Transcript The Canine Spontaneous Model for Breast Cancer

Animal models
of
breast and prostate cancer
“Advances in targeting cancer pathways” by Cinbo delegates
MEDITERRANEAN SCHOOL OF ONCOLOGY
08 April 2016, Rome, Italy
In Vivo Model Systems In Cancer Research:
• Laboratory rodent models  xenograft
and genetically-engineered mouse models
• Spontaneous animal models
 companion animals (pet dogs and cats)
naturally developing cancer
Comparative Oncology
discipline that integrates
the study of naturally occurring cancers in veterinary patients
into studies of human cancer biology and therapy
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
Advantages of spontaneous models 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
In addition:
• Spontaneous cancers of pets share tumor biology /genetics
and clinical behaviour with human cancers
• Frequently, 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
The Canine Spontaneous Model for Breast Cancer (BC) Research
Spontaneously occurring canine mammary tumours (CMTs)
are the most common neoplasm in the intact adult female dog
Malignant tumors account for up to 50% of cases
Strong clinical (e.g. hormonal dependence, age of onset, histological
features, prognostic factors, course of the disease)
and molecular
similarities to human BC
Canine mammary carcinomas (CMCs)
harbor extensive genetic alterations, like human BC
Common up-regulation of prominent oncogenic pathways and related genes
(e.g. PI3K/AKT, KRAS, MAPK, Wnt / β-catenin, BRCA2, ESR1, P-cadherin)
Down-regulation of representative tumor suppressive pathways
(e.g. p53, p16/INK4A, PTEN, E-cadherin)
Comprehensive expression profiles of miRNAs in CMCs (e.g. miR-21)
 altered regulation strongly correlated with those found in human BC
 Valid model for basic and
translational BC research
The Feline Spontaneous Model for Breast Cancer (BC) Research
Most of feline mammary tumours are malignant
Associated with aggressive clinical course and rapid metastasization
Suitable model for hormone-independent human BC
due to the frequent lack of oestrogen dependency
So far, studies mainly focused on the canine 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
Research topics for the canine BC model
Triple-negative (TN) subtype has been identified among CMCs
• Distinct clinicopathological features related to unfavourable
prognosis
• Basal-like phenotype for the majority of TN CMCs
 Possibility to investigate molecular prognostic markers and
to identify targetable driver mutations / signaling pathways
in TN CMCs
Research topics for the canine BC model
Inflammatory mammary carcinoma (IMC):
the most aggressive mammary neoplasia affecting female dogs
Considerable epidemiologic, clinical and histopathological
similarities shared
by human inflammatory breast cancer (IBC) and canine IMC
 Basic and translational studies are needed to understand
IBC and IMC disease biology and identify specific biomarkers
Research topics for the canine BC model
Studies on IBC are limited by the few available IBC cell lines,
experimental models, and paucity of patient samples
 Canine IMC has been proposed as the best spontaneous
animal model for the study of human IBC
2015
Comparative oncology is also
acquiring a relevant role
in cancer research on
cancer stem cells (CSCs):
- Studies on primary CSC cultures derived from human postsurgical
BC samples are limited (only small amounts of fresh tissue are obtainable
from individual human BCs)
- Most studies concerning CSCs rely on established cancer cell lines
CSCs has been isolated and characterized from
primary canine and feline mammary carcinomas
Primary canine and feline mammary carcinomas represent:
 Relevant source of biological material necessary to isolate
mammary CSCs
 Valuable translational models for human BC and to assay drug
targeting to tumor-initiating cells
The Canine Spontaneous Model for Prostate Cancer (PC) Research
The dog is the only species other than man
to spontaneously develop PC
at a significant incidence
The Canine Spontaneous Model for Prostate Cancer (PC) Research
Unique features of canine PC
 usually arise in an androgen-independent manner,
with increased risk in dogs castrated early in life
 skeletal metastases are osteoblastic or mixed
osteoblastic/osteolytic in nature,
similar to men
Common occurrence of bone metastases and
androgen-independent disease in dogs with PC
 good model for studying advanced,
hormone-refractory PC in humans
Valid model for investigating
prostate-specific effects on bone
The larger size of dogs makes them helpful to investigate
new molecular imaging tools
that cannot be performed readily on mice
Conclusive remarks:
The value of spontaneous cancers in understanding and
managing cancer has been evident to veterinary oncologists
and cancer researchers for many years but …
… the awareness of naturally occurring cancer models
is still relatively limited in the cancer research community
Future challenges for improving comparative oncology studies:
• broader awareness of the usefulness of naturally occurring cancer
models
• needs that comparative oncology answers very specific questions
• increased collaboration and interaction between veterinary /
comparative oncologists and the cancer research community
• centralized resources for the establishment of comparative
oncology programs
”Man's best friend in more ways than one”…
Thank you for your attention!