Abstract B46: Evaluation of JQ1 as a cytotoxic agent in canine sarcoma cell lines
Authors: Yang Ya-Ting , Takada Marilia , Yuzbasiyan-Gurkan Vilma 
Published: October 2015

Abstract
Spontaneous cancers in dogs present valuable opportunities to evaluate novel treatment approaches. Among the range of cancers seen in dogs, sarcomas are among the most frequent. In dogs as in humans, the treatment of the sarcomas presents clinical challenges. Here we report evaluation of JQ1, a novel bromodomain inhibitor that has been shown to inhibit MYC signaling, as a cytotoxic agent in cell lines derived from two canine sarcomas, osteosarcoma (OS) and histiocytic sarcoma (HS). Osteocytic sarcoma is the most common primary tumor of dogs and humans, with the incidence in dogs being nearly ten times that observed in humans. The survival rate in humans has stagnated in the past two decades, and thus novel approaches are needed. Histiocytic sarcoma is a very rare but highly malignant disorder in humans. In dogs, HS is seen with appreciable frequency in certain breeds, and is especially common in Bernese mountain dogs. Treatment options are limited and the prognosis is poor. In the current study, we evaluated the IC50 of JQ1 in three canine OS cell lines (D17, Abrams and Gracie) along with two human OS cell lines (SAOAS2 and U2OS), and in two canine HS cell lines (DH82 and BD, a novel cell line recently derived in our laboratory). The IC50 of JQ1 varied in the OS cell lines from 0.5 to 12 µM. The IC50 in the canine OS cell lines were 0.5, 12.5 and 0.47 µM, in D17, Abrams and Gracie, respectively. In the human OS cell lines, SAOS2 and U2OS, the IC50 values were 3.5 and 8.37 µM, in the same range as observed in the canine cell lines. In the HS cell lines, the IC50 of JQ1 was 0.05 and 0.19 µM, in DH82 and BD, respectively. These are all within clinically achievable and tolerable plasma concentrations based on mouse studies. Scratch wound healing assays were carried out in D17 and SOAS2 cell lines. JQ1 at 0.4 µM was found to decrease the migration ability of the cells and to delay wound healing. While the gap was closed in untreated cell by 48hrs, the gap was only decreased by about 25% in the JQ1 treated group, indicating that JQ1 inhibited cell migration. These results are very promising for evaluation of JQ1 as a potential therapeutic agent in both of these sarcomas. The effects of JQ1 on the transcriptome of these sarcomas is being further evaluated. In addition, in vivo xenograft studies are underway in nude mice to test efficacy of JQ1 in treating both sets of sarcomas. If the xenograft studies yield promising results, further safety and clinical efficacy studies in dogs can be undertaken. The spontaneous canine sarcomas will allow the early clinical evaluation of novel agents, such as JQ1, and hopefully, decrease the time to translation to the clinic for humans.
We gratefully acknowledge that JQ1 used in these studies was a generous gift from Dr. James Bradner and the Dana-Farber Cancer Institute.
Citation Format: Ya-Ting Yang, Marilia Takada, Vilma Yuzbasiyan-Gurkan. Evaluation of JQ1 as a cytotoxic agent in canine sarcoma cell lines. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B46.