What is Comparative Oncology and Why Has it Gone to the Dogs?

Categorized As:
Oncology

Deciding which model system to use to answer biological questions is a critical choice in research. Many human diseases occur naturally or can be reproduced in animals. Depending on the disease, a variety of species are available as animal models, each with their own advantages and disadvantages in terms of their ability to reproduce human physiology and particular aspects of a disease, the tools with which they can be studied, etc.  

Comparative oncology

Traditionally, most studies using animal models in biomedical research use laboratory animals like rodents. In the field of cancer biology, comparative oncology (defined by the NCI Center for Cancer Research as “the study of naturally developing cancers in animals as models for human disease”) promotes a distinct approach to research rooted in evolutionary biology, epidemiology, and genetics. Studying naturally occurring, spontaneous cancers across different species presents an opportunity to better understand cancer mechanisms related to risk/susceptibility, defense, and tumor progression that can be translated therapeutically to treat cancer in both humans and other animals.1Schiffman JD, Breen M. Comparative oncology: what dogs and other species can teach us about humans with cancer. Philosophical Transactions of the Royal Society B: Biological Sciences. 2015;370(1673):20140231. Epub 2015/06/10. doi: doi:10.1098/rstb.2014.0231. PubMed PMID: 26056372; PMCID: PMC4581033.

Studying naturally occurring, spontaneous cancers across different species presents an opportunity to better understand cancer mechanisms related to risk/susceptibility, defense, and tumor progression.

An evolutionary view helps provide context for the utility and unique translational applications of comparative oncology. For example, consider the natural variation across species in “life history” in rates of survival, growth, and reproduction. Some animal species (like humans and elephants) have long lifespans with a lengthened period of development and a small number of offspring, whereas other animals such as fish or mice have shorter lifespans, develop much more quickly, and produce many offspring. In the context of comparative oncology, one could hypothesize that “slow” life history animals should experience cancer with reduced frequency as compared to “fast” life history animals, as the evolutionary fitness of “slow” life history animals is dependent on their extended lifespan.2Boddy AM, Harrison TM, Abegglen LM. Comparative Oncology: New Insights into an Ancient Disease. iScience. 2020;23(8):101373. Epub 2020/08/02. doi: https://doi.org/10.1016/j.isci.2020.101373. PubMed PMID: 32738614; PMCID: PMC7394918. Current data support this prediction, suggesting that these “slow” life history species have more effective cancer suppression mechanisms. For example, some elephant species are particularly sensitive to mutations by virtue of having extra copies of TP53, a gene which induces apoptosis in response to DNA damage.3Abegglen LM, Caulin AF, Chan A, Lee K, Robinson R, Campbell MS, Kiso WK, Schmitt DL, Waddell PJ, Bhaskara S, Jensen ST, Maley CC, Schiffman JD. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. Jama. 2015;314(17):1850-60. Epub 2015/10/09. doi: 10.1001/jama.2015.13134. PubMed PMID: 26447779; PMCID: PMC4858328. This possible mechanism of cancer resistance has been reproduced using genetic tools in mice4García-Cao I, García-Cao M, Martín-Caballero J, Criado LM, Klatt P, Flores JM, Weill JC, Blasco MA, Serrano M. “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. Embo j. 2002;21(22):6225-35. Epub 2002/11/12. doi: 10.1093/emboj/cdf595. PubMed PMID: 12426394; PMCID: PMC137187. and could be leveraged to treat or even prevent cancer in humans and other species.2Boddy AM, Harrison TM, Abegglen LM. Comparative Oncology: New Insights into an Ancient Disease. iScience. 2020;23(8):101373. Epub 2020/08/02. doi: https://doi.org/10.1016/j.isci.2020.101373. PubMed PMID: 32738614; PMCID: PMC7394918.

