1. role of comparative oncology in translational research
The canine model
in the cancer fight:
role of comparative oncology
in translational research
“Cancer translational research:
from molecular biology to the real world setting”
Sala Convegni – Ce.S.I. – Me.T
20 April 2018, Chieti

2. Comparative Oncology The biological complexity of cancer in pet
discipline that integrates
the study of naturally occurring cancers in veterinary patients
into studies of human cancer biology and therapy
The biological complexity of cancer in pet
animals captures the essence of cancer
in human patients

3. for translational research:
Advantages of naturally occurring cancers
for translational research:
naturally-occurring, with individual-to-individual heterogeneity within and across cancer types
growth in immunocompetent organisms within the tumor microenvironment
shorter natural history
sharing of the same environment with humans
highly comparable risk factors

4. for translational research:
Advantages of naturally occurring cancers
for translational research:
Spontaneous cancers in pets share tumor biology /genetics and clinical behaviour with human cancers
Similar tumor histology and response rates to conventional chemotherapy
Sufficient prevalence for biological studies and clinical trials
Feasibility of multi-modality protocols
Rapid progression and early metastatic failure
 rapid completion of clinical trials

5. Main objectives of comparative oncology:
Study of cancer pathogenesis  cancer-associated genes and proteins
- Understanding of environmental risk factors for cancer
- Examination of genetic/familial determinants for cancer predispositions
- Development of new treatment options for the management of cancer in both humans and animals

6. Clinical trials for veterinary patients with cancer can serve as a useful
intermediary between traditional preclinical studies and human clinical trials in the translational research pathway

7. The canine spontaneous model
Several anatomic and physiologic similarities with humans
Frequently comparable drug metabolism with humans
Availability of a high-quality draft genome sequence, together with a dense map of single nucleotide polymorphisms:
High level of sequence conservation between
canine and human genomes
Possibility of extensive
genomic analyses

8. Advantages of Clinical Trials for Canine Patients
in Translational Cancer Research
Use data from clinical trials for canine patients to inform the design of
subsequent clinical trials for human patients (to select the best compound and to prioritize the most promising combinations)
• Learn from trials enrolling dogs with treatment-naïve disease
(many human patients enrolled in trials have advanced, treatment-resistant disease)
• Develop trials for frequently occurring cancers in dogs in order to
address unmet needs for rare human cancers
• Use genomic information from canine patients to identify cancer genes
not yet identified in humans and to accelerate the development of
targeted therapies

9. Historical timeline on the use of pet dogs in cancer research
The first was the descriptive phase in which dogs were used
as models for surgical or therapeutic intervention owing to their similarity
to humans in size, anatomy and tumour histology. This included the
development of bone-marrow transplant regimens
Early efforts led to advances in limb-sparing techniques for
children with osteosarcoma
Dogs were then used to
define the activity of agents first in measurable disease and then in
minimal residual disease.
The present phase involves the use of dogs
for biology-intensive studies often correlating pharmacokinetic (PK) and
pharmacodynamic (PD) endpoints

10. Pharmacokinetically and pharmacodynamically rich trials
Comparative Oncology Trials Consortium  active network of twenty academic comparative oncology centers, centrally managed by the NIH-NCI-Center for Cancer Research's Comparative Oncology Program (2003)
Aims to design and execute clinical trials in dogs with cancer to assess novel therapies
Pharmacokinetically and pharmacodynamically rich trials
directly integrated into the
design of human Phase I and II
clinical trials
Comparative Oncology Trials Consortium  active network of twenty academic comparative oncology centers, centrally managed by the NIH-NCI-Center for Cancer Research's Comparative Oncology Program
Aims to design and execute clinical trials in dogs with cancer to assess novel therapies. The goal of this effort is to answer biological questions geared to inform the development path of these agents for future use in human cancer patients. Trials conducted by the COTC are pharmacokinetically and pharmacodynamically rich with the product of this work directly integrated into the design of current human Phase I and II clinical trials. Our trials are carried at COTC member institutions, which currently include 22 sites.
COTC member institutions currently include 22 sites

11. Comparative and integrated approach to cancer drug development
Comparative oncology trials precede or are conducted in parallel with human trials,
and may guide the development of such trials
Comparative oncology trials often precede or are conducted in parallel with human trials,
and in many cases guide the development of such trials
Largest opportunities for integrative approaches are between
phase I and II human clinical trials and in contributing
to better designs for phase II trials

13. The use of the dog as a model of cancer drug translation
The use of the dog as a model of cancer drug translation
has not been exploited as widely in Europe
as in the United States
Clinical trials for pet patients with naturally occurring tumors are underutilized in the drug development process

14. Lymphoma Mainly studied cancer types in translational research
Among the most common types of tumors in dogs
Remarkable similarities between
clinical features and cytogenetic aberrations
of canine lymphomas
and human NHL
More than 50 years ago, optimization of bone marrow transplantation protocols was undertaken in dogs (Thomas et al., 1962; Epstein et al., 1969)

15. Significant similarities between genomic profiles in dog and human
Sarcomas
Sarcomas are more prevalent in dogs than in humans
Significant similarities between genomic profiles in dog and human
soft tissue sarcomas

16. Osteosarcoma Strong similarity in the global expression patterns
of canine and human OSA
Limb-sparing techniques
optimized
in canine OSA (LaRue et al., 1989; Withrow et al., 1993)

17. Brain tumours - Glioma

18. Urinary bladder cancer
Melanoma
Urinary bladder cancer

19. Mast cell tumours (MCT)
Similar if not identical cancer-causing gene mutations can also result in different cancers in humans and dogs:
Mast cell tumours (MCT)
Similar mutations in KIT
identified in both GIST in humans
and MCT in dogs
Studies in dogs with MCT aided
translational development of
tyrosine kinase inhibitors by defining
toxicity, activity, pharmacokinetic and
tumour pharmacodynamic relationships
High prevalence of canine MCT
provides significant opportunities to study
therapeutic strategies targeting
KIT-driven cancers

20. Canine spontaneous tumours  valuable but underutilized model
Perceived concerns
Study duration  timelines for completion of studies in pet dogs are longer than those in rodent models
Cancer prevalence
Drug and budget requirements
Patient-to-patient variability  concern that the ‘uncontrolled’ nature of pet
dog studies may falsely associate a toxicity with a new cancer drug
Species concerns  canine gastrointestinal sensitivity recognized to be higher than human patients

21. Cancer research community has not reached agreement concerning:
the value of clinical trial data in dogs for advancing human cancer research
- when and how best to integrate comparative oncology trials within the cancer research continuum

22. Future needs and directions
- Availability of large, highly trained, multi-disciplinary teams of investigators to design studies that are integrated within the development path of cancer drugs
- Conduction of studies under clear regulatory guidance (standardized guidelines) and results translated to studies in human patients

23. Thank you for your attention!
“Between animal and human medicine there is no dividing line—nor should there be. The object is different but the experience obtained constitutes the basis of all medicine.”
— Rudolf Virchow (1821–1902)
Conquering cancer: Walking the path together (LeBlanc et al., 2015)
Thank you for your attention!