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Improving human cancer therapy through the evaluation of pet dogs


Comparative oncology clinical trials play an important and growing role in cancer research and drug development efforts. These trials, typically conducted in companion (pet) dogs, allow assessment of novel anticancer agents and combination therapies in a veterinary clinical setting that supports serial biologic sample collections and exploration of dose, schedule and corresponding pharmacokinetic/pharmacodynamic relationships. Further, an intact immune system and natural co-evolution of tumour and microenvironment support exploration of novel immunotherapeutic strategies. Substantial improvements in our collective understanding of the molecular landscape of canine cancers have occurred in the past 10 years, facilitating translational research and supporting the inclusion of comparative studies in drug development. The value of the approach is demonstrated in various clinical trial settings, including single-agent or combination response rates, inhibition of metastatic progression and randomized comparison of multiple agents in a head-to-head fashion. Such comparative oncology studies have been purposefully included in the developmental plan for several US FDA-approved and up-and-coming anticancer drugs. Challenges for this field include keeping pace with technology and data dissemination/harmonization, improving annotation of the canine genome and immune system, and generation of canine-specific validated reagents to support integration of correlative biology within clinical trial efforts.

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Fig. 1: Comparative molecular features of canine and human osteosarcoma.
Fig. 2: Comparative aspects of immune cell subsets in dogs and humans.


  1. 1.

    LeBlanc, A. K. et al. Perspectives from man’s best friend: National Academy of Medicine’s Workshop on Comparative Oncology. Sci. Transl Med. 8, 324ps325 (2016).

    Google Scholar 

  2. 2.

    Khanna, C., London, C., Vail, D., Mazcko, C. & Hirschfeld, S. Guiding the optimal translation of new cancer treatments from canine to human cancer patients. Clin. Cancer Res. 15, 5671–5677 (2009).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Burton, J. & Khanna, C. The role of clinical trials in veterinary oncology. Vet. Clin. North Am. Small Anim. Pract. 44, 977–987 (2014).

    PubMed  Google Scholar 

  4. 4.

    Alvarez, C. E. Naturally occurring cancers in dogs: insights for translational genetics and medicine. ILAR J. 55, 16–45 (2014).

    CAS  PubMed  Google Scholar 

  5. 5.

    Duran-Struuck, R., Huang, C. A. & Matar, A. J. Cellular therapies for the treatment of hematological malignancies; swine are an ideal preclinical model. Front. Oncol. 9, 418 (2019).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Johnson, P. A. & Giles, J. R. The hen as a model of ovarian cancer. Nat. Rev. Cancer 13, 432–436 (2013).

    CAS  PubMed  Google Scholar 

  7. 7.

    van der Weyden, L. et al. Cross-species models of human melanoma. J. Pathol. 238, 152–165 (2016).

    PubMed  Google Scholar 

  8. 8.

    van Zeeland, Y. Rabbit oncology: diseases, diagnostics, and therapeutics. Vet. Clin. North Am. Exot. Anim. Pract. 20, 135–182 (2017).

    PubMed  Google Scholar 

  9. 9.

    Schachtschneider, K. M. et al. Oncopig soft-tissue sarcomas recapitulate key transcriptional features of human sarcomas. Sci. Rep. 7, 2624 (2017).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Schoemaker, N. J. Ferret oncology: diseases, diagnostics, and therapeutics. Vet. Clin. North Am. Exot. Anim. Pract. 20, 183–208 (2017).

    PubMed  Google Scholar 

  11. 11.

    Schiffman, J. D. & Breen, M. Comparative oncology: what dogs and other species can teach us about humans with cancer. Philos. Trans. R. Soc. Lond. B Biol. Sci. 370, 20140231 (2015).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Cannon, C. M. Cats, cancer and comparative oncology. Vet. Sci. 2, 111–126 (2015).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Gustafson, D. L., Duval, D. L., Regan, D. P. & Thamm, D. H. Canine sarcomas as a surrogate for the human disease. Pharmacol. Ther. 188, 80–96 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Gardner, H. L., Fenger, J. M. & London, C. A. Dogs as a model for cancer. Annu. Rev. Anim. Biosci. 4, 199–222 (2016).

    CAS  PubMed  Google Scholar 

  15. 15.

    Gordon, I., Paoloni, M., Mazcko, C. & Khanna, C. The comparative oncology trials consortium: using spontaneously occurring cancers in dogs to inform the cancer drug development pathway. PLoS Med. 6, e1000161 (2009).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Barutello, G. et al. Strengths and weaknesses of pre-clinical models for human melanoma treatment: dawn of dogs’ revolution for immunotherapy. Int. J. Mol. Sci. 19, 799 (2018).

    PubMed Central  Google Scholar 

  17. 17.

    Tarone, L. et al. Naturally occurring cancers in pet dogs as pre-clinical models for cancer immunotherapy. Cancer Immunol. Immunother. 68, 1839–1853 (2019).

    PubMed  Google Scholar 

  18. 18.

    Garden, O. A., Volk, S. W., Mason, N. J. & Perry, J. A. Companion animals in comparative oncology: One Medicine in action. Vet. J. 240, 6–13 (2018).

    CAS  PubMed  Google Scholar 

  19. 19.

    Page, R. et al. Conduct, oversight, and ethical considerations of clinical trials in companion animals with cancer: report of a workshop on best practice recommendations. J. Vet. Intern. Med. 30, 527–535 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Paoloni, M. & Khanna, C. Translation of new cancer treatments from pet dogs to humans. Nat. Rev. Cancer 8, 147–156 (2008).

    CAS  PubMed  Google Scholar 

  21. 21.

    LeBlanc, A. K., Mazcko, C. N. & Khanna, C. Defining the value of a comparative approach to cancer drug development. Clin. Cancer Res. 22, 2133–2138 (2016).

    CAS  PubMed  Google Scholar 

  22. 22.

    Paoloni, M. C. et al. Launching a novel preclinical infrastructure: comparative oncology trials consortium directed therapeutic targeting of TNFα to cancer vasculature. PLoS ONE 4, e4972 (2009).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Thamm, D. H. Canine cancer: strategies in experimental therapeutics. Front. Oncol. 9, 1257 (2019).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Pryer, N. K. et al. Proof of target for SU11654: inhibition of KIT phosphorylation in canine mast cell tumors. Clin. Cancer Res. 9, 5729–5734 (2003).

    CAS  PubMed  Google Scholar 

  25. 25.

    Khanna, C. & Gordon, I. Catching cancer by the tail: new perspectives on the use of kinase inhibitors. Clin. Cancer Res. 15, 3645–3647 (2009).

    CAS  PubMed  Google Scholar 

  26. 26.

