Glioblastoma multiforme (GBM) is a highly aggressive and malignant brain tumor that is resistant to many treatments. Unfortunately, the median survival time after diagnosis is 15 months. GBM arises from glial cells, which support neurons in the brain. The exact cause of GBM is unclear, but common risk factors include age, exposure to radiation, genetic disorders, and previous head trauma. Symptoms can vary with disease progression. Patients can experience seizures, headaches, cognitive dysregulation, motor weakness, vision problems, nausea, and vomiting. Physicians diagnose GMB through a brain scan and biopsy. While therapeutic efficacy is limited, treatment usually involves a combination of therapies that can mitigate symptoms including surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, and stem cell transplant.
Tumor heterogeneity or the variability between cells in the tumor is what drives therapy resistance. It is difficult to target a complex system that rapidly proliferates uncontrollably. Not only do cancer cells obtain different mutations and characteristics, but the tumor microenvironment (TME) consists of various immune cells that commonly promote tumor progression. Normally, immune cells would identify and target the tumor. However, in the context of cancer, proteins and molecules secreted by cancer cells polarize healthy immune cells to become pro-tumor. In this case, immune cells will secrete molecules that allow the tumor to growth, while also suppressing healthy immune cells in the area. Scientists have been working to target multiple aspects of the tumor and the environment around it to effectively stop progression and shrink cancer.
A recent article in Cell Reports, by Dr. Johanna Joyce and others, demonstrates that a novel targeted cancer therapy can stop GBM proliferation and generate a strong anti-tumor response in the TME. Joyce is a Professor and Principal Investigator at the Ludwig Institute for Cancer Research affiliated with the University of Lausanne in Switzerland. Her research focuses on the cancer TME and how it regulates cancer progression. Specifically, she investigates the spread of cancer to other parts of the body, known as metastasis, and how different therapies respond to aggressive tumors. She has identified macrophages as a key immune cell target that drives therapeutic efficacy in certain brain cancers.
Joyce’s current work, recently published, revealed that loss of a surface protein, ADAR1, on cancer cells stops their proliferation and alters the TME to identify the tumor. ADAR1 is involved in the anti-viral alarm system specific to mammalian cells. Interestingly, researchers found that dysregulating or silencing ADAR1 slows GBM cell proliferation. This then allows immune cells to “catch up” and target the cancer cells. This specifically describes a balance between cell proliferation in competition with the immune response. Joyce and her team have found that therapeutic targeting of ADAR1 in mouse models and in human cancer cells slows GBM growth.
The innate anti-viral system in healthy immune cells allows for detection of viruses that enter the body. ADAR1 helps prevent false alarms and regulates the anti-viral response. However, in cancer, this mechanism is upregulated preventing a strong defense against the tumor. Therefore, by blocking this protein, Joyce and others can enhance inflammatory response and anti-tumor immunity. Overall, this work has the potential to sensitize GBM to novel immunotherapies and improve patient survival.
Article, Cell Reports, Johanna Joyce, Ludwig Institute for Cancer Research, University of Lausanne
