Abstract 6134: A comparative oncology approach to biomarker and drug discovery for cancer diagnosis and treatment in dogs and humans
Authors: Amy Kathleen LeBlanc, Christina N. Mazcko, Matthew Breen, Rachael Thomas, Douglas H. Thamm
Journal: Cancer Research (2020)

Abstract The goals of this work are biomarker and drug discovery to advance cancer diagnostic and therapeutic strategies in humans through the study of naturally-occurring canine cancers. Many factors, including shared environment, intact host immunity, and greater cancer gene family homology between dogs and humans than mice and humans, make spontaneous canine cancers valuable complementary models of human cancer. Transcriptomic profiling utilizing RNA sequencing (RNA SEQ) of 5 canine cancers, including osteosarcoma, melanoma, B cell lymphoma, T cell lymphoma, and pulmonary carcinoma, have revealed five distinct gene co-expression models. From these unique module expression profiles, cancer-specific gene panels were derived. A similar analysis performed on existing RNA-SEQ data from human tumor samples produced cancer-specific human gene panels. Comparison of the canine and human gene panels found significant correlation (Spearman correlation &amp;gt; 0.6) which supports the translational relevance of naturally-occurring canine cancers to their human counterparts. Further, proteomic profiles derived from matched tumor tissue and peripheral blood samples mirror those of the tumor transcriptome, demonstrating these cancer-specific gene panels and their encoded proteins may represent robust canine diagnostic biomarker and/or therapeutic target candidates. Therapeutic hypotheses associated with each cancer specific gene panel were derived through matching of drugs documented to alter expression of panel genes in opposition to that exhibited by each cancer type. We identified 60 candidate drugs and screened them against a panel of canine cancer cell lines, finding 40 drugs that inhibited cell growth by 75% or more. Three or more active compounds were found for each cell line. From these 40 active compounds we then derived 30 synergistic drug combinations with the requirement that that they alter two or more panel genes in opposition to that exhibited by each cancer type. Additional studies to document drug synergism are underway and those confirmed as such will be considered good drug combination candidates for future canine clinical trials. Biomarker and drug combination candidates that perform well in canine clinical trials will then be considered for human trials. This work exemplifies the type of approach meant to further establish the comparative relevance of canine to human cancer and provide opportunities to explore hypotheses related to detection and treatment in both species. Citation Format: Amy Kathleen LeBlanc, Christina N. Mazcko, Matthew Breen, Rachael Thomas, Douglas H. Thamm. A comparative oncology approach to biomarker and drug discovery for cancer diagnosis and treatment in dogs and humans [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6134.