    Liao, A. T. et al. Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors. Blood 100, 585–593 (2002).

    CAS  PubMed  Google Scholar 

  27. 27.

    London, C. A. et al. Phase I dose-escalating study of SU11654, a small molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous malignancies. Clin. Cancer Res. 9, 2755–2768 (2003).

    CAS  PubMed  Google Scholar 

  28. 28.

    Lin, T. Y. et al. The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors. Exp. Hematol. 36, 1266–1277 (2008).

    CAS  PubMed  Google Scholar 

  29. 29.

    London, C. A. et al. KTN0158, a humanized anti-KIT monoclonal antibody, demonstrates biologic activity against both normal and malignant canine mast cells. Clin. Cancer Res. 23, 2565–2574 (2017).

    CAS  PubMed  Google Scholar 

  30. 30.

    Davis, B. W. & Ostrander, E. A. Domestic dogs and cancer research: a breed-based genomics approach. ILAR J. 55, 59–68 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005). This work presents the first comprehensive description and annotation of the canine genome, which enables further study in canine comparative genomics.

    CAS  PubMed  Google Scholar 

  32. 32.

    Ostrander, E. A., Dreger, D. L. & Evans, J. M. Canine cancer genomics: lessons for canine and human health. Annu. Rev. Anim. Biosci. 7, 449–472 (2019).

    CAS  PubMed  Google Scholar 

  33. 33.

    Ostrander, E. A. et al. Dog10K: an international sequencing effort to advance studies of canine domestication, phenotypes and health. Natl Sci. Rev. 6, 810–824 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Megquier, K. et al. BarkBase: epigenomic annotation of canine genomes. Genes 10, 433 (2019).

    CAS  PubMed Central  Google Scholar 

  35. 35.

    Paoloni, M. et al. Prospective molecular profiling of canine cancers provides a clinically relevant comparative model for evaluating personalized medicine (PMed) trials. PLoS ONE 9, e90028 (2014).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    London, C. A. et al. Impact of toceranib/piroxicam/cyclophosphamide maintenance therapy on outcome of dogs with appendicular osteosarcoma following amputation and carboplatin chemotherapy: a multi-institutional study. PLoS ONE 10, e0124889 (2015).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Turner, H. et al. Prognosis for dogs with stage III osteosarcoma following treatment with amputation and chemotherapy with and without metastasectomy. J. Am. Vet. Med. Assoc. 251, 1293–1305 (2017).

    PubMed  Google Scholar 

  38. 38.

    Bishop, M. W., Janeway, K. A. & Gorlick, R. Future directions in the treatment of osteosarcoma. Curr. Opin. Pediatr. 28, 26–33 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Lagmay, J. P. et al. Outcome of patients with recurrent osteosarcoma enrolled in seven phase II trials through children’s cancer group, pediatric oncology group, and children’s oncology group: learning from the past to move forward. J. Clin. Oncol. 34, 3031–3038 (2016).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Selmic, L. E., Burton, J. H., Thamm, D. H., Withrow, S. J. & Lana, S. E. Comparison of carboplatin and doxorubicin-based chemotherapy protocols in 470 dogs after amputation for treatment of appendicular osteosarcoma. J. Vet. Intern. Med. 28, 554–563 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Roberts, R. D. et al. Provocative questions in osteosarcoma basic and translational biology: a report from the Children’s Oncology Group. Cancer 125, 3514–3525 (2019).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Fenger, J. M., London, C. A. & Kisseberth, W. C. Canine osteosarcoma: a naturally occurring disease to inform pediatric oncology. ILAR J. 55, 69–85 (2014).

    CAS  PubMed  Google Scholar 

  43. 43.

    Grohar, P. J., Janeway, K. A., Mase, L. D. & Schiffman, J. D. Advances in the treatment of pediatric bone sarcomas. Am. Soc. Clin. Oncol. Educ. Book 37, 725–735 (2017).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Paoloni, M. et al. Canine tumor cross-species genomics uncovers targets linked to osteosarcoma progression. BMC Genomics 10, 625 (2009). This comparative array-based assessment of gene expression shows that canine and human osteosarcomas are indistinguishable from each other from a transcriptomic standpoint, and that canine osteosarcoma could inform novel gene and target discovery in human osteosarcoma.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Angstadt, A. Y. et al. Characterization of canine osteosarcoma by array comparative genomic hybridization and RT-qPCR: signatures of genomic imbalance in canine osteosarcoma parallel the human counterpart. Genes Chromosomes Cancer 50, 859–874 (2011).

    CAS  PubMed  Google Scholar 

  46. 46.

    Angstadt, A. Y., Thayanithy, V., Subramanian, S., Modiano, J. F. & Breen, M. A genome-wide approach to comparative oncology: high-resolution oligonucleotide aCGH of canine and human osteosarcoma pinpoints shared microaberrations. Cancer Genet. 205, 572–587 (2012).

    CAS  PubMed  Google Scholar 

  47. 47.

    Scott, M. C. et al. Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach. Bone 49, 356–367 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Gröbner, S. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Gardner, H. L. et al. Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2. Commun. Biol. 2, 266 (2019). This study provides a comprehensive whole-genome, whole-exome and transcriptomic assessment of canine osteosarcoma, providing further evidence of similarities between human and canine osteosarcomas.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Chen, X. et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 7, 104–112 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Shao, Y. W. et al. Cross-species genomics identifies DLG2 as a tumor suppressor in osteosarcoma. Oncogene 38, 291–298 (2019).

    CAS  PubMed  Google Scholar 

  52. 52.

    Sakthikumar, S. et al. SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma. Cancer Res. 78, 3421–3431 (2018).

    CAS  PubMed  Google Scholar 

  53. 53.

    Perry, J. A. et al. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc. Natl Acad. Sci. USA 111, E5564–E5573 (2014).

    CAS  PubMed  Google Scholar 

  54. 54.

    Roy, J., Wycislo, K. L., Pondenis, H., Fan, T. M. & Das, A. Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin. PLoS ONE 12, e0183930 (2017).

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Kovac, M. et al. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat. Commun. 6, 8940 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Gulhan, D. C., Lee, J. J., Melloni, G. E. M., Cortes-Ciriano, I. & Park, P. J. Detecting the mutational signature of homologous recombination deficiency in clinical samples. Nat. Genet. 51, 912–919 (2019).

    CAS  PubMed  Google Scholar 

  57. 57.