Canines as models of cancer

Elephants may not be an accessible animal model for many scientists, but one of our most beloved pet companions has become an increasingly valuable model for comparative oncology. In the context of evolutionary medicine, dogs represent a powerful tool to help us understand cancer biology. As a cancer model, dogs have several advantages over laboratory animals like mice. Spontaneous cancers occur in dogs as in humans, with similar features from histopathology to metastasis and genetic predisposition. Thus, canine cancers better reproduce human cancer pathology as compared to rodent models in which cancer typically must be induced.1Schiffman JD, Breen M. Comparative oncology: what dogs and other species can teach us about humans with cancer. Philosophical Transactions of the Royal Society B: Biological Sciences. 2015;370(1673):20140231. Epub 2015/06/10. doi: doi:10.1098/rstb.2014.0231. PubMed PMID: 26056372; PMCID: PMC4581033.5Sultan F, Ganaie BA. Comparative oncology: Integrating human and veterinary medicine. Open Vet J. 2018;8(1):25-34. Epub 2018/02/16. doi: 10.4314/ovj.v8i1.5. PubMed PMID: 29445618; PMCID: PMC5806664. Specific breeds of dogs exhibit an increased incidence of certain types of cancer, a fact which can be utilized for cancer gene discovery.

The similar genetics of humans and dogs suggests a high likelihood of translatability – in fact, mutations associated with hereditary cancer in humans (such as mutations in BRCA1, BRCA2, and TP53) have already been identified in dogs.1Schiffman JD, Breen M. Comparative oncology: what dogs and other species can teach us about humans with cancer. Philosophical Transactions of the Royal Society B: Biological Sciences. 2015;370(1673):20140231. Epub 2015/06/10. doi: doi:10.1098/rstb.2014.0231. PubMed PMID: 26056372; PMCID: PMC4581033. Additionally, our pets live in our homes, walk with us in our neighborhoods and parks, and often even drink the same water and eat the same food that we do. Dogs thus represent a model to study both genetic and environmental risk factors for cancer.1Schiffman JD, Breen M. Comparative oncology: what dogs and other species can teach us about humans with cancer. Philosophical Transactions of the Royal Society B: Biological Sciences. 2015;370(1673):20140231. Epub 2015/06/10. doi: doi:10.1098/rstb.2014.0231. PubMed PMID: 26056372; PMCID: PMC4581033.5Sultan F, Ganaie BA. Comparative oncology: Integrating human and veterinary medicine. Open Vet J. 2018;8(1):25-34. Epub 2018/02/16. doi: 10.4314/ovj.v8i1.5. PubMed PMID: 29445618; PMCID: PMC5806664.

Recent innovations from canine cancer research

Since NanoString introduced the nCounter® Canine IO Panel in 2020, a number of publications have demonstrated how this gene expression panel can be applied to evaluate the safety, efficacy, feasibility, and translatability of novel treatments in dogs with spontaneously occurring cancer.6Chambers MR, Foote JB, Bentley RT, Botta D, Crossman DK, Della Manna DL, Estevez-Ordonez D, Koehler JW, Langford CP, Miller MA, Markert JM, Olivier AK, Omar NB, Platt SR, Rissi DR, Shores A, Sorjonen DC, Yang ES, Yanke AB, Gillespie GY. Evaluation of immunologic parameters in canine glioma patients treated with an oncolytic herpes virus. J Transl Genet Genom. 2021;5(4):423-42. Epub 2021/01/01. doi: 10.20517/jtgg.2021.31. PubMed PMID: 35342877; PMCID: PMC8955901.7Carroll J, Coutermarsh-Ott S, Klahn SL, Tuohy J, Barry SL, Allen IC, Hay AN, Ruth J, Dervisis N. High intensity focused ultrasound for the treatment of solid tumors: a pilot study in canine cancer patients. Int J Hyperthermia. 2022;39(1):855-64. Epub 2022/07/19. doi: 10.1080/02656736.2022.2097323. PubMed PMID: 35848421; PMCID: PMC9724480.8Vujanovic L, Chuckran C, Lin Y, Ding F, Sander CA, Santos PM, Lohr J, Mashadi-Hossein A, Warren S, White A, Huang A, Kirkwood JM, Butterfield LH. CD56(dim) CD16(-) Natural Killer Cell Profiling in Melanoma Patients Receiving a Cancer Vaccine and Interferon-α. Front Immunol. 2019;10:14. Epub 2019/02/15. doi: 10.3389/fimmu.2019.00014. PubMed PMID: 30761123; PMCID: PMC6361792.9Ammons DT, Guth A, Rozental AJ, Kurihara J, Marolf AJ, Chow L, Griffin JFt, Makii R, MacQuiddy B, Boss MK, Regan DP, Frank C, McGrath S, Packer RA, Dow S. Reprogramming the Canine Glioma Microenvironment with Tumor Vaccination plus Oral Losartan and Propranolol Induces Objective Responses. Cancer Res Commun. 2022;2(12):1657-67. Epub 2023/01/17. doi: 10.1158/2767-9764.crc-22-0388. PubMed PMID: 36644324; PMCID: PMC9835010.

