Research in Canine Improving the Outlook for and Humans Deborah W. Knapp, DVM, Dipl. ACVIM – Specialty Purdue University, West Lafayette, Indiana

The field of “comparative oncology” in which naturally-occurring cancer in pet dogs is studied in order to generate new knowledge to help humans with similar cancers has been in existence for more than three decades. However, this field has never been more poised for success than it is now!1 With approximately nine of every ten human cancer treatment trials failing, the cancer research community is having frank discussions on the need for additional, more clinically-relevant, animal models to complement experimentally-induced models of human cancer.2,3 Although experimental models will remain a critical part of cancer research, models that more closely mimic the human condition and treatment effects are crucial.2,3 Specifically, there is a need for immunocompetent animal models that accurately represent the complexities (tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior) that are hallmarks of human cancer.

In the case of urinary bladder cancer, naturally-occurring transitional cell carcinoma (TCC), is exquisitely similar to human invasive bladder cancer.1 [Invasive bladder cancer must not be mistaken for the less aggressive, lower grade, superficial bladder cancer that is common in humans.] Similarities between TCC in dogs and humans include: cellular and molecular features, invasive and metastatic behaviors (50-60% distant rate), and response to chemotherapy.1 The molecular similarities are especially intriguing with the emergence of targeted therapies. Although the molecular characterization of canine TCC is only just beginning, intriguing similarities to human TCC have been found. Our group, in collaboration with the Ostrander lab (NHGRI), have identified mutations in several genes of importance in human TCC including EGFR, CDKN2B, PIK3CA, BRCA2, and NFkB.4 In expression array studies of normal canine bladder and canine TCC tissues, in which data were compared to that previously reported for human TCC, there were 436 genes differentially expressed between normal and tumor that were shared between dogs and humans.5

Interestingly, there is an intriguing difference between canine and human TCC. The majority of canine TCCs carry a mutation in the MAPK signaling pathway reported in several human cancers.4 In fact, this precise mutation, the homologue of the BRAFV600E mutation, drives 50% of human metastatic , and is an important target for therapy. While BRAF mutations are rare in human TCC, other activating mutations in the MAPK pathway occur in ~30% of cases.6 The finding of the BRAF mutation in canine TCC provides one example for an extremely important concept that is appreciated more and more in cancer research, that is the importance of characterizing and classifying cancer according to its molecular signatures, rather than simply relying on the site of origin. In fact, there is a pioneering clinical trial program organized by the National Cancer Institute called the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) Trial in which human patients with cancers that originated from a variety of different organ sites, are being treated based on specific molecular features of their cancer and the corresponding targeted cancer drugs. In this trial, a patient with colon cancer, a patient with melanoma, and a patient with thyroid cancer could be treated with the same drug. This molecular view of cancer means that naturally-occurring dog cancer models can expand far beyond specific organ-type cancers. In the case of TCC, though, even with the BRAF mutation, microarray studies still reveal numerous similarities between dog and human TCC.5

In the presentation, the use of the “dog model” for human invasive bladder cancer will be discussed in regards to targeted therapies, immune-based therapies, epigenetic treatments, and repurposing old drugs for new benefits. In addition, key examples of the huge advantages in cancer research afforded by very strong breed- associated risk for canine TCC will be presented. Indeed, there is true excitement for the progress that has already been made, and the progress that is expected to be made for dogs and humans facing cancer through near-term research!

References:

1. Knapp DW, Ramos-Vara JA, Moore GE, Dhawan D, Bonney PL, Young KE. Urinary bladder cancer in dogs, a naturally occurring model for cancer biology and drug development. ILAR J. 2014;55(1):100–118.

2. Mak IW, Evaniew N, Ghert M. Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res. 2014;6(2):114–118.

3. Kobayashi T, Owczarek TB, McKiernan JM, Abate-Shen C. Modelling bladder cancer in mice: opportunities and challenges. Nat Rev Cancer. 2015 Jan;15(1):42–54.

4. Decker B, Parker HG, Dhawan D, Kwon EM, Karlins E, Davis BW, Ramos-Vara JA, Bonney PL, McNiel EA, Knapp DW, Ostrander EA. 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. 2015 Jun;13(6):993–1002.

5. Dhawan D, Paoloni M, Shukradas S, Choudhury DR, Craig BA, Ramos-Vara JA, Hahn N, Bonney PL, Khanna C, Knapp DW. Comparative gene expression analyses identify luminal and basal subtypes of canine invasive urothelial carcinoma that mimic patterns in human invasive bladder cancer. PLoS ONE. 2015;10(9):e0136688.

6. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014 Mar 20;507(7492):315–322.