    Withers, S. S. et al. Metastatic immune infiltrates correlate with those of the primary tumour in canine osteosarcoma. Vet. Comp. Oncol. 17, 242–252 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Sorenson, L., Fu, Y., Hood, T., Warren, S. & McEachron, T. A. Targeted transcriptional profiling of the tumor microenvironment reveals lymphocyte exclusion and vascular dysfunction in metastatic osteosarcoma. Oncoimmunology 8, e1629779 (2019).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Wu, C. C. et al. Immuno-genomic landscape of osteosarcoma. Nat. Commun. 11, 1008 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Bergman, P. J. Cancer immunotherapies. Vet. Clin. North Am. Small Anim. Pract. 49, 881–902 (2019).

    PubMed  Google Scholar 

  61. 61.

    Maekawa, N. et al. A canine chimeric monoclonal antibody targeting PD-L1 and its clinical efficacy in canine oral malignant melanoma or undifferentiated sarcoma. Sci. Rep. 7, 8951 (2017).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Endo-Munoz, L. et al. Auranofin improves overall survival when combined with standard of care in a pilot study involving dogs with osteosarcoma. Vet. Comp. Oncol. 18, 206–213 (2020).

    CAS  PubMed  Google Scholar 

  63. 63.

    Mason, N. J. et al. Immunotherapy with a HER2-targeting listeria induces HER2-specific immunity and demonstrates potential therapeutic effects in a phase I trial in canine osteosarcoma. Clin. Cancer Res. 22, 4380–4390 (2016).

    CAS  PubMed  Google Scholar 

  64. 64.

    Sayles, L. C. et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov. 9, 46–63 (2019).

    CAS  PubMed  Google Scholar 

  65. 65.

    Richards, K. L. & Suter, S. E. Man’s best friend: what can pet dogs teach us about non-Hodgkin’s lymphoma? Immunol. Rev. 263, 173–191 (2015).

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Marconato, L. et al. Conformity and controversies in the diagnosis, staging and follow-up evaluation of canine nodal lymphoma: a systematic review of the last 15 years of published literature. Vet. Comp. Oncol. 15, 1029–1040 (2017).

    CAS  PubMed  Google Scholar 

  67. 67.

    Cozzi, M. et al. Canine nodal marginal zone lymphoma: descriptive insight into the biological behaviour. Vet. Comp. Oncol. 16, 246–252 (2018).

    CAS  PubMed  Google Scholar 

  68. 68.

    Davies, O. et al. Prognostic significance of clinical presentation, induction and rescue treatment in 42 cases of canine centroblastic diffuse large B-cell multicentric lymphoma in the United Kingdom. Vet. Comp. Oncol. 16, 276–287 (2018).

    CAS  PubMed  Google Scholar 

  69. 69.

    Dias, J. N. R. et al. Canine multicentric lymphoma exhibits systemic and intratumoral cytokine dysregulation. Vet. Immunol. Immunopathol. 218, 109940 (2019).

    CAS  PubMed  Google Scholar 

  70. 70.

    Ewing, T. S., Pieper, J. B. & Stern, A. W. Prevalence of CD20+ cutaneous epitheliotropic T-cell lymphoma in dogs: a retrospective analysis of 24 cases (2011–2018) in the USA. Vet. Dermatol. 30, 51-e14 (2019).

    PubMed  Google Scholar 

  71. 71.

    Ito, D., Frantz, A. M. & Modiano, J. F. Canine lymphoma as a comparative model for human non-Hodgkin lymphoma: recent progress and applications. Vet. Immunol. Immunopathol. 159, 192–201 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Seelig, D. M., Avery, A. C., Ehrhart, E. J. & Linden, M. A. The comparative diagnostic features of canine and human lymphoma. Vet. Sci. 3, 11 (2016).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Modiano, J. F., Breen, M., Valli, V. E., Wojcieszyn, J. W. & Cutter, G. R. Predictive value of p16 or Rb inactivation in a model of naturally occurring canine non-Hodgkin’s lymphoma. Leukemia 21, 184–187 (2007).

    CAS  PubMed  Google Scholar 

  74. 74.

    Morton, L. M. et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood 107, 265–276 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    DeWeerdt, S. How dogs are teaching researchers new tricks for treating cancer. Nature 563, S50–S51 (2018).

    CAS  PubMed  Google Scholar 

  76. 76.

    Wolf-Ringwall, A. et al. Prospective evaluation of flow cytometric characteristics, histopathologic diagnosis and clinical outcome in dogs with naive B-cell lymphoma treated with a 19-week CHOP protocol. Vet. Comp. Oncol. 18, 342–352 (2020).

    CAS  PubMed  Google Scholar 

  77. 77.

    Burton, J. H. et al. NCI Comparative Oncology Program testing of non-camptothecin indenoisoquinoline topoisomerase I inhibitors in naturally occurring canine lymphoma. Clin. Cancer Res. 24, 5830–5840 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Yamazaki, H. et al. Effects of toceranib phosphate (Palladia) monotherapy on multidrug resistant lymphoma in dogs. J. Vet. Med. Sci. 7, 1225–1229 (2017).

    Google Scholar 

  79. 79.

    London, C. A. et al. Phase I evaluation of STA-1474, a prodrug of the novel HSP90 inhibitor ganetespib, in dogs with spontaneous cancer. PLoS ONE 6, e27018 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Habineza Ndikuyeze, G. et al. A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma. PLoS ONE 9, e95404 (2014).

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Honigberg, L. A. et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl Acad. Sci. USA 107, 13075–13080 (2010).

    CAS  PubMed  Google Scholar 

  82. 82.

    Vail, D. M. et al. Assessment of GS-9219 in a pet dog model of non-Hodgkin’s lymphoma. Clin. Cancer Res. 15, 3503–3510 (2009).

    CAS  PubMed  Google Scholar 

  83. 83.

    Dias, J. N. R. et al. The histone deacetylase inhibitor panobinostat is a potent antitumor agent in canine diffuse large B-cell lymphoma. Oncotarget 9, 28586–28598 (2018).

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Kalakonda, N. et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 7, e511–e522 (2020).

    PubMed  Google Scholar 

  85. 85.

    Sadowski, A. R. et al. Phase II study of the oral selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in dogs with lymphoma. BMC Vet. Res. 14, 250 (2018).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    London, C. A. et al. Preclinical evaluation of the novel, orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study. PLoS ONE 9, e87585 (2014).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Thomas, R. et al. Refining tumor-associated aneuploidy through ‘genomic recoding’ of recurrent DNA copy number aberrations in 150 canine non-Hodgkin lymphomas. Leuk. Lymphoma 52, 1321–1335 (2011).

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Ferraresso, S. et al. DNA methylation profiling reveals common signatures of tumorigenesis and defines epigenetic prognostic subtypes of canine diffuse large B-cell lymphoma. Sci. Rep. 7, 11591 (2017).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Gaurnier-Hausser, A. & Mason, N. J. Assessment of canonical NF-κB activity in canine diffuse large B-cell lymphoma. Methods Mol. Biol. 1280, 469–504 (2015).

