Glioblastoma is the most common and aggressive form of brain cancer in adults. There are about 12,000 new cases diagnosed each year in the United States. There are many different risk factors that could lead to glioblastoma. Age is a large risk factor as well as family history and environmental exposure. Symptoms include headaches, seizures, confusion/memory loss, difficulty speaking or understanding speech, vision problems, nausea, vomiting, and numbness. Many patients will have a change in personality, could become moody, as well as have difficulty walking/coordinating movements. Unfortunately, the median survival after diagnosis is only 15 months with a 5-year survival rate of 5%. Different factors play into prognosis including age of the patient, tumor location, and the type of treatment provided. Currently, standard-of-care treatment includes surgery (if possible), in combination with radiation and/or chemotherapy.
Key barriers to glioblastoma include the blood-brain barrier (BBB), which prevents drugs from reaching the tumor, as well as the physical inability to surgically remove the mass, and the sensitivity of the brain in response to cytotoxic drugs. Scientists are working to overcome these barriers and improve therapeutic efficacy.
A recent article in the Proceedings of the National Academy of Sciences (PNAS), by Dr. Rakesh Jain and others, demonstrate how combination therapy could overcome glioblastoma resistance. Jain is the Director of the Edwin Steele Laboratories for Tumor Biology in the Department of Radiation Oncology at the Massachusetts General Hospital and the Andrew Werk Professor of Radiation Oncology at Harvard Medical School. He is a renowned cancer biologist and pioneered work on blood vessel development around the tumor. He is internationally recognized as a champion in the field of oncology and is a Fellow of the National Academy of Science.
Jain and his team set out to discover approaches to overcome glioblastoma resistance. They investigated an intracellular pathway known as Wnt signaling, which contributes to therapy resistance in glioblastoma cells. Wnt signaling is commonly known to regulate aspects of stem cell behavior; however, in cancer it is upregulated and drives rapid tumor proliferation. Researchers identified a marker part of the Wnt pathway, Wnt7b, that is highly expressed on glioblastoma cells. Interestingly, high expression of Wnt7b is associated with resistance to immunotherapy.
Scientists tested what would happen if you blocked Wnt7b. As a result, tumors became sensitized to immunotherapy. The inhibitor used was also tested in clinical trials and revealed to be safe in patients. Additionally, it synergized well with other immunotherapies and elicited strong antitumor immunity. Patients were found to have better outcomes and prolonged survival. Researchers are now working to use Wnt7b inhibition in combination with novel immunotherapies in the clinic to see if patients do even better.
Jain and his team have identified a novel biomarker on glioblastoma cells that have sensitized an aggressive tumor to novel immunotherapies. As a result, the immune system can recognize and act on the tumor providing a safe therapeutic alternative. Future studies hope to further improve treatment regimens and create a new gold standard for glioblastoma patients. Overall, this work provides a new approach to target brain tumors resulting in improved treatment outcomes and prolonged patient survival.
Article, PNAS, Rakesh Jain, Massachusetts General Hospital, Harvard Medical School