For example, Carrol et al. used the Canine IO Panel to perform the first prospective pilot study in dogs of a technique called high intensity focused ultrasound (HIFU) to thermally ablate subcutaneous solid tumors.7Carroll J, Coutermarsh-Ott S, Klahn SL, Tuohy J, Barry SL, Allen IC, Hay AN, Ruth J, Dervisis N. High intensity focused ultrasound for the treatment of solid tumors: a pilot study in canine cancer patients. Int J Hyperthermia. 2022;39(1):855-64. Epub 2022/07/19. doi: 10.1080/02656736.2022.2097323. PubMed PMID: 35848421; PMCID: PMC9724480. Gene expression at the transition zone between the ablated and unablated tissue was quantified pre- and post-HIFU treatment. The changes in gene expression after treatment suggest that HIFU increased anti-tumor signaling by immune cells, with upregulation of genes associated with signaling and/or survival of T cells, B and T lymphocytes, and NK cells as well as increased activity of the NF-κB and Wnt signaling pathways. Given that the therapy was well tolerated, this is a promising avenue of investigation.

canine IO wheel

Several other studies tested combinatorial approaches which incorporate multiple therapeutic strategies at once, taking advantage of the Canine IO Panel to investigate the effects of the treatments on immune cells and inflammatory signaling within the tumor microenvironment (TME). An ongoing area of investigation in developing cancer therapies is manipulating the immune response within the TME to boost the anti-tumor function of tumor-resident immune cells while simultaneously administering another therapy with anti-cancer activity.

In one such study, Magee et al. aimed to cross-validate data obtained in mouse models and evaluate the potential feasibility of translating a trimodal immuno-radiotherapy approach in dogs with advanced stage melanoma or osteosarcoma.10Magee K, Marsh IR, Turek MM, Grudzinski J, Aluicio-Sarduy E, Engle JW, Kurzman ID, Zuleger CL, Oseid EA, Jaskowiak C, Albertini MR, Esbona K, Bednarz B, Sondel PM, Weichert JP, Morris ZS, Hernandez R, Vail DM. Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting. PLoS One. 2021;16(8):e0255798. Epub 2021/08/13. doi: 10.1371/journal.pone.0255798. PubMed PMID: 34383787; PMCID: PMC8360580. This approach utilizes sub-ablative external beam radiation therapy (EBRT) and intratumoral immunocytokine treatment (IT-IC) to achieve in situ vaccination and is combined with targeted radionuclide therapy (TRT). Using the Canine IO Panel, the authors constructed a time course of immunomodulatory changes following this therapeutic treatment, including changes in gene expression and assessment of infiltrating lymphocytes in the primary tumor. Despite the small sample size of this preliminary sampling, it was possible to identify several immunologic changes in the animals receiving the EBRT/IT-IC/TRT treatment. At both timepoints (6 and 13 days after treatment), six annotated pathways were upregulated (costimulatory signaling, TNF superfamily, cytokines, interleukins, B cell function, and NK cell function). At six days post-therapy, there was also an increase in the gene signatures for several immune cell types, with TH1 and NK CD56dim having a significant increase.