    CAS  PubMed  Google Scholar 

  90. 90.

    Seelig, D. M. et al. Constitutive activation of alternative nuclear factor κB pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies. Leuk. Lymphoma 58, 1702–1710 (2017).

    CAS  PubMed  Google Scholar 

  91. 91.

    Richards, K. L. et al. Gene profiling of canine B-cell lymphoma reveals germinal center and postgerminal center subtypes with different survival times, modeling human DLBCL. Cancer Res. 73, 5029–5039 (2013). This study highlights the molecular phenotyping, based on comparative gene expression profiling, of canine lymphoma and how it relates to human DLBCL.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Gaurnier-Hausser, A., Patel, R., Baldwin, A. S., May, M. J. & Mason, N. J. NEMO-binding domain peptide inhibits constitutive NF-κB activity and reduces tumor burden in a canine model of relapsed, refractory diffuse large B-cell lymphoma. Clin. Cancer Res. 17, 4661–4671 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Avery, A. C. The genetic and molecular basis for canine models of human leukemia and lymphoma. Front. Oncol. 10, 23 (2020).

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Bushell, K. R. et al. Genetic inactivation of TRAF3 in canine and human B-cell lymphoma. Blood 125, 999–1005 (2015).

    CAS  PubMed  Google Scholar 

  95. 95.

    Elvers, I. et al. Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background. Genome Res. 25, 1634–1645 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Zain, J. M. Aggressive T-cell lymphomas: 2019 updates on diagnosis, risk stratification, and management. Am. J. Hematol. 94, 929–946 (2019).

    CAS  PubMed  Google Scholar 

  97. 97.

    Heavican, T. B. et al. Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. Blood 133, 1664–1676 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Harris, L. J. et al. Canine CD4+ T-cell lymphoma identified by flow cytometry exhibits a consistent histomorphology and gene expression profile. Vet. Comp. Oncol. 17, 253–264 (2019).

    CAS  PubMed  Google Scholar 

  99. 99.

    McDonald, J. T. et al. Comparative oncology DNA sequencing of canine T cell lymphoma via human hotspot panel. Oncotarget 9, 22693–22702 (2018).

    PubMed  PubMed Central  Google Scholar 

  100. 100.

    Panjwani, M. K. et al. Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma. Oncoimmunology 9, 1676615 (2020).

    PubMed  Google Scholar 

  101. 101.

    Panjwani, M. K. et al. Feasibility and safety of RNA-transfected CD20-specific chimeric antigen receptor T cells in dogs with spontaneous B cell lymphoma. Mol. Ther. 24, 1602–1614 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Marconato, L. et al. Opportunities and challenges of active immunotherapy in dogs with B-cell lymphoma: a 5-year experience in two veterinary oncology centers. J. Immunother. Cancer 7, 146 (2019).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Rue, S. M. et al. Identification of a candidate therapeutic antibody for treatment of canine B-cell lymphoma. Vet. Immunol. Immunopathol. 164, 148–159 (2015).

    CAS  PubMed  Google Scholar 

  104. 104.

    Mizuno, T. et al. Generation of a canine anti-canine CD20 antibody for canine lymphoma treatment. Sci. Rep. 10, 11476 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Haran, K. P. et al. Generation and validation of an antibody to canine CD19 for diagnostic and future therapeutic purposes. Vet. Pathol. 57, 241–252 (2020).

    CAS  PubMed  Google Scholar 

  106. 106.

    Shapiro, S. G. et al. Canine urothelial carcinoma: genomically aberrant and comparatively relevant. Chromosome Res. 23, 311–331 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Dhawan, D., Hahn, N. M., Ramos-Vara, J. A. & Knapp, D. W. Naturally-occurring canine invasive urothelial carcinoma harbors luminal and basal transcriptional subtypes found in human muscle invasive bladder cancer. PLoS Genet. 14, e1007571 (2018). This paper provides a comprehensive description of histologic subtypes and molecular features of canine urothelial carcinoma, relating these findings to human bladder cancer.

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Knapp, D. W. et al. Naturally-occurring invasive urothelial carcinoma in dogs, a unique model to drive advances in managing muscle invasive bladder cancer in humans. Front. Oncol. 9, 1493 (2019).

    PubMed  Google Scholar 

  109. 109.

    Jack, S. et al. A novel, safe, fast and efficient treatment for Her2-positive and negative bladder cancer utilizing an EGF–anthrax toxin chimera. Int. J. Cancer 146, 449–460 (2020).

    CAS  PubMed  Google Scholar 

  110. 110.

    Fazekas-Singer, J. et al. Development of a radiolabeled caninized anti-EGFR antibody for comparative oncology trials. Oncotarget 8, 83128–83141 (2017).

    PubMed  PubMed Central  Google Scholar 

  111. 111.

    Nagaya, T. et al. Near infrared photoimmunotherapy targeting bladder cancer with a canine anti-epidermal growth factor receptor (EGFR) antibody. Oncotarget 9, 19026–19038 (2018).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Fulkerson, C. M., Dhawan, D., Ratliff, T. L., Hahn, N. M. & Knapp, D. W. Naturally occurring canine invasive urinary bladder cancer: a complementary animal model to improve the success rate in human clinical trials of new cancer drugs. Int. J. Genomics 2017, 6589529 (2017).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Mohammed, S. I. et al. Effects of the cyclooxygenase inhibitor, piroxicam, on tumor response, apoptosis, and angiogenesis in a canine model of human invasive urinary bladder cancer. Cancer Res. 62, 356–358 (2002).

    CAS  PubMed  Google Scholar 

  114. 114.

    Dhawan, D. et al. Effects of short-term celecoxib treatment in patients with invasive transitional cell carcinoma of the urinary bladder. Mol. Cancer Ther. 9, 1371–1377 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Sabichi, A. L. et al. A randomized controlled trial of celecoxib to prevent recurrence of nonmuscle-invasive bladder cancer. Cancer Prev. Res. 4, 1580–1589 (2011).

    CAS  Google Scholar 

  116. 116.

    Chand, D. et al. Immune checkpoint B7x (B7-H4/B7S1/VTCN1) is over expressed in spontaneous canine bladder cancer: the first report and its implications in a preclinical model. Bladder Cancer 5, 63–71 (2019).

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    Decker, B. et al. Homologous mutation to human BRAF V600E is common in naturally occurring canine bladder cancer — evidence for a relevant model system and urine-based diagnostic test. Mol. Cancer Res. 13, 993–1002 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Mochizuki, H., Kennedy, K., Shapiro, S. G. & Breen, M. BRAF mutations in canine cancers. PLoS ONE 10, e01295344 (2015).

