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

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 In addition:

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 The Canine Spontaneous Model for Breast Cancer (BC) Research

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)  Valid model for basic and translational BC research Comprehensive expression profiles of miRNAs in CMCs (e.g. miR-21)  altered regulation strongly correlated with those found in human BC

Suitable model for hormone-independent human BC due to the frequent lack of oestrogen dependency Most of feline mammary tumours are malignant Associated with aggressive clinical course and rapid metastasization The Feline Spontaneous Model for Breast Cancer (BC) Research

So far, studies mainly focused on the canine model 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 Several anatomic and physiologic similarities with humans Frequently comparable drug metabolism with humans

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  Canine IMC has been proposed as the best spontaneous animal model for the study of human IBC 2015 Studies on IBC are limited by the few available IBC cell lines, experimental models, and paucity of patient samples

- 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) CSCs has been isolated and characterized from primary canine and feline mammary carcinomas Comparative oncology is also acquiring a relevant role in cancer research on cancer stem cells (CSCs): - Most studies concerning CSCs rely on established cancer cell lines

 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 Primary canine and feline mammary carcinomas represent:

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 The Canine Spontaneous Model for Prostate Cancer (PC) Research

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

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 Conclusive remarks:

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

Thank you for your attention! ”Man's best friend in more ways than one”…