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Annual Meeting Information

Christopher T. Starost Memorial Oncology Scholarship

Aaron M. Sargeant, DVM, Ohio State University

CHEMOPREVENTIVE EFFECTS OF OSU-A9, A POTENT INDOLE-3-CARBINOL-DERIVED AGENT, IN PROSTATE CANCER. A. Sargeant,1,2 S. Kulp,1 A. Yeater,3 R. Rengel,4 S. Clinton,4 C. S. Chen1,2. 1Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University (OSU), Columbus, Ohio; 2Department of Veterinary Biosciences, College of Veterinary Medicine, OSU, Columbus, Ohio; 3University of Toledo Medical Center, Toledo, Ohio; 4Div. of Hematology and Oncology, College of Medicine, OSU, Columbus, Ohio.
We recently reported our development of an acid-stable indole-3-carbinol analogue, OSU-A9, and its potent, broad-spectrum antitumor activity in prostate cancer. Here, we assess both the efficacy and safety of orally-administered OSU-A9 in a series of preclinical studies carried out, in part, in preparation for a long-term prevention trial in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. In vitro, OSU-A9 exhibited IC50’s of two orders-of- magnitude greater potency than indole-3-carbinol in suppressing the viability of human (PC-3) and murine (TRAMP-C2) cancer cell lines. Histopathology and body and organ weight evaluations of mice treated in a 14-day dose-ranging study showed that OSU-A9 was without toxicity up to 200 mg/kg/day. When administered daily to PC-3 xenograft-bearing nude mice at 25, 50, and 100 mg/kg, the drug suppressed tumor growth by 49%, 54%, and 55%, respectively, compared to vehicle-treated controls (P<0.05). Fifty mg/kg/day OSU-A9 prolonged the tumor-defined lifespan of a syngeneic model (C57BL/6 mice bearing subcutaneous TRAMP-C2 tumors) from 16.3 ± 2.4 days to 24 ± 2.7 days (48% increase, P<0.01) in association with increased tumor apoptosis and decreased proliferation. Based on these results, an AIN-76A diet was formulated containing 500 ppm OSU-A9, a concentration estimated to deliver approximately 50 mg/kg of drug per day to each mouse. TRAMP mice receiving this diet will be evaluated for the drug’s molecular and morphologic effects on the development of prostatic intraepithelial neoplasia and carcinoma.

Tzu-Yin Lin, DVM, Ohio State University

OSUHDAC-42, A NOVEL HDAC INHIBITOR, EXHIBITS BIOLOGIC ACTIVITY AGAINST HUMAN AND CANINE MALIGNANT MAST CELLS THROUGH BOTH HISTONE DEPENDENT AND HSP90 DEPENDENT PATHWAYS. T-Y. Lin1, M. Sridhar2, S. Fossey1, C. A. London1,2. 1Department of Veterinary Biosciences, 2Department of Veterinary Clinical Sciences. Ohio State University, Columbus, OH.
Epigenetic changes including DNA hypermethylation and histone hypoacetylation are found in many cancers. Evidence suggests that inhibition of histone deacetylation is a promising approach to modulating some of these epigenetic changes in both solid tumors and hematologic malignancies. Preliminary data indicate that histone deacetylase inhibitors (HDACis) may have biologic activity against malignant mast cell disease. The purpose of the following studies was to investigate the histone-dependent and histone-independent mechanisms of HDAC inhibition in malignant mast cells. Briefly, human and canine malignant mast cell lines were treated with OSUHDAC-42 (a novel phenylbutyrate-based HDACi) and 17-AAG (an HSP90 inhibitor), and cell viability, cell cycling, cell invasion, and the effects on several signaling pathways were evaluated. Treatment with OSUHDAC-42, but not 17-AAG, induced hyperacetylation of H3, H4 and alpha-tubulin along with upregulation of p21. Both OSUHDAC-42 and 17-AAG downregulated the expression of pKit, total Kit, pAkt, total Akt, and total HER2/Neu in a time-dependent and reversible manner. 17-AAG downregulated both pSTAT3/STAT5 and total STAT3/STAT5, but OSUHDAC-42 exhibited variable effects on these targets. OSUHDAC-42 and 17-AAG induced dissociation between HSP90 and Kit and subsequent upregulation of HSP70 expression following loss of HSP90 activity. Additionally, treatment of the malignant mast cells with OSUHDAC-42 induced loss of cell viability, cell cycle arrest and apoptosis via activation of caspase3/7. Lastly, OSUHDAC-42 and 17-AAG blocked malignant mast cell invasion and downregulated MMP2 expression. In conclusion, the novel HDACi OSUHDAC-42 exhibits biologic activity against malignant mast cells through both histone-dependent and HSP90-dependent pathways, representing a promising new therapeutic approach for mast cell disease.

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