Grant: Project Grant

Soft tissue sarcomas (STS) are connective tissue (fat, muscle, tendon, ligament) derived malignancies that affect both children and adults. Apart from a few select subtypes, there are no effective systemic therapies against STS. There have been no meaningful therapeutic advances for these cancers in decades. Present treatment involves a combination of morbid surgical resections and high-dose radiation. Unfortunately, in patients who develop metastatic disease, there are very limited treatment options. The average survival in patients with metastatic STS is 14 months. There is a desperate need to discover new systemic therapies for these aggressive cancers. Our group has developed an immune-competent mouse model of one of the most common STS subtypes: undifferentiated pleomorphic sarcoma (UPS). Using this model we have demonstrated that intra-tumoural activation of an immune pathway (STING pathway), can lead to immune-mediated tumour destruction and the development of protective immunologic memory against further UPS tumours. In this proposal, using multiple different immune-competent mouse models of sarcoma, our goal is to evaluate different clinically relevant therapeutic strategies to activate the STING pathway in STS. These include, small molecular activators of STING, engineering specific immune populations to over-express activated STING within tumours, and using viruses to infect tumour cells with activated STING. We will also combine STING therapy with standard clinical practice (radiation and surgery) to determine if pre-treating STS with STING therapy prior to surgical resection can shrink tumours pre-operatively and protect against tumour relapse and metastatic spread after surgery. The results stemming from this work will expand the scientific rationale and justification for pursuing clinical applications of STING agonist therapy for sarcoma patients.