Method to overcome treatment resistant cancer by rescuing STING signaling

Unmet Need

Among types of brain cancer, glioblastoma (GBM) is the most common and the most devastating. Over 8000 patients are diagnosed annually in the United States, accounting for half of all primary malignant brain tumors. Patients suffer from headaches, seizures, nausea, and memory loss; with an average survival of just 14 months following initial diagnosis. Tragically, there are no curative treatments for GBM. The current standard of care consists of maximal surgical resection, followed by radiation therapy and treatment with temozolomide, an alkylating agent. However, even when GBM tumors appear to be fully removed, they almost always come back within 6-8 months. This is due to their invasive nature, coupled with their characteristic treatment resistance. Surgery cannot eliminate invasive microscopic tendrils of the tumor which extend into healthy tissue and resist treatment. GBM treatment resistance is complex, but a major component is suppression of signaling pathways that detect damaged DNA and flag the cancerous cell for destruction by the immune system. Radiation therapy and alkylating agents induce DNA damage, but cancerous cells evade detection by the immune system by suppressing such pathways. There is an urgent need for a method to rescue cellular mechanisms of detecting DNA damage to enable better outcomes for GBM and other cancers.

Technology

Duke inventors have developed a method to combat cancer cell evasion of the immune system, by de-suppressing signaling pathways that detect and report damaged DNA. This is intended to be used by a physician for both diagnostic and therapeutic purposes, allowing them to assess whether the pathway is suppressed, rescue this if necessary, and select the most effective treatment strategy. Specifically, the cGAS-STING pathway is responsible for detection of damaged DNA and flagging the cell for destruction by the immune system. This pathway is suppressed in GBM and other cancers by hypermethylation of the STING promoter. Administering Decitabine (demethylating agent) to the tumor can reverse this, enhancing the efficacy of conventional cancer treatments that utilize DNA damage (e.g. radiation therapy and alkylating agents) as well as immunotherapies. This is because rescuing STING function forces cancerous cells to signal their compromised status to the immune system, by expression of surface antigens that encourage their recognition and destruction by immune cells. Furthermore, STING activity promotes secretion of pro-inflammatory factors that activate T cells and Natural Killer cells. This has been demonstrated by analyzing STING mRNA and protein expression, using databases of GBM patient samples, cell culture assays of GBM cell lines, and fresh tumor tissue samples from GBM patients, before and after Decitabine treatment. These diverse experimental approaches provide convergent lines of evidence that affirm the efficacy of this method in enhancing immune detection of various cancer types including GBM. This technology could improve GBM patient outcomes by sensitizing cancerous cells to various treatments including chemotherapy, radiation therapy, and immunotherapy.

Other Applications

This technology could also be applied to non-GBM cancer types that share the STING silencing mechanism, including extracranial tumors of neuronal origin. STING hypermethylation is also present in non-cancerous cerebral disease states including neurodegenerative conditions such as Alzheimer’s and Parkinson diseases, neuroinflammatory conditions such as multiple sclerosis, and psychiatric diseases such as bipolar and schizophrenia.

Advantages

• Improved treatment outcomes by overcoming cancer cell immunosuppression
• Predict treatment response and guide clinical strategy via STING epigenetic biomarker
• Transforms difficult to treat immunologically “cold” tumors into immunologically active tumors, sensitizing cancer to treatment