The authors note that some of these changes are promising when considered in the context of human cancer patients, with this trimodal treatment indicating a possible persistent antitumor response via memory T and NK cells. More specifically, increased expression of genes related to NK cells expressing CD56dim has been associated with improved clinical outcomes following cancer treatment, perhaps because these cells exhibit enhanced cytolytic activity.8Vujanovic L, Chuckran C, Lin Y, Ding F, Sander CA, Santos PM, Lohr J, Mashadi-Hossein A, Warren S, White A, Huang A, Kirkwood JM, Butterfield LH. CD56(dim) CD16(-) Natural Killer Cell Profiling in Melanoma Patients Receiving a Cancer Vaccine and Interferon-α. Front Immunol. 2019;10:14. Epub 2019/02/15. doi: 10.3389/fimmu.2019.00014. PubMed PMID: 30761123; PMCID: PMC6361792. Thus, expansion of this trimodal immuno-radiotherapy approach in companion dogs, a model more clinically relevant to humans than the mouse model in which this approach has been characterized, will help determine how this regimen could be adapted in clinical trials.

In another study, Ammons et al. characterized a combination immunotherapy in treating glioma in a small pilot study of eight dogs.9Ammons DT, Guth A, Rozental AJ, Kurihara J, Marolf AJ, Chow L, Griffin JFt, Makii R, MacQuiddy B, Boss MK, Regan DP, Frank C, McGrath S, Packer RA, Dow S. Reprogramming the Canine Glioma Microenvironment with Tumor Vaccination plus Oral Losartan and Propranolol Induces Objective Responses. Cancer Res Commun. 2022;2(12):1657-67. Epub 2023/01/17. doi: 10.1158/2767-9764.crc-22-0388. PubMed PMID: 36644324; PMCID: PMC9835010. Two repurposed drugs (losartan and propranolol) were used to deplete the tumor of myeloid cells and were combined with an anti-cancer stem cell (CSC) vaccination of lysates from multiple canine cancer cell lines. Overall, the therapy was well tolerated and produced an 80% clinical benefit rate (partial tumor regression was achieved in two dogs, and disease became stable in six dogs). Survival time was increased in dogs with anti-CSC antibody responses, indicating that this combinatorial therapy has therapeutic potential. Gene expression in tumor samples from four of these dogs was compared to that of untreated dogs using the Canine IO Panel, and while there were no significant differences, further analysis of the dataset revealed changes in expression between high-grade and low-grade tumors in immune regulatory pathways. The authors noted that only one dog in the treated group exhibited an anti-CSC response, and additional profiling of treated tumors may provide a clearer picture of how this immunotherapy is affecting the transcriptome within the tumor.

Using the Canine IO Panel, researchers demonstrated that M032 induced tumor-specific immune responses within the tumors of five out of six patients.

A fourth study, also focusing on a potential combinatorial approach to treat glioma, presented interim data from an ongoing phase 1 clinical trial from CANINE (“CANine ImmunoNEurotherapeutics”) funded by the NIH Cancer Moonshot Program.6Chambers MR, Foote JB, Bentley RT, Botta D, Crossman DK, Della Manna DL, Estevez-Ordonez D, Koehler JW, Langford CP, Miller MA, Markert JM, Olivier AK, Omar NB, Platt SR, Rissi DR, Shores A, Sorjonen DC, Yang ES, Yanke AB, Gillespie GY. Evaluation of immunologic parameters in canine glioma patients treated with an oncolytic herpes virus. J Transl Genet Genom. 2021;5(4):423-42. Epub 2021/01/01. doi: 10.20517/jtgg.2021.31. PubMed PMID: 35342877; PMCID: PMC8955901. These clinical trials aim to assess the efficacy and safety of oHSV M032, an oncolytic herpes virus designed to infect glial tumors. M032 is engineered to stimulate an immune response via its antigenicity, expression of IL-12, and ability to activate toll-like receptors through its high proportion of unmethylated CpG sequences, with the goal of activating T cells and inducing anti-tumor activity. In this preliminary study, Chambers et al. focused on the effects of M032 on the immune response within the TME to identify possible biomarkers that could predict the patient’s response to the therapy. Using the Canine IO Panel, they demonstrated that M032 induced tumor-specific immune responses within the tumors of five out of six patients, consistent with changes in interferon signaling, lymphoid and myeloid cell activation, recruitment, and T and B cell immunity. The ability of M032 to produce an immunomodulatory effect within the tumor suggests that it could be utilized in combinatorial immunotherapy approaches like those described above.