    Google Scholar 

  119. 119.

    Longo, T. et al. Targeted exome sequencing of the cancer genome in patients with very high-risk bladder cancer. Eur. Urol. 70, 714–717 (2016).

    CAS  PubMed  Google Scholar 

  120. 120.

    Sorenmo, K. U. in Withrow & MacEwen’s Small Animal Clinical Oncology (eds Thamm D. H., Liptak J. M. & Vail D.) 604-625 (Elsevier, 2020).

  121. 121.

    Sorenmo, K. U. et al. Canine mammary gland tumours; a histological continuum from benign to malignant; clinical and histopathological evidence. Vet. Comp. Oncol. 7, 162–172 (2009).

    CAS  PubMed  Google Scholar 

  122. 122.

    Nguyen, F. et al. Canine invasive mammary carcinomas as models of human breast cancer. Part 1: natural history and prognostic factors. Breast Cancer Res. Treat. 167, 635–648 (2018).

    CAS  PubMed  Google Scholar 

  123. 123.

    Raposo, T. P. et al. Comparative aspects of canine and human inflammatory breast cancer. Semin. Oncol. 44, 288–300 (2017).

    PubMed  Google Scholar 

  124. 124.

    Carvalho, M. I. et al. A comparative approach of tumor-associated inflammation in mammary cancer between humans and dogs. Biomed. Res. Int. 2016, 4917387 (2016).

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Varallo, G. R. et al. Prognostic phenotypic classification for canine mammary tumors. Oncol. Lett. 18, 6545–6553 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Lutful Kabir, F. M., Alvarez, C. E. & Bird, R. C. Canine mammary carcinomas: a comparative analysis of altered gene expression. Vet. Sci. 3, 1 (2015).

    PubMed Central  Google Scholar 

  127. 127.

    Lee, K. H., Hwang, H. J., Noh, H. J., Shin, T. J. & Cho, J. Y. Somatic mutation of PIK3CA (H1047R) is a common driver mutation hotspot in canine mammary tumors as well as human breast cancers. Cancers 11, 2006 (2019).

    CAS  PubMed Central  Google Scholar 

  128. 128.

    Vasan, N., Toska, E. & Scaltriti, M. Overview of the relevance of PI3K pathway in HR-positive breast cancer. Ann. Oncol. 30, x3–x11 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Burrai, G. P. et al. Investigation of HER2 expression in canine mammary tumors by antibody-based, transcriptomic and mass spectrometry analysis: is the dog a suitable animal model for human breast cancer? Tumour Biol. 36, 9083–9091 (2015).

    CAS  PubMed  Google Scholar 

  130. 130.

    Pena, L. et al. Canine mammary tumors: a review and consensus of standard guidelines on epithelial and myoepithelial phenotype markers, HER2, and hormone receptor assessment using immunohistochemistry. Vet. Pathol. 51, 127–145 (2014).

    CAS  PubMed  Google Scholar 

  131. 131.

    Lorch, G. et al. Identification of recurrent activating her2 mutations in primary canine pulmonary adenocarcinoma. Clin. Cancer Res. 25, 5866–5877 (2019). This study describes the molecular landscape of canine lung cancer, reporting on the similarities to and differences from human NSCLC.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Seung, B. J., Cho, S. H., Kim, S. H., Lim, H. Y. & Sur, J. H. Quantitative analysis of HER2 mRNA expression by RNA in situ hybridization in canine mammary gland tumors: comparison with immunohistochemistry analysis. PLoS ONE 15, e0229031 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Thumser-Henner, P., Nytko, K. J. & Rohrer Bley, C. Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy. BMC Vet. Res. 16, 30 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Saba, C. et al. A comparative oncology study of iniparib defines its pharmacokinetic profile and biological activity in a naturally-occurring canine cancer model. PLoS ONE 11, e0149194 (2016).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    Connolly, N. P. et al. Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma. Sci. Rep. 8, 1180 (2018).

    PubMed  PubMed Central  Google Scholar 

  136. 136.

    Miller, A. D., Miller, C. R. & Rossmeisl, J. H. Canine primary intracranial cancer: a clinicopathologic and comparative review of glioma, meningioma, and choroid plexus tumors. Front. Oncol. 9, 1151 (2019).

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Thomas, R. et al. ‘Putting our heads together’: insights into genomic conservation between human and canine intracranial tumors. J. Neurooncol. 94, 333–349 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Filley, A. et al. Immunologic and gene expression profiles of spontaneous canine oligodendrogliomas. J. Neurooncol 137, 469–479 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Dickinson, P. J. et al. Chromosomal aberrations in canine gliomas define candidate genes and common pathways in dogs and humans. J. Neuropathol. Exp. Neurol. 75, 700–710 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Koehler, J. W. et al. A revised diagnostic classification of canine glioma: towards validation of the canine glioma patient as a naturally occurring preclinical model for human glioma. J. Neuropathol. Exp. Neurol. 77, 1039–1054 (2018).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Ostrom, Q. T., Cote, D. J., Ascha, M., Kruchko, C. & Barnholtz-Sloan, J. S. Adult glioma incidence and survival by race or ethnicity in the United States from 2000 to 2014. JAMA Oncol. 4, 1254–1262 (2018).

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Chen, R., Smith-Cohn, M., Cohen, A. L. & Colman, H. Glioma subclassifications and their clinical significance. Neurotherapeutics 14, 284–297 (2017).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    LeBlanc, A. K. et al. Creation of an NCI Comparative Brain Tumor Consortium: informing the translation of new knowledge from canine to human brain tumor patients. NeuroOncol. 18, 1209–1218 (2016).

    Google Scholar 

  144. 144.

    Amin, S. B. et al. Comparative molecular life history of spontaneous canine and human gliomas. Cancer Cell 37, 243–257.e247 (2020). This study comprehensively describes the genomic landscape of >80 canine gliomas, demonstrating that canine glioma more closely resembles paediatric rather than adult human glioma.

    CAS  PubMed  Google Scholar 

  145. 145.

    Reitman, Z. J. et al. IDH1 and IDH2 hotspot mutations are not found in canine glioma. Int. J. Cancer 127, 245–246 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Latouche, E. L. et al. High-frequency irreversible electroporation for intracranial meningioma: a feasibility study in a spontaneous canine tumor model. Technol. Cancer Res. Treat. 17, 1533033818785285 (2018).

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Schlein, L. J. et al. Immunohistochemical characterization of procaspase-3 overexpression as a druggable target with PAC-1, a procaspase-3 activator, in canine and human brain cancers. Front. Oncol. 9, 96 (2019).

