Abstract 2667: Patient-derived lymphoma cell lines and high-throughput screening enable identification of potential cytotoxic therapeutic agents for dogs and cats with lymphoma

Abstract

Abstract Treatment success in lymphoma, the most common hematopoietic cancer seen in dogs and cats, continues to be elusive. The clinical arsenal is limited to a few conventional chemotherapeutic drug protocols that result in short-term responses. In this study, dog and cat patient-derived tumor cells were tested via high-throughput screening (HTS) against a pool of over 100 FDA-approved compounds for human cancer treatment as a means to identify potential treatment strategies that can be relatively easily adapted to the dog and cat, as well as over 500 protein kinase inhibitors as a means to identify potential oncogenic driver pathways. Cells from lymph node fine needle aspirates, pleural effusions, or peripheral blood mononuclear cells from over 20 lymphoma patients were placed in cell culture media with and without growth factors. Cells from two cases, ZS15 from a Boxer dog and MT16 from a domestic shorthair cat, have continued to expand for over 12 and 6 months, respectively. Characterization by flow cytometry for detection of CD3 and CD21 identified these patient-derived cells to be T-cell lymphocytes. HTS and follow-up dose response curve (DRC) assays were performed, identifying multiple drugs effective in inhibiting growth of MT16 and ZS15 cells at nanomolar concentrations in vitro; these included anthracenedione/anthracycline-class and actinomycin-class drugs, as well as mRNA synthesis, microtubule/spindle formation, proteasome, histone deacetylase, or insulin growth factor-1 receptor inhibitors, many of which are currently not used in veterinary species. Notably, ZS15 cell growth was inhibited by mammalian target of rapamycin (mTOR) inhibitors, corroborating previous exome sequencing data of Boxer T-cell lymphomas that identified recurrent driver mutations in the PTEN-mTOR pathway. In addition, many of these drugs showed much higher IC50s in HTS and DRC assays on primary canine and feline fibroblasts, used as surrogates for normal tissue, revealing the specificity of their action on the cancer cells. These results advocate use of HTS and DRC assays as a means for identification of oncogenic driving mechanisms and for identification of drugs novel to veterinary medicine that warrant further investigation as alternative treatments for lymphoma in companion animals, which in turn can serve as valuable and accessible models for human lymphomas. Citation Format: Garrick M. Moll, Vilma Yuzbasiyan-Gurkan. Patient-derived lymphoma cell lines and high-throughput screening enable identification of potential cytotoxic therapeutic agents for dogs and cats with lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2667.