Translation of canine cancer studies

There is a serious need for preclinical models that better capture features of human biology. Not only would this expedite drug development and progression to human clinical trials, but it would also help determine which therapies are likely to be successful in late-stage clinical trials. The results described above are from small pilot studies, yet they clearly demonstrate the potential for new therapies to be investigated in the context of canine cancer and then translated to humans. This is exemplified by the CANINE clinical trial, as a concurrent adult human clinical trial is also ongoing (NCT02062827) and will be informed by the results from the therapy in dogs.

Two experts in canine biology agree that the study of canine cancer represents a unique and powerful opportunity to move forward our understanding of cancer biology. Expanding the scope of this approach to other species will push us even further toward understanding the biological mechanisms underlying differential susceptibility to cancer. However, for these kinds of comparative studies, large networks of collaborators must work together to build shared databases of standardized biomarkers across humans and animals, using assays like the nCounter Canine IO, PanCancer Immune Profiling, and PanCancer IO 360™ panels.

Circular "Wheel" graphic with a dog illustration

The introduction of the GeoMx® Canine Cancer Atlas puts another tool in the hands of scientists to add spatial resolution to gene expression analysis. The Canine Cancer Atlas covers 1,962 genes involved in the onset and progression of cancer as well as the tumor microenvironment and immune response.  It can be customized with up to 400 targets to add additional biology, exogenous genes, synthetic DNA, and viral/bacterial content to the assay. The Canine Cancer Atlas has overlapping content with the nCounter Canine IO Panel, allowing for a seamless transition from bulk to spatial gene expression studies or paired sample studies. With this tool and the Canine IO panel, NanoString hopes that the integration of animal and human clinical trial data will help ensure resources are being devoted toward the most promising therapeutic avenues.1Schiffman JD, Breen M. Comparative oncology: what dogs and other species can teach us about humans with cancer. Philosophical Transactions of the Royal Society B: Biological Sciences. 2015;370(1673):20140231. Epub 2015/06/10. doi: doi:10.1098/rstb.2014.0231. PubMed PMID: 26056372; PMCID: PMC4581033.2Boddy AM, Harrison TM, Abegglen LM. Comparative Oncology: New Insights into an Ancient Disease. iScience. 2020;23(8):101373. Epub 2020/08/02. doi: https://doi.org/10.1016/j.isci.2020.101373. PubMed PMID: 32738614; PMCID: PMC7394918.5Sultan F, Ganaie BA. Comparative oncology: Integrating human and veterinary medicine. Open Vet J. 2018;8(1):25-34. Epub 2018/02/16. doi: 10.4314/ovj.v8i1.5. PubMed PMID: 29445618; PMCID: PMC5806664.