    PubMed  PubMed Central  Google Scholar 

  148. 148.

    Dickinson, P. J. et al. Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging: laboratory investigation. J. Neurosurg. 108, 989–998 (2008).

    CAS  PubMed  Google Scholar 

  149. 149.

    Debinski, W., Dickinson, P., Rossmeisl, J. H., Robertson, J. & Gibo, D. M. New agents for targeting of IL-13RA2 expressed in primary human and canine brain tumors. PLoS ONE 8, e77719 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    MacDiarmid, J. A. et al. Targeted doxorubicin delivery to brain tumors via minicells: proof of principle using dogs with spontaneously occurring tumors as a model. PLoS ONE 11, e0151832 (2016).

    PubMed  PubMed Central  Google Scholar 

  151. 151.

    Sayour, E. J. et al. Personalized tumor RNA loaded lipid-nanoparticles prime the systemic and intratumoral milieu for response to cancer immunotherapy. Nano. Lett. 18, 6195–6206 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Olin, M. R. et al. Treatment combining CD200 immune checkpoint inhibitor and tumor-lysate vaccination after surgery for pet dogs with high-grade glioma. Cancers 11, 137 (2019).

    CAS  PubMed Central  Google Scholar 

  153. 153.

    Olin, M. R. et al. Victory and defeat in the induction of a therapeutic response through vaccine therapy for human and canine brain tumors: a review of the state of the art. Crit. Rev. Immunol. 34, 399–432 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Andersen, B. M. et al. Vaccination for invasive canine meningioma induces in situ production of antibodies capable of antibody-dependent cell-mediated cytotoxicity. Cancer Res. 73, 2987–2997 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Pluhar, G. E. et al. Anti-tumor immune response correlates with neurological symptoms in a dog with spontaneous astrocytoma treated by gene and vaccine therapy. Vaccine 28, 3371–3378 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Yin, Y. et al. Checkpoint blockade reverses anergy in IL-13Rα2 humanized scFv-based CAR T cells to treat murine and canine gliomas. Mol. Ther. Oncolytics 11, 20–38 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Lee, B., Clarke, D., Watson, M. & Laver, T. Retrospective evaluation of a modified human lung cancer stage classification in dogs with surgically excised primary pulmonary carcinomas. Vet. Comp. Oncol. (2020).

    Article  PubMed  Google Scholar 

  158. 158.

    Hellmann, M. D. et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019).

    CAS  PubMed  Google Scholar 

  159. 159.

    Dafni, U., Tsourti, Z., Vervita, K. & Peters, S. Immune checkpoint inhibitors, alone or in combination with chemotherapy, as first-line treatment for advanced non-small cell lung cancer. A systematic review and network meta-analysis. Lung Cancer 134, 127–140 (2019).

    PubMed  Google Scholar 

  160. 160.

    D’Arcangelo, M., D’Incecco, A. & Cappuzzo, F. Rare mutations in non-small-cell lung cancer. Future Oncol. 9, 699–711 (2013).

    PubMed  Google Scholar 

  161. 161.

    Govindan, R. et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150, 1121–1134 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Nishiya, A. T. et al. Comparative aspects of canine melanoma. Vet. Sci. 3, 7 (2016).

    PubMed Central  Google Scholar 

  163. 163.

    Simpson, R. M. et al. Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma. Pigment. Cell Melanoma Res. 27, 37–47 (2014).

    CAS  PubMed  Google Scholar 

  164. 164.

    Hernandez, B. et al. Naturally occurring canine melanoma as a predictive comparative oncology model for human mucosal and other triple wild-type melanomas. Int. J. Mol. Sci. 19, 394 (2018).

    PubMed Central  Google Scholar 

  165. 165.

    Hendricks, W. P. D. et al. Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis. PLoS Genet. 14, e1007589 (2018).

    PubMed  PubMed Central  Google Scholar 

  166. 166.

    Prouteau, A. & Andre, C. Canine melanomas as models for human melanomas: clinical, histological, and genetic comparison. Genes 10, 501 (2019).

    CAS  PubMed Central  Google Scholar 

  167. 167.

    Wong, K. et al. Cross-species genomic landscape comparison of human mucosal melanoma with canine oral and equine melanoma. Nat. Commun. 10, 353 (2019). This report provides an overview of shared genomic lesions from humans, horses and dogs, demonstrating biologic convergence despite differences in upstream driver mutational events.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Poorman, K. et al. Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization. Chromosome Res. 23, 171–186 (2015).

    CAS  PubMed  Google Scholar 

  169. 169.

    Wei, B. R. et al. Synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma. Pigment. Cell Melanoma Res. 29, 643–655 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Hayward, N. K. et al. Whole-genome landscapes of major melanoma subtypes. Nature 545, 175–180 (2017).

    CAS  PubMed  Google Scholar 

  171. 171.

    Fowles, J. S., Denton, C. L. & Gustafson, D. L. Comparative analysis of MAPK and PI3K/AKT pathway activation and inhibition in human and canine melanoma. Vet. Comp. Oncol. 13, 288–304 (2013).

    PubMed  Google Scholar 

  172. 172.

    Hartley, G. et al. Immune regulation of canine tumour and macrophage PD-L1 expression. Vet. Comp. Oncol. 15, 534–549 (2017).

    CAS  PubMed  Google Scholar 

  173. 173.

    Dow, S. A role for dogs in advancing cancer immunotherapy research. Front. Immunol. 10, 2935 (2019).

    CAS  PubMed  Google Scholar 

  174. 174.

    Klingemann, H. Immunotherapy for dogs: running behind humans. Front. Immunol. 9, 133 (2018).

    PubMed  PubMed Central  Google Scholar 

  175. 175.

    Bergeron, L. M. et al. Comparative functional characterization of canine IgG subclasses. Vet. Immunol. Immunopathol. 157, 31–41 (2014). This work is the only comprehensive, comparative description of the functional subclasses of the canine IgG family, which highlights similarities and differences with humans.

    CAS  PubMed  Google Scholar 

  176. 176.

    Hartley, G., Elmslie, R., Dow, S. & Guth, A. Checkpoint molecule expression by B and T cell lymphomas in dogs. Vet. Comp. Oncol. 16, 352–360 (2018).

    CAS  PubMed  Google Scholar 

  177. 177.

    Coy, J., Caldwell, A., Chow, L., Guth, A. & Dow, S. PD-1 expression by canine T cells and functional effects of PD-1 blockade. Vet. Comp. Oncol. 15, 1487–1502 (2017).

    CAS  PubMed  Google Scholar 

  178. 178.

    Kumar, S. R. et al. Programmed death ligand 1 is expressed in canine B cell lymphoma and downregulated by MEK inhibitors. Vet. Comp. Oncol. 15, 1527–1536 (2017).

