Drugs used to slow Amyotrophic lateral sclerosis (ALS) progression may also suppress self-renewing cancerous stem cells in grade 4 glioblastoma, the most aggressive and incurable brain tumor in adults as per research from the University of Ottawa published in the journal Stem Cell Reports (1✔ ✔Trusted Source
Targeting glioblastoma with a brain-penetrant drug that impairs brain tumor stem cells via NLE1-Notch1 complex
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Glioblastoma is the most common – and the most malignant – primary brain tumor in adults. It’s aggressive and incurable. Despite current treatments, including surgery and chemotherapy, the median survival for glioblastoma patients remains just 18 months.
Now, innovative new research led by Dr. Arezu Jahani-Asl, Canada Research Chair in Neurobiology of Disease at the University of Ottawa, provides highly compelling evidence that a drug used to slow the progression of the disease ALS shows promise in suppressing the self-renewing cancerous stem cells that challenge the present standards of care for these lethal grade 4 brain tumors.
Her team’s findings could prove highly impactful because brain tumor stem cells (BTSCs) are at the very core of therapeutic resistance and tumor recurrence in glioblastoma, a devasting and treatment-resistant type of cancer that impacts four per 100,000 people in Canada.
Indeed, discovering ways to effectively target these rare populations of highly resistant cells could have major implications for global efforts to combat brain cancer, according to Dr. Jahani-Asl, associate professor in the Department of Cellular and Molecular Medicine and a member of the Ottawa Brain and Mind Institute.
Suppressing Cancerous Stem Cells
The uOttawa-led team found that the drug edaravone (brand name Radicava) inhibits the self-renewal and proliferation of brain tumor stem cells, so repurposing the drug may prove to be a potent weapon against glioblastoma.
“We show that edaravone specifically targets cancer stem cells and is particularly effective in combination with ionizing radiation,” she says.
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“The study suggests that edaravone in combination with ionizing radiation can be effective in eradicating cancer stem cells, and thus is expected to decrease the chance of resistance to therapy and recurrence in glioblastoma patients.”
Ionizing radiation is a type of radiation that is used in cancer therapy to kill or inhibit the growth of malignant cells.
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The next steps for the researchers include writing a protocol on the best ways to optimize edaravone drug dosage in combination with ionizing radiation and chemotherapy.
Repurposing existing marketed drugs already approved for human use is an increasingly popular strategy for battling different types of cancer cells. Compounds that have already been proven safe could potentially advance swiftly to clinical trials.
Since edaravone is an approved compound that has already been shown safe in humans, Dr. Jahani-Asl says repurposing the drug and translating it for glioblastoma is “very promising.”
Edaravone was approved by the U.S. Food and Drug Administration in 2017 to treat ALS, and Health Canada approved the drug’s oral formulation in 2022. It’s also used to treat stroke.
Before the completed study provided compelling evidence that edaravone sensitizes glioblastoma tumors to radiation therapy in animal models, the research team conducted gene expression analysis in patient-derived brain tumor stem cells in the absence and presence of the drug.
“We found significantly deregulated gene panels related to stemness and DNA repair mechanisms which was the spark to begin a new major line of investigation,” Dr. Jahani-Asl says.
Achieving new insights into BTSC regulation is at the forefront of efforts to battle glioblastoma, and Dr. Jahani-Asl is an international leader in this effort.
Her research program at the Ottawa Faculty of Medicine is centered on developing novel therapeutic strategies for complex and devastating brain diseases.
Any new drug for glioblastoma is expected to be used in combination with the present standard treatments which include ionizing radiation and chemotherapy.
“Our goal is now to try to optimize dosage for a safe therapeutic window,” Dr. Jahani-Asl says. “Once we establish a dose that is safe for use in combination therapy, we will be well equipped with the knowledge to move this forward to clinic.”
Reference:
- Targeting glioblastoma with a brain-penetrant drug that impairs brain tumor stem cells via NLE1-Notch1 complex
– (https://www.sciencedirect.com/science/article/pii/S2213671124002698?via%3Dihub)
Source-Eurekalert