References

  • 1
    Schiffman JD, Breen M. Comparative oncology: what dogs and other species can teach us about humans with cancer. Philosophical Transactions of the Royal Society B: Biological Sciences. 2015;370(1673):20140231. Epub 2015/06/10. doi: doi:10.1098/rstb.2014.0231. PubMed PMID: 26056372; PMCID: PMC4581033.
  • 2
    Boddy AM, Harrison TM, Abegglen LM. Comparative Oncology: New Insights into an Ancient Disease. iScience. 2020;23(8):101373. Epub 2020/08/02. doi: https://doi.org/10.1016/j.isci.2020.101373. PubMed PMID: 32738614; PMCID: PMC7394918.
  • 3
    Abegglen LM, Caulin AF, Chan A, Lee K, Robinson R, Campbell MS, Kiso WK, Schmitt DL, Waddell PJ, Bhaskara S, Jensen ST, Maley CC, Schiffman JD. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. Jama. 2015;314(17):1850-60. Epub 2015/10/09. doi: 10.1001/jama.2015.13134. PubMed PMID: 26447779; PMCID: PMC4858328.
  • 4
    García-Cao I, García-Cao M, Martín-Caballero J, Criado LM, Klatt P, Flores JM, Weill JC, Blasco MA, Serrano M. “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. Embo j. 2002;21(22):6225-35. Epub 2002/11/12. doi: 10.1093/emboj/cdf595. PubMed PMID: 12426394; PMCID: PMC137187.
  • 5
    Sultan F, Ganaie BA. Comparative oncology: Integrating human and veterinary medicine. Open Vet J. 2018;8(1):25-34. Epub 2018/02/16. doi: 10.4314/ovj.v8i1.5. PubMed PMID: 29445618; PMCID: PMC5806664.
  • 6
    Chambers MR, Foote JB, Bentley RT, Botta D, Crossman DK, Della Manna DL, Estevez-Ordonez D, Koehler JW, Langford CP, Miller MA, Markert JM, Olivier AK, Omar NB, Platt SR, Rissi DR, Shores A, Sorjonen DC, Yang ES, Yanke AB, Gillespie GY. Evaluation of immunologic parameters in canine glioma patients treated with an oncolytic herpes virus. J Transl Genet Genom. 2021;5(4):423-42. Epub 2021/01/01. doi: 10.20517/jtgg.2021.31. PubMed PMID: 35342877; PMCID: PMC8955901.
  • 7
    Carroll J, Coutermarsh-Ott S, Klahn SL, Tuohy J, Barry SL, Allen IC, Hay AN, Ruth J, Dervisis N. High intensity focused ultrasound for the treatment of solid tumors: a pilot study in canine cancer patients. Int J Hyperthermia. 2022;39(1):855-64. Epub 2022/07/19. doi: 10.1080/02656736.2022.2097323. PubMed PMID: 35848421; PMCID: PMC9724480.
  • 8
    Vujanovic L, Chuckran C, Lin Y, Ding F, Sander CA, Santos PM, Lohr J, Mashadi-Hossein A, Warren S, White A, Huang A, Kirkwood JM, Butterfield LH. CD56(dim) CD16(-) Natural Killer Cell Profiling in Melanoma Patients Receiving a Cancer Vaccine and Interferon-α. Front Immunol. 2019;10:14. Epub 2019/02/15. doi: 10.3389/fimmu.2019.00014. PubMed PMID: 30761123; PMCID: PMC6361792.
  • 9
    Ammons DT, Guth A, Rozental AJ, Kurihara J, Marolf AJ, Chow L, Griffin JFt, Makii R, MacQuiddy B, Boss MK, Regan DP, Frank C, McGrath S, Packer RA, Dow S. Reprogramming the Canine Glioma Microenvironment with Tumor Vaccination plus Oral Losartan and Propranolol Induces Objective Responses. Cancer Res Commun. 2022;2(12):1657-67. Epub 2023/01/17. doi: 10.1158/2767-9764.crc-22-0388. PubMed PMID: 36644324; PMCID: PMC9835010.
  • 10
    Magee K, Marsh IR, Turek MM, Grudzinski J, Aluicio-Sarduy E, Engle JW, Kurzman ID, Zuleger CL, Oseid EA, Jaskowiak C, Albertini MR, Esbona K, Bednarz B, Sondel PM, Weichert JP, Morris ZS, Hernandez R, Vail DM. Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting. PLoS One. 2021;16(8):e0255798. Epub 2021/08/13. doi: 10.1371/journal.pone.0255798. PubMed PMID: 34383787; PMCID: PMC8360580.
By Alicia Lane
For research use only. Not for use in diagnostic procedures.