Research Project
10251927
PROJECT SUMMARY Osteosarcoma (OS) survival has not improved substantially for humans and dogs in the past 30 years. OS is the 3rd most commonly diagnosed tumor in adolescents 12-18 years of age, and is the most common primary bone tumor in the dog. Current standard-of-care treatment for OS includes surgical resection of the primary tumor via limb amputation or limb salvage surgery, and chemotherapy for treatment of metastatic disease. Limb salvage surgery is associated with a high complication rate, and metastasis remains the primary cause of death despite chemotherapeutics. Despite attempts with various permutations of adjunctive therapies, the median survival for dogs with OS remains at 10-12 months. Similarly, the 5-year survival rate in humans with non-metastatic OS remains around 70%, with no better than 20-30% long-term survival in OS patients with metastatic disease. The problems with limb salvage surgery and with metastatic disease in OS need a new and innovative approach. A non-surgical option for treating the primary tumor and controlling local disease in OS will help canine and human patients preserve their limb and avoid the complications of surgical limb-salvage. A therapy that stimulates an anti-tumor immune response can increase OS survival. Histotripsy is a precision non-thermal focused ultrasound method that mechanically disintegrates tissues through the precise control of acoustic cavitation generated by high-pressure pulses. Histotripsy does not have the limitations of thermal ablation and can produce consistent ablation, even when delivered near vessels. Histotripsy can treat large tumor volumes and potentially induce activation towards an anti-tumor immune response. Thus histotripsy, as a novel ablation treatment for OS, has the potential to fulfill the dual role of being a non-surgical limb salvage option and an immunotherapeutic for OS. However, it has not been evaluated for treatment of bone tumors. This study aims to demonstrate the feasibility of treating canine OS with histotripsy, optimize the histotripsy treatment strategies for targeting OS, and evaluate the effect of histotripsy on tumor cells, the OS immune microenvironment, as well as the immune profile and clinical outcome of canine OS patients. Aim 1 proposes to develop the optimal histotripsy parameters for treating OS. Aim 2 proposes to evaluate the oncological and immunological effects of histotripsy treatment for OS. Since canine OS shares many biologic similarities to human OS, treatment advances investigated in canine patients have high potential of being translatable to human OS patients. The results of this study will advance the development of histotripsy as a novel limb salvage treatment option for primary OS and an immunotherapeutic against metastatic disease for OS, thereby improving the standard of care and outcomes for OS patients.
