Similarities in Cancer Disease and Drug Targets in Dogs and Humans
Overview
“One Health” refers to the interconnection of health of humans, animals, and the environment. Scientists, doctors, and veterinarians working together can improve health for everyone. One example is controlling and treating cancer. Cancer is the number two cause of death in humans in the United States. Cancer accounts for almost half of the deaths of pet dogs over 10 years of age. Dogs get cancer at roughly the same rate as humans, while cats get fewer cancers. Common cancers in dogs include hemangiosarcoma, mast cell tumors, lymphoma, melanoma, breast cancer, and osteosarcoma (www.wearethecure.org/more_cancer_facts.htm).1
There is a growing recognition that spontaneous canine and human cancers share many features in common, including histology, resistance/recurrence, and metastasis.2 Accordingly, there are many benefits to using naturally occurring pathologies that cannot be derived through the use of in vitro and rodent-based approaches. Cell cultures are highly controlled and allow for highly repeatable conditions to evaluate cancer growth and therapeutics. However, cell cultures are two dimensional, in contrast to the much different three-dimensional tumor “shapes” within humans. Defining the response of cells and using this to predict behavior of drugs in vivo are very difficult. Alternatively, use of rodent xenograft cancer models can fail to accurately predict the interaction between therapeutic agent and the cancer cells. Prediction errors can reflect the failure of these xenographs to develop the blood flow characteristics that occur in the natural host, where tumors grow in a variety of different solid tissues. Furthermore, because the murine model involves immunocompromised mice, the role of the immune system in tumor progression and drug response cannot be evaluated. Genetically engineered mice have also been used to induce tumors. While an improvement over cell cultures and xenograph in predicting drug response in the targeted host, differences in genetic and phenotypic expression of the tumor can interfere with translation of drug response to human disease. Mice also have a much a higher tolerance to cytotoxic agents compared with that seen in humans. Hence, only 8% of therapeutics have been successfully transferred from rodents to humans.3,4
The dog’s response to therapeutic agents is similar to how humans respond to cytotoxic agents and has been demonstrated to be an outstanding model for exploring potential therapeutic solutions to human cancers. Examples include the utility of bone marrow transplantation (with cyclophosphamide) for the treatment of lymphoma, the effectiveness of antiangiogenic thrombospondin-1- peptide mimetics (with or without chemotherapy) for the treatment of non-Hodgkin’s lymphoma, and the effectiveness of GS-9219, a prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG), that delivers PMEG and its phosphorylated metabolites to lymphoid cells and exerts a cytotoxic effect on cells with a high proliferation index.
Underlying the use of dogs in the advancement of cancer therapy is the similarity in the growth, tissue origin, and molecular characteristics of the disease, reflecting the greater genome similarities in dogs and humans versus mice.3 For example, similarities in molecular targets have been shown in tumor suppressor p53, breast cancer type 1 (BRCA1), tyrosine protein kinase Kit (c-Kit/ CD117), cytoplasmic-myelocytomatosis oncoprotein (c-Myc), Kirsten rat sarcoma viral oncoprotein (K-RAS), and many more. In addition, the regulatory requirements for registration of a new therapeutic are less time consuming for animals, providing an opportunity for immediate benefit to dogs while paving the way for future registration in humans.3,4
Commonality of Disease
Lymphoma: The rate of increase in certain cancers (such as lymphomas) has doubled in dogs over the past 40 years, a rate that is similar for the increase in non-Hodgkin’s lymphoma in people.3,4 Lymphomas in dogs are similar to non-Hodgkin’s lymphomas in humans in epidemiology and biology, including molecular characteristics as well as clinical manifestations. RNA sequencing with microarray analysis confirmed numerous molecular similarities between canine lymphomas and human non-Hodgkin’s lymphoma. These included the PI3-K/Akt/mTor pathway. The B-cell lymphomagenesis signaling system including CD19, PI3, MYC, and GSK3® along with LYN and SYK, tyrosine kinases involved in B-cell signaling, and cross talk with the PI3/Akt signaling pathway have also been identified in canine lymphoma cells. The PSME1/2 proteasome activator and NFkB activity were also identified in canine lymphoma. There is also evidence that infectious agents such as Epstein–Barr virus (EBV) may play a role in canine lymphoma in a manner similar to non-Hodgkin’s lymphoma in humans, because a majority of dogs have serological titers to EBV. Furthermore, there is currently no evidence of PI3 kinase or pAkt activity in lymph nodes from dogs without lymphoma, further confirming the role of these pathways in the disease state. These findings strongly support the use of dogs as a translational model to study the genetic basis of lymphoma in humans as well as evaluation of potential therapeutic strategies.5
