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2007 ACVP Annual Meeting

2007 Christopher T. Starost Memorial Oncology Scholarship

First Place -- $1,000

INVESTIGATING THE ROLE OF STAT3 ACTIVATION IN HUMAN AND CANINE OSTEOSARCOMA. S.L. Fossey1, A.T. Liao1, J. Lin2, P.K. Li3, and C.A. London1. 1Department of Veterinary Biosciences; 2Department of Pediatrics; 3Division of Medicinal Chemistry, The Ohio State University, Columbus, OH, USA.
Osteosarcoma (OSA) is the most common malignant bone tumor in children and dogs. Treatment for both involves removal of the primary tumor followed by adjuvant chemotherapy. Approximately 30% of children and over 90% of dogs will develop metastatic disease post treatment. Differences in outcome are likely due to higher dose intensities used in their treatment of children when compared to dogs. Recent evidence suggests that the molecular biology of OSA in dogs is similar to that in children and includes the existence of p53 mutations, aberrant Met expression, and over-expression of ezrin, in addition to indistinguishable transcriptional profiles. Given the similarities in biology and clinical behavior between canine and pediatric OSA, canine OSA represents a relevant animal model in which to investigate the molecular biology of this disease. While evaluating signaling pathways in OSA cell lines, we identified the presence of constitutive STAT3 activation in all lines tested. This could not be altered by culture conditions or inhibition of Met signal transduction. Treatment of OSA cell lines with a small molecule STAT3 inhibitor, LLL3, promoted loss of cell viability and apoptosis. Furthermore, treatment with SU6656, a small molecule Src inhibitor, reduced phosphorylation of Src and its downstream target STAT3 in a majority of canine OSA cell lines tested with a corresponding reduction in proliferation. Lastly, OSA cells transfected with STAT3 siRNAs exhibited loss of STAT3 protein and underwent apoptosis. These data support the notion that dysregulation of STAT3 is common in canine OSA and serves as relevant target for therapeutic intervention.

Second Place -- $500

A TRANSGENIC MOUSE MODEL OF PANCREATIC DUCTAL ADENOCARCINOMA. M.M. Schutten, E.P. Sandgren, Dept. of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI.
Pancreatic ductal adenocarcinoma (PDA) is one of the leading causes of cancer-related deaths in the United States with approximately 30,000 new cases diagnosed yearly. The prognosis and treatment options for PDA remain poor, reflected in the fact that the number of newly diagnosed cases each year often equals the number of deaths. A clear understanding of the molecular events underlying disease initiation and progression could direct development of novel chemotherapeutic agents, assist in identification of potential disease biomarkers, and allow earlier successful intervention into the susceptible human population. Studies using human pancreatic tumor samples have identified several mutated oncogenes and altered tumor suppressors proposed to act on pancreatic ductal cells in a progressive sequence of dysplastic to neoplastic lesions. The most common oncogene alteration, an activating mutation of K-ras, has been identified in the majority of the tumor specimens in conjunction with inactivated p16, p53 or SMAD4 tumor suppressor genes. Although many of these genetic alterations have been recapitulated in transgenic mouse models, fundamental questions about the disease pathogenesis and putative cell of origin remain unanswered. Ductal epithelial cells are the most logical progenitor population to give rise to PDA, but there is strong evidence for the existence of acinar-ductal metaplasia in neoplastic pancreas tissue. By specifically targeting mutant K-ras to pancreatic acinar cells, in combination with partial loss of the tumor suppressor gene p16, our lab has developed a mouse model of PDA that accurately models the sequence of preinvasive ductal lesions and invasive ductal adenocarcinoma. This suggests that acinar-ductal metaplasia could potentially function as a tumor initiating population. Additionally, phenotypic characterization of these pancreatic tumors using immunohistochemistry, microPET/CT, and MRI will be presented.

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