PROJECT SUMMARY
Soft tissue sarcomas (STS) represent less than 1% of human cancers, but result in a greater loss of life per
patient compared to that of all cancers. There are more than 70 subtypes of STS, tumors are large (>5cm) at
diagnosis, and may involve critical structures (nerves, blood vessels), necessitating multi-modal treatment with
wide surgical excision, radiation therapy, and chemotherapy. Treatments can be debilitating, with significant
negative impact on quality of life and functional outcome. Despite aggressive treatment, tumor recurrence occurs
in 40-50% of patients, and re-treatment with conventional strategies may be impossible. Non-invasive, non-
ionizing, non-thermal, image-guided tumor ablation strategies are direly needed. This proposal will focus on
histotripsy, a non-ionizing and non-thermal focused ultrasound ablation method that mechanically destroys
tissue and preserves critical structures through the precise control of acoustic cavitation with real-time imaging
feedback. Recently, our team completed proof-of-concept studies demonstrating that histotripsy can safely and
effectively partially ablate naturally-occurring STS in pet dogs. However, limitations in the current histotripsy
technology prevent rapid and precise treatment of entire tumors. Furthermore, lack of clinical outcomes of patient
safety and long-term tumor control hinders
clinical implementation of histotripsy as a treatment strategy for STS.
Clinically-useful advances require innovative device development and clinical evaluation in a relevant tumor
model. Our team proposes 1) the development of a novel ultra-high rate histotripsy system that overcomes
limitations in the current technology and, 2) evaluation of the application of this system as an entire-tumor, stand-
alone treatment of STS in pet dogs. STS affecting pet dogs have similar clinical presentation, tumor subtypes,
and clinical outcomes, resulting in data with high translatability to humans with STS. Our central hypothesis is
that ultra-high rate histotripsy systems and methods can be developed to safely, rapidly, and effectively achieve
entire-tumor ablation of STS as a viable alternative to surgical treatment. In Aim 1, our team will investigate and
validate ablation efficacy and the optimal histotripsy rate and dose needed for complete ablation. In Aim 2, we
will determine the maximum clinical histotripsy ablation volume and evaluate the clinical outcome measures of
entire-tumor ablation safety, safety of repeated histotripsy ablations, and long-term tumor response of entire-
tumor, stand-alone histotripsy treatment of STS in pet dogs. The results of this study will provide critical clinical
outcome data to directly inform human and veterinary clinical trials, accelerating the clinical translation of
histotripsy as a treatment strategy for STS, with high potential to extend to the treatment of other tumors.