    CAS  PubMed  Google Scholar 

  179. 179.

    Pinheiro, D. et al. Phenotypic and functional characterization of a CD4+CD25highFOXP3high regulatory T-cell population in the dog. Immunology 132, 111–122 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Wu, Y. et al. Phenotypic characterisation of regulatory T cells in dogs reveals signature transcripts conserved in humans and mice. Sci. Rep. 9, 13478 (2019).

    PubMed  PubMed Central  Google Scholar 

  181. 181.

    Hutchison, S. et al. Characterization of myeloid-derived suppressor cells and cytokines GM-CSF, IL-10 and MCP-1 in dogs with malignant melanoma receiving a GD3-based immunotherapy. Vet. Immunol. Immunopathol. 216, 109912 (2019).

    CAS  PubMed  Google Scholar 

  182. 182.

    Paoloni, M. et al. Defining the pharmacodynamic profile and therapeutic index of NHS-IL12 immunocytokine in dogs with malignant melanoma. PLoS ONE 10, e0129954 (2015).

    PubMed  PubMed Central  Google Scholar 

  183. 183.

    Yasuda, N., Masuda, K., Tsukui, T., Teng, A. & Ishii, Y. Identification of canine natural CD3-positive T cells expressing an invariant T-cell receptor α chain. Vet. Immunol. Immunopathol. 132, 224–231 (2009).

    CAS  PubMed  Google Scholar 

  184. 184.

    Park, J. S. et al. Canine cancer immunotherapy studies: linking mouse and human. J. Immunother. Cancer 4, 97 (2016).

    PubMed  PubMed Central  Google Scholar 

  185. 185.

    Overgaard, N. H. et al. Of mice, dogs, pigs, and men: choosing the appropriate model for immuno-oncology research. ILAR J. 59, 247–262 (2018).

    CAS  PubMed  Google Scholar 

  186. 186.

    Biller, B. J., Elmslie, R. E., Burnett, R. C., Avery, A. C. & Dow, S. W. Use of FoxP3 expression to identify regulatory T cells in healthy dogs and dogs with cancer. Vet. Immunol. Immunopathol. 116, 69–78 (2007).

    CAS  PubMed  Google Scholar 

  187. 187.

    Weiss D. J. in Schalm’s Veterinary Hematology (eds Weiss, D. J., Wardrop, K. J. & Schalm, O. W.) 1206 (Wiley-Blackwell, 2011).

  188. 188.

    Lepone, L. M. et al. Analyses of 123 peripheral human immune cell subsets: defining differences with age and between healthy donors and cancer patients not detected in analysis of standard immune cell types. J. Circ. Biomark 5, 5 (2016).

    PubMed  PubMed Central  Google Scholar 

  189. 189.

    Withers, S. S. et al. Association of macrophage and lymphocyte infiltration with outcome in canine osteosarcoma. Vet. Comp. Oncol. 17, 49–60 (2019).

    CAS  PubMed  Google Scholar 

  190. 190.

    Biller, B. J., Guth, A., Burton, J. H. & Dow, S. W. Decreased ratio of CD8+ T cells to regulatory T cells associated with decreased survival in dogs with osteosarcoma. J. Vet. Intern. Med. 24, 1118–1123 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Gingrich, A. A., Modiano, J. F. & Canter, R. J. Characterization and potential applications of dog natural killer cells in cancer immunotherapy. J. Clin. Med. 8, 1802 (2019).

    CAS  PubMed Central  Google Scholar 

  192. 192.

    Graves, S. S. et al. Development and characterization of a canine-specific anti-CD94 (KLRD-1) monoclonal antibody. Vet. Immunol. Immunopathol. 211, 10–18 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193.

    Goulart, M. R. et al. Phenotypic and transcriptomic characterization of canine myeloid-derived suppressor cells. Sci. Rep. 9, 3574 (2019). This report describes canine MDSCs from both morphologic and gene expression contexts.

    PubMed  PubMed Central  Google Scholar 

  194. 194.

    Hlavaty, S. I. et al. Bacterial killing activity of polymorphonuclear myeloid-derived suppressor cells isolated from tumor-bearing dogs. Front. Immunol. 10, 2371 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195.

    Chen, B. et al. Predicting HLA class II antigen presentation through integrated deep learning. Nat. Biotech. 37, 1332–1343 (2019).

    CAS  Google Scholar 

  196. 196.

    Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197.

    Kumai, T., Fan, A., Harabuchi, Y. & Celis, E. Cancer immunotherapy: moving forward with peptide T cell vaccines. Curr. Opin. Immunol. 47, 57–63 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    Kennedy, L. J. et al. Nomenclature for factors of the dog major histocompatibility system (DLA), 2000: second report of the ISAG DLA Nomenclature Committee. Tissue Antigens 58, 55–70 (2001).

    CAS  PubMed  Google Scholar 

  199. 199.

    Ross, P. et al. The canine MHC class Ia allele DLA-88*508:01 presents diverse self- and canine distemper virus-origin peptides of varying length that have a conserved binding motif. Vet. Immunol. Immunopathol. 197, 76–86 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200.

    Ross, P., Holmes, J. C., Gojanovich, G. S. & Hess, P. R. A cell-based MHC stabilization assay for the detection of peptide binding to the canine classical class I molecule, DLA-88. Vet. Immunol. Immunopathol. 150, 206–212 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201.

    Xiao, J. et al. Diversified anchoring features the peptide presentation of DLA-88*50801: first structural insight into domestic dog MHC class I. J. Immunol. 197, 2306–2315 (2016).

    CAS  PubMed  Google Scholar 

  202. 202.

    Venkataraman, G. M. et al. Thirteen novel canine dog leukocyte antigen-88 alleles identified by sequence-based typing. HLA 90, 165–170 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203.

    Nemec, P. S., Kapatos, A., Holmes, J. C. & Hess, P. R. The prevalent Boxer MHC class Ia allotype dog leukocyte antigen (DLA)-88*034:01 preferentially binds nonamer peptides with a defined motif. HLA 92, 403–407 (2018).

    CAS  PubMed  Google Scholar 

  204. 204.

    Ross, P. et al. Allelic diversity at the DLA-88 locus in Golden Retriever and Boxer breeds is limited. Tissue Antigens 80, 175–183 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Barth, S. M. et al. Characterization of the canine MHC class I DLA-88*50101 peptide binding motif as a prerequisite for canine T cell immunotherapy. PLoS ONE 11, e0167017 (2016).

    PubMed  PubMed Central  Google Scholar 

  206. 206.

    Finocchiaro, L. M. E. & Glikin, G. C. Recent clinical trials of cancer immunogene therapy in companion animals. World J. Exp. Med. 7, 42–48 (2017).

