A recent study led by John Hopkins Medicine has found that combining two ‘old therapies’ can offer a surprising new purpose – fighting Medulloblastoma, the most common malignant brain tumor in children. The fast-growing cancerous tumor originates in the brain or spinal cord and has traditionally been treated with surgery to remove the tumor followed by radiation and chemotherapy.
The prospective therapy which comprises of copper ions and Disulfiram (DSF-Cu++), paves the way toward a successful treatment that can be used alone or in conjunction with traditional therapy. “Disulfiram, [is] a medication that’s been used for nearly 70 years to treat chronic alcoholism,” explains Betty Tyler, the study’s senior author and associate professor of neurosurgery at Johns Hopkins. “It has great promise being ‘repurposed’ as an anticancer agent, especially when it is complexed with metal ions such as copper.”
The researchers tested the anticancer activity of DSF-Cu++ and, in their attempts to define what it targeted at the molecular level to achieve these effects, were able to highlight four key findings.
First, the team of researchers found that DSF-Cu++ blocks two biological pathways in medulloblastomas that the cancer cells need in order to remove proteins threatening their survival. With these pathways blocked, these proteins accumulate in the tumor and cause the malignant cells to die, leaving them to eventually be removed by the body’s own immune system.
Second, the researchers discovered that just a few hours of exposure to DSF-Cu++ not only kills medulloblastoma cells but can also effectively reduce the cancer stem cells responsible for their creation.
The third finding in the study revealed that DSF-CU++ keeps cancer cells from recovering. By impairing the ability of medulloblastoma cells to repair the damage done to their DNA, DSF-CU++ enhances the cell killing power of the treatment.
Lastly, the promising combo of DSF-CU++ demonstrated significant increases in prolonging survival days of mice whose brains were implanted with two subtypes of medulloblastoma.
Imagine sitting in the doctor’s office and being told the heartbreaking news that your child has been diagnosed with a malignant brain tumor. As one might expect, the doctor states that the most effective treatment option is typically a combination of chemotherapy and radiation. However, the doctor reveals that there are additional risks to take into account that apply to children. Since children’s tiny bodies are still growing and developing, chemotherapy and radiation can cause long-term side effects such as intellectual disabilities. As a parent, it is painful enough to have to watch a child go through chemotherapy and radiation without adding permanent damage into the fold.
Sadly, this scenario is not unique. Medulloblastoma is the most prevalent form of a pediatric brain tumor with more than 350 children diagnosed with cancer each year. There are four distinct subtypes of medulloblastoma, with the deadliest being known as Group 3.
Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) are trying to minimize the collateral damage by finding personalized treatments that reduce side effects while remaining effective. Scientists at SBP are working with an inhibitor known as LSD1 that specifically targets Group 3 medulloblastoma in a mouse model. The study, published in Nature Communications, showed that the drug dramatically decreased the size of tumors grown under the mouse’s skin by shrinking the cancer by more than 80 percent. This suggested that it could also be effective against patients’ tumors if it could be delivered to the brain. The LSD1 inhibitor has shown promise in clinical trials, where it has been tested for treating other types of cancer.
According to Robert Wechsler-Reya, Ph.D., senior author of the paper and director of the Tumor Initiation and Maintenance Program at SBP: “Our lab is working to understand the genetic pathways that drive medulloblastoma so we can find better ways to intervene and treat tumors. This study shows that a personalized treatment based upon a patient’s specific tumor type might be within our reach.”
Dr. Wechsler-Reya’s work on medulloblastoma was, in part, funded by the CIRM (LA1-01747) in the form of a Research Leadership Award for $5,226,049.