(P 115) PROSPECTIVE EVALUATION OF THORACOSCOPIC METASTASECTOMY IN DOGS: A NOVEL TRANSLATIONAL DRUG DEVELOPMENT PIPELINE TAGETING METASTATIC OSTEOSARCOMA

Objective: Osteosarcoma (OS) remains one of the deadliest childhood cancers with metastasis as the prevailing cause of death. There is an unmet need to develop drugs that target metastatic progression in OS. Novel single-arm phase 2 clinical trials have been successfully launched to that identify active drugs that extend progression free survival (PFS) in patients following lung metastasis. There is a translational imperative to rapidly prioritize novel therapeutics that may be active in these phase 2 human trials. Ethos Discovery, a non-profit incubator of scientific innovation, seeks to evolve the existing paradigm regarding OS metastasis in dogs and close the integration gap by leveraging our successfully recruiting Minimally Invasive Metastasectomy in Canines (MIMIC) trial to create alignment of the dog model with the OS patients of highest need, those with distant metastasis. We will screen potentially valuable therapeutics in canines undergoing minimally invasive metastasectomy for OS. In addition, on-drug “window” exposures in small cohorts of dogs will help identify necessary pharmacologic correlates for human translation. In addition to evaluating drug activity to fuel a novel OS translational path of agents for human phase 2 development, these trials will allow the collection of valuable metastatic tissue and blood samples to improve our understanding of metastasis biology, tumor heterogeneity, liquid biopsy science, and novel drug pharmacodynamics.

Methods: In the MIMIC study, client-owned dogs with lung metastasis are recruited to one of our participating sites for thoracoscopic pulmonary metastasectomy. This is a prospective trial targeting the initial recruitment of 36 dogs to optimize our delivery of a minimally invasive metastasectomy approach with low morbidity in canine patients. The first cohort of 18 dogs with pulmonary metastasis are being recruited with various tumor histologies. Blood and tissue biospecimens from this initial cohort will act as proof-of-principle for workflow optimization, collection, and turnaround of high-quality canine biospecimens for translational research. The second stage of this study will solely recruit 18 dogs with stage III OS, providing a new model phase 2-aligned preclinical strategy that seeks to rapidly identify active drugs that improve PFS in patients following lung metastasis.

Results: To date, 20 patients have been screened for enrollment, with 16 dogs having completed thoracoscopic metastasectomy. All dogs have survived to discharge, with the majority discharged within 24 hours after surgery. In our initial cohort of 16 dogs, minimal morbidity was associated with the surgical approach. Only one major complication has been encountered, a postoperative pneumothorax treated conservatively with continual chest drainage until sealing 4 days later. We successfully established a canine biobank of resected lung lesions and paired normal lung tissue, along with fecal samples, and serial blood samples that provide an opportunity for parallel, same patient/timepoint tissue and liquid biopsy analysis. Iterative optimization of our biospecimen collection protocols, including triaging, processing, preserving, and shipping samples has produced high-quality canine biospecimens amenable to downstream multi-omic analysis, including sensitive assays such as single cell RNA sequencing and ATAC-seq (Figure 1).

Conclusion: The MIMIC trial provides a highly relevant in vivo model of OS metastasis and biobanking efforts providing precious, serial post-treatment tissue and blood samples that are extremely difficult to garner in human trials. This work sets the stage for a more impactful phase of this study (from a biology standpoint) where the dog model will help test and validate translational hypotheses and include correlative pharmacodynamic endpoints. Future studies evaluating promising novel therapies will include on-drug “window” exposures in small cohorts of dogs where staged metastasectomy can be considered with subsequent biospecimen collection, thereby creating the opportunity for “informative failure” correlative studies.