Research is conducted to characterize and develop new animal models of human disease and to develop the means to better characterize a model's relevance, addressing critical barriers to research progress. Additional aims include the development of new research technologies for the evaluation and application of disease biomarkers. Progress was made in developing cancer diagnostics and in research resources useful in developing and characterizing new models of human cancer and for the proper development and utilization of tissue biobanks. This research project included developing capabilities in molecular diagnostics for cancer models, developing methods for automated morphometric image analysis of cancer specimens for quantitative pathology, and preclinical development of targeted therapy for mucosal melanoma. Unique spatial-spectral image analysis algorithms were developed for applying automated pattern recognition morphometric image analysis to quantify histologic tumor and non-tumor tissue areas in biospecimen tissue sections. Additional progress was made in developing and validating algorithms for cancers of lung and cancer metastasis. Contributions to new models important for understanding mechanisms of drug resistance were developed and validated using quantitative optical imaging. Investigations were conducted that led to new insight from novel models involving several cancer types. These included carbohydrate metabolism in prostate cancer, drug resistance mechanisms at the blood placental barrier, MET signaling in cutaneous squamous cancer, EGFR driven lung cancer, and an ovarian cancer cell model of cysplatin-mediated cytotoxicity. In addition matched primary and metastatic liver and colon cancers were characterized. Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant pre-clinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intraepithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS and c-kit mutations uncommonly, compared to human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a pre-clinical model. An analogous interdisciplinary approach to comparing the suitability of naturally occurring canine brain tumors to inform human brain cancer research was organized with the CCR Comparative Oncology Program and extramural investigators.
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