Malignant melanoma: Malignant melanoma is one of the most common cancers in both dogs and humans. In dogs, canine malignant melanomas (CMM) are often associated with oral mucosa, whereas in humans metastatic melanomas (HMM) are found in the skin. There is a high fatality rate for human and canine melanoma patients, and the tumors are resistant to all forms of therapy for both host species. As for lymphomas, PI3/Akt signaling pathways are common in both CMM and HMM. Furthermore, there are genetic similarities seen in cancer of dogs and humans. Similarities are also seen in the micro-RNA (miRNA) involvement in dog and human disease progression (cell growth and oncogenesis). In disease and health, miRNAs are typically involved in a negative regulation of gene expression, with each miRNA controlling hundreds of genes. This is true in cancer as well, where miRNA can regulate cell replication. This prompted the study of adding exogenous made miRNAs to down regulate sites of binding of oncomirs (miRNAs involved in cancer) to reduce growth of abnormal cells. Mir-203 and Mir-205 were found to target gene erbb3 of the EGFR tyrosine kinase receptors, thereby reducing cell growth of malignant melanoma cells in dogs and humans. This is another example in which the dog can serve as a translational model to study melanoma in humans.6
Osteosarcoma: Osteosarcoma is an aggressive tumor of bone. Although progress has been made in therapy for primary osteosarcoma tumors (OSA), treatment of metastases is much less effective, and the targeting of resistant cells within metastatic tumors is a primary goal of ongoing research. Primary and metastatic OSA is also found in dogs. Genetic analysis of 30 primary osteosarcoma tumor samples in humans and dogs could not be divided by species, suggesting that similarities in gene expression signatures in osteosarcoma are due primarily to shared biology across species. For example, recent studies have found that dogs and humans share expression of BMI1, a member of the c-Myc receptor complex of transcriptional regulation. BMI1 is integral for self- renewal capacity of normal and cancer stem cells. BMI1 is essential for OSA growth in humans, metastatic activity, and resistance to therapeutic drugs in humans. Similar characteristics have been confirmed for canine OSA. BMI1 has also been confirmed to be expressed in metastatic tumors in both dogs and humans. Small molecules that inhibit BMI1 expression in human OSA work in a similar manner in dogs. These small molecules, as well as siRNA, work together with chemotherapeutic agents to reduce growth of OSA cells in vitro. BMI1 has also been suspected as being a key factor in stimulating cancer stem cell replication in both dogs and humans. These shared characteristics make dogs an ideal large animal model to evaluate the progression and control of OSA in humans.2,7
Concluding Thoughts
These examples show the value of using naturally occurring canine cancer as a model and integral part of research into similar human cancers. Importantly, a wide range of therapeutics has been rapidly advanced for human use by studies conducted in canine cancer patients. Based upon an examination of progress in the treatment of the various shared cancers, it was concluded that studies conducted in the dog (in conjunction with an appreciation of species-associated similarities and differences) have resulted in faster go/ no-go decisions, along with the identification and validation of biological endpoints and surrogate markers critical to quick translation into phase I and phase II human clinical trials.2
Pet animal studies provide support of the mechanistic pathway. Studies that would be difficult to complete in humans, including multiple biopsy and collection time points, are feasible in pet animal studies and can lead to improvements in the design of human clinical trials (e.g., treatment schedules, drug combination strategies, effect of chronic drug exposures, and an assessment of potential correlative and surrogate endpoints).8 In the third and final article in this series, the use of dog models in developing delivery systems to treat cancers will be discussed.
References
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2. Ranieri, G, Gadaleta, CD, Patruno, R, Zizzo, N, Daidone, MG, Hansson, MG, Paradiso, A, Ribatti, D. A model of study for human cancer: Spontaneous occurring tumors in dogs. Biological features and translation for new anticancer therapies. Crit. Rev. Oncol./Hematol. 88:187-197 (2013).
3. Cekanova, M, Rathore, K. Animal models and therapeutic molecular targets of cancer: Utility and limitations. Drug Des., Dev. Ther. 8:1911-1922 (2014).
4. Richards, KL, Suter, SE. Man’s best friend: What can pet dogs teach us about non-Hodgkin’s lymphoma? Immunol. Rev. 263:173-191 (2015).
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6. Noguchi, S, Mori, T, Hoshino, Y, Yamada, N, Maruo, K, Akao, Y. MicroRNAs as tumour suppressors in canine and human melanoma cells and as a prognostic factor in canine melanomas. Vet. Compar. Oncol. 11:113-123 (2011).
7. Shahi, MH, York, D, Gandour-Edwards, R, Withers, SS, Holt, R, Rebhun, RB. BMI1 is expressed in canine osteosarcoma and contributes to cell growth and chemotherapy resistance. PLOS One 10:e0131006, http://dx.doi.org/10.1371/journal.pone.0131006 (2015).
8. 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. 5:5671-5677 (2009).
a Zoetis, LLC (formerly Pfizer Animal Health), U.S.A. b U.S. Food and Drug Administration, U.S.A.
This article is in the public domain and not copyrightable. It may be freely reprinted with customary crediting of the source. Controlled Release Society, 2016.