    PubMed  PubMed Central  Google Scholar 

  207. 207.

    Perales, M. A. et al. Phase I/II study of GM-CSF DNA as an adjuvant for a multipeptide cancer vaccine in patients with advanced melanoma. Mol. Ther. 16, 2022–2029 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208.

    Wolchok, J. D. et al. Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma. Mol. Ther. 15, 2044–2050 (2007).

    CAS  PubMed  Google Scholar 

  209. 209.

    Strauss, J. et al. First-in-human phase I trial of a tumor-targeted cytokine (NHS-IL12) in subjects with metastatic solid tumors. Clin. Cancer Res. 25, 99–109 (2019).

    CAS  PubMed  Google Scholar 

  210. 210.

    Canter, R. J. et al. Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial. J. Immunother. Cancer 5, 98 (2017).

    PubMed  PubMed Central  Google Scholar 

  211. 211.

    Judge, S. J. et al. Blood and tissue biomarker analysis in dogs with osteosarcoma treated with palliative radiation and intra-tumoral autologous natural killer cell transfer. PLoS ONE 15, e0224775 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212.

    Knapp, D. W., Dhawan, D. & Ostrander, E. ‘Lassie,’ ‘Toto,’ and fellow pet dogs: poised to lead the way for advances in cancer prevention. Am. Soc. Clin. Oncol. Educ. Book (2015).

  213. 213.

    Serrano, D., Lazzeroni, M. & Bonanni, B. Cancer chemoprevention: much has been done, but there is still much to do. State of the art and possible new approaches. Mol. Oncol. 9, 1008–1017 (2015).

    PubMed  Google Scholar 

  214. 214.

    Li, J. et al. SETD2: an epigenetic modifier with tumor suppressor functionality. Oncotarget 7, 50719–50734 (2016).

    PubMed  PubMed Central  Google Scholar 

  215. 215.

    Jiang, C., He, C., Wu, Z., Li, F. & Xiao, J. Histone methyltransferase SETD2 regulates osteosarcoma cell growth and chemosensitivity by suppressing Wnt/β-catenin signaling. Biochem. Biophys. Res. Commun. 502, 382–388 (2018).

    CAS  PubMed  Google Scholar 

  216. 216.

    Tagawa, M., Maekawa, N., Konnai, S. & Takagi, S. Evaluation of costimulatory molecules in peripheral blood lymphocytes of canine patients with histiocytic sarcoma. PLoS ONE 11, e0150030 (2016).

    PubMed  PubMed Central  Google Scholar 

  217. 217.

    Shimizu, K. et al. Eomes transcription factor is required for the development and differentiation of invariant NKT cells. Commun. Biol. 2, 150 (2019).

    PubMed  PubMed Central  Google Scholar 

  218. 218.

    North American Pet Health Insurance Association. Willis Towers Watson Actuary Consultants. State of the industry report (2020).

  219. 219.

    Mullin, C. & Clifford, C. A. Histiocytic sarcoma and hemangiosarcoma update. Vet. Clin. North Am. Small Anim. Pract. 49, 855–879 (2019).

    PubMed  Google Scholar 

  220. 220.

    Megquier, K. et al. Comparative genomics reveals shared mutational landscape in canine hemangiosarcoma and human angiosarcoma. Mol. Cancer Res. 17, 2410–2421 (2019). This paper describes the shared molecular features of malignant vascular tumours in dogs and humans, providing the first evidence that canine hemangiosarcoma could serve as a model for human angiosarcoma.

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 221.

    Takada, M. et al. Activating mutations in PTPN11 and KRAS in canine histiocytic sarcomas. Genes 10, 505 (2019).

    CAS  PubMed Central  Google Scholar 

  222. 222.

    Takada, M. et al. Targeting MEK in a translational model of histiocytic sarcoma. Mol. Cancer Ther. 17, 2439–2450 (2018).

    CAS  PubMed  Google Scholar 

  223. 223.

    Mingus, L. Canine cancer prevention vaccine study seeks participants (2019).

  224. 224.

    Guy, M. K. et al. The Golden Retriever Lifetime Study: establishing an observational cohort study with translational relevance for human health. Philos. Trans. R. Soc. Lond. B Biol. Sci. 370, 20140230 (2015).

    PubMed  PubMed Central  Google Scholar 

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The authors thank W. Hendricks, P. Choyke and N. Mason for their critical review of this manuscript. They thank J. Meyer for artistic input and technical assistance with the figures, and A. Cherukuri for assistance with manuscript preparation. This work was supported by the Intramural Program of the National Cancer Institute, National Institutes of Health (NIH; Z01-BC006161). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

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A.K.L. researched data for the article and wrote the article. A.K.L. and C.N.M. both made substantial contributions to discussion of content and reviewed/edited the manuscript before submission.

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Correspondence to Amy K. LeBlanc.

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Nature Reviews Cancer thanks M. Breen, S. Day and T. Fan for their contribution to the peer review of this work.

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Related Links

American Veterinary Medical Association:

Brazilian Veterinary Cancer Society:

Cancer Moonshot Immunotherapy Trials Network in Comparative Oncology:

Clinical and Translational Science Award One Health Alliance:

Comparative Oncology Program:

Consortium for Canine Comparative Oncology:

European Society of Veterinary Oncology:

Integrated Canine Data Commons:

Japan Veterinary Cancer Society:

PRECINCT (Pre-medical Cancer Immunotherapy Network for Canine Trials):

PRECINCT Project Synopses:

Veterinary Cancer Society:


Array-based comparative genome hybridization

A genomic DNA hybridization technique that allows high-resolution analysis of copy number changes between two populations (such as normal versus tumour DNA).

Homologous recombination DNA repair pathway

A repair mechanism in which an identical or nearly identical DNA sequence from a homologous chromosome is used as a template for the repair of a DNA break.

Mismatch repair

A strand-specific mechanism for editing mismatched bases inserted in the daughter strand during DNA replication. This damage is repaired by recognition of the deformity caused by the mismatch.

Blood–brain barrier

An interconnected network of capillaries that carries blood to the brain and spinal cord, but also blocks the passage of certain harmful substances.

Convection-enhanced delivery

A technique that generates a pressure gradient at the tip of an infusion catheter to facilitate delivery of therapeutics to the central nervous system.

Volume of drug distribution

A pharmacokinetic parameter that represents the theoretical volume into which a drug is distributed throughout the body based on solubility, charge, size and so forth.

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LeBlanc, A.K., Mazcko, C.N. Improving human cancer therapy through the evaluation of pet dogs. Nat Rev Cancer 20, 727–742 (2020).

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