STING Pathway Activation: The Missing Link between Genomic Instability and Antitumor Immunity in Osteosarcoma

Institution: 

University of California San Francisco

Researcher(s): 

Elizabeth Young, MD

Grant Type: 

Young Investigator Grants

Year Awarded: 

2021

Type of Childhood Cancer: 

Osteosarcoma

Osteosarcoma is a bone tumor occurring most often in children and young adults. These patients have a 5-year survival rate of less than 20% if the cancer has spread to distant sites at the time of diagnosis. Unfortunately, the remaining 80% of these patients are suspected to have spread of the cancer which is undetectable. The treatment strategy for this disease has not seen significant improvement in 30 years, and there is no specific treatment to target tumors that have spread throughout the body. These distant tumors, particularly those in the lung, are responsible for causing the death of most patients with osteosarcoma. Therefore, understanding how and why these tumors spread to distant sites and learning how to target them is vital to extending the lives of patients. New treatments to be used concurrently with the standard chemotherapy to help prevent the cancer from spreading are desperately needed in pediatric osteosarcoma.

Project Update 2024:

In cancers including osteosarcoma (OS), malfunctioning DNA replication results in a warning signal to the immune system via the cGAS-STING pathway, which we believe is modified in OS tumors to evade immune-mediated tumor killing. We have identified that about 50% of OS patient-derived cell lines respond to cGAS-STING activation with a drug treatment, whereas the other half do not. Additionally, using RNA sequencing, we defined the specific genetic changes that occur in OS upon activation of the cGAS-STING pathway. Our preliminary studies of a STING activating drug in animal models have shown that this therapy can slow tumor growth and increase anti-tumor immunity. Overall, we have discovered two subsets of OS with differing capacity to generate an anti-tumor immune signal and demonstrated the benefits of activating STING in patients and in immune assays. Our proposed ongoing work will confirm the effects of STING activation, supporting the translation of this novel approach to activating immune surveillance in osteosarcoma.

Final Project Update 2025:

We identified that cell lines with the highest degree of cGAS activation have STING in an OFF state, and lines with low cGAS activation have STING in an ON state and retain the capacity to produce downstream signals through this pathway. We tested this relationship between cGAS activity and STING repression by treating STING-OFF cells with a cGAS inhibitor. cGAS inhibition results in increased STING protein levels, suggesting that chronic activation of cGAS may result in repression of STING. Additionally, using bulk RNA sequencing, we have defined the specific genetic changes that occur in osteosarcoma upon activation of the cGAS-STING pathway. This osteosarcoma-specific “gene signature” is only present in a small subset of patient samples, but these patients have significantly improved disease-free and overall survival. Importantly, we also identified that a STING activating drug also slows growth of osteosarcoma tumors in small animals by increasing anti-tumor immunity. Overall, we have discovered two subsets of osteosarcoma with differing capacity to generate an anti-tumor immune signal and demonstrated the benefits of activating STING in patients and animal models, supporting the translation of this novel approach to activating immune surveillance in osteosarcoma.