Using Canine Organoids to Advance Therapeutic Drug Development in Bladder Cancer

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PROJECT SUMMARY/ABSTRACT Muscle-Invasive Bladder Cancer (MIBC) is associated with an extremely poor survival rate of only 40% at 5 years follow-up, which, importantly, has not improved over the last 10 years. Two important factors that contribute to poor treatment outcomes are (1) the shortage of truly innovative and effective drug candidates for MIBC, and (2) the phenotypic and molecular heterogeneity of MIBC tumors, which limits the translational value of some rodent models to evaluate therapeutic drug efficacy. Although murine models have been extensively used for the study of bladder cancer, they typically do not faithfully reflect the biological behavior of MIBC in human patients. As opposed to mice, dogs with spontaneously occurring bladder cancer have been shown to be a highly relevant model for human MIBC. This is highlighted by the fact that canine MIBC presents with very similar molecular features, tumor heterogeneity and subtypes, as well as clinical and metastatic behavior as humans. Therefore, canine MIBC constitutes an ideal preclinical study population to evaluate novel therapeutic options for patients with bladder cancer. Although clinical trials in dogs with MIBC can be performed in significantly shorter time-frames than in people, so far, only very few large-scale trials using the canine model have been performed. Validation of predictive ex vivo assays to evaluate the potential efficacy of novel treatment modalities before formal testing in canine clinical trials will therefore enhance translational efforts for the development of novel therapeutics. A promising technology for the ex vivo screening of candidate drug efficacy lies in the culture of patient-derived tumor organoids (PDOs). Compared with 2D cell lines, 3D PDOs better reflect the underlying biology of the tumor and are therefore considered more robust ex vivo models to accurately predict clinical response to treatment compared with molecular testing alone. We therefore propose that future therapeutic leads for MIBC be screened ex vivo using canine organoids to select the most promising drug candidates. Subsequently, these novel therapeutics could be tested in vivo in dogs with bladder cancer prior to clinical testing in human patients with MIBC. The research proposed in this application is innovative, in our opinion, because it represents a new and substantive paradigm shift in drug research and development, using the dog as a spontaneous animal disease model to characterize the preclinical efficacy of chemotherapeutic candidates. This contribution will be significant as it will streamline the development of new therapeutic strategies in man and man’s best friend with bladder cancer. Ultimately, the research proposed in this R21 grant will lay the foundation to an R01 application focusing on the development of new therapeutics using canine MIBC as a preclinical model for candidate drug testing in collaboration with the NCI.