A. C. Arias, D. A. Yool, R. Muirhead, and D. J. Argyle, “Identification of tumour initiating cells in feline head and neck squamous cell carcinoma and evidence for gefitinib induced epithelial to mesenchymal transition,” The Veterinary Journal, vol. 193, no. 1, pp. 46–52, 2012.
[51]
P. A. Kyzas, I. W. Cunha, and J. P. A. Ioannidis, “Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis,” Clinical Cancer Research, vol. 11, no. 4, pp. 1434–1440, 2005.
[52]
J. M. Wypij, Anti-neoplastic effects of zoledronate in feline oral squamous cell carcinoma [Masters], University of Illinois at Urbana-Champaign, Urbana, Ill, USA, 2009.
[53]
O. Gallo, E. Masini, B. Bianchi, L. Bruschini, M. Paglierani, and A. Franchi, “Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma,” Human Pathology, vol. 33, no. 7, pp. 708–714, 2002.
[54]
G. Pannone, P. Bufo, M. F. Caiaffa et al., “Cyclooxygenase-2 expression in oral squamous cell carcinoma,” International Journal of Immunopathology and Pharmacology, vol. 17, no. 3, pp. 273–282, 2004.
[55]
S. L. Beam, K. M. Rassnick, A. S. Moore, and S. P. McDonough, “An immunohistochemical study of cyclooxygenase-2 expression in various feline neoplasms,” Veterinary Pathology, vol. 40, no. 5, pp. 496–500, 2003.
[56]
L. DiBernardi, M. Doré, J. A. Davis et al., “Study of feline oral squamous cell carcinoma: potential target for cyclooxygenase inhibitor treatment,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 76, no. 4, pp. 245–250, 2007.
[57]
A. Hayes, T. Scase, J. Miller, S. Murphy, A. Sparkes, and V. Adams, “COX 2 expression in feline oral squamous cell carcinoma (FOSCC)—an immunohistochemical study and analysis of survival,” Veterinary and Comparative Oncology, vol. 3, no. 1, pp. 44–45, 2005.
[58]
D. A. Heller, C. A. Clifford, M. H. Goldschmidt, D. E. Holt, M. J. Manfredi, and K. U. Sorenmo, “Assessment of cyclooxygenase-2 expression in canine hemangiosarcoma, histiocytic sarcoma, and mast cell tumor,” Veterinary Pathology, vol. 42, no. 3, pp. 350–353, 2005.
[59]
J. J. Wakshlag, J. Peters-Kennedy, J. J. Bushey, and J. P. Loftus, “5-lipoxygenase expression and tepoxalin-induced cell death in squamous cell carcinomas in cats,” American Journal of Veterinary Research, vol. 72, no. 10, pp. 1369–1377, 2011.
[60]
A. Cabelguenne, H. Blons, I. De Waziers et al., “p53 alterations predict tumor response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma: a prospective series,” Journal of Clinical Oncology, vol. 18, no. 7, pp. 1465–1473, 2000.
[61]
J. P. Teifke and C. V. Lohr, “Immunohistochemical detection of P53 overexpression in paraffin wax-embedded squamous cell carcinomas of cattle, horses, cats and dogs,” Journal of Comparative Pathology, vol. 114, no. 2, pp. 205–210, 1996.
[62]
P. J. Slootweg, R. Koole, and G. J. Hordijk, “The presence of p53 protein in relation to Ki-67 as cellular proliferation marker in head and neck squamous cell carcinoma and adjacent dysplastic mucosa,” European Journal of Cancer B, vol. 30, no. 2, pp. 138–141, 1994.
[63]
S. D. Silva, M. Agostini, I. N. Nishimoto et al., “Expression of fatty acid synthase, ErbB2 and Ki-67 in head and neck squamous cell carcinoma. A clinicopathological study,” Oral Oncology, vol. 40, no. 7, pp. 688–696, 2004.
[64]
C. K. Martin, J. L. Werbeck, N. K. Thudi et al., “Zoledronic acid reduces bone loss and tumor growth in an orthotopic xenograft model of osteolytic oral squamous cell carcinoma,” Cancer Research, vol. 70, no. 21, pp. 8607–8616, 2010.
