A new therapy that combines copper ions with a drug once heralded as a treatment for alcoholism may help save children from a common but devastating central nervous system cancer known as medulloblastoma.
Copper has been clinically improving the lives of people since about 1500 BCE, when an Egyptian physician first recorded its use as a treatment for inflammation. Some 35 centuries later, researchers have provided solid evidence for a new role for the first metal ever used medicinally.
A medulloblastoma is a fast-growing, cancerous tumor originating in the brain or spinal cord, according to the National Cancer Institute. Predominantly seen in children younger than 10, medulloblastoma is the most common pediatric brain malignancy, with between 250 and 500 new cases diagnosed annually.
Overall, the survival rate for children with medulloblastoma that has not spread is about 70%, but this can drop to as low as 40% depending on the patient’s age, the molecular subtype of the tumor (there are four), the extent of any surgical removal of previous tumors, and whether there has been metastasis (spread to other parts of the body).
Treatment for pediatric medulloblastoma has traditionally been surgery, radiation, and chemotherapy, individually or in combination. The new study looked at an alternative therapy.
“Disulfiram [DSF], a medication that’s been used for nearly 70 years to treat chronic alcoholism, has great promise being ‘repurposed’ as an anticancer agent, especially when it is complexed with metal ions such as copper [Cu++],” says study senior author Betty Tyler, associate professor of neurosurgery at Johns Hopkins University School of Medicine.
“Since the combination [DSF- Cu++] hasn’t previously been evaluated for potential pediatric use, we wanted to assess its safety and effectiveness against the two pediatric medulloblastoma subtypes with the worst five-year survival rates.”
“Our goal is to pave the way toward a successful treatment that could be used for children, either alone or teamed with conventional radiation and chemotherapy,” says coauthor Henry Brem, director of the neurosurgery department. “Characterizing how DSF-Cu++ works at the molecular level was critical for future exploration of its clinical use against pediatric medulloblastoma.”
For the study, researchers tested the anticancer activity of DSF-Cu++ and attempted to define what it targeted at the molecular level to achieve these effects, both in cell cultures and mice. They first found that DSF-Cu++ blocks two biological pathways in medulloblastomas that the cancer cells need to remove proteins threatening their survival.
“With the pathways shut down, these proteins accumulate in the tumors, cause the malignant cells to die, and tag them for removal by the immune system,” Brem says.
Secondly, the researchers discovered that DSF-Cu++ not only kills medulloblastoma cells but also curtails the cells responsible for their creation.
“Cancer stem cells initiate the processes that result in tumorigenesis [tumor birth], as well as play a role in cancer recurrence after treatment and metastasis from the tumor’s original location,” Tyler says. “We were able to effectively reduce cancer stem cell numbers using very tiny amounts of DSF-Cu++ after just a few hours of exposure.”
A third finding from the study reveals that DSF-CU++ impairs the ability of medulloblastoma cells to repair damage to their DNA, thereby enhancing the cytotoxic (cell killing) power of the treatment.
“This suggests that DSF-Cu++ keeps the cancer cells from recovering after disrupting the genes controlling their growth and survival, a definite therapeutic advantage,” says Brem. “It also means that DSF-Cu++ has potential as an adjuvant therapy, helping keep a tumor’s DNA repair mechanism from overcoming the cytotoxic impact of radiation treatment or chemotherapy.”
Finally, the researchers tested the impact that combining DSF and copper had on survival rates of mice whose brains were implanted with two subtypes of medulloblastoma. The saw significant increases in prolonging survival days (19% and 27%).
The paper appears in PLOS ONE. Riccardo Serra, a postdoctoral fellow in Tyler and Brem’s brain tumor laboratory and a neurosurgery resident at the University of Maryland, is lead author. Additional coauthors are from Catholic University of the Sacred Heart in Rome and Johns Hopkins.
Tyler is a consultant for Accelerating Combination Therapies. Brem serves as a consultant for AsclepiX Therapeutics, StemGen, InSightec, Accelerating Combination Therapies, Camden Partners, Like Minds, Galen Robotics, and Nurami Medical. The remaining authors do not have any financial disclosures or conflicts of interest to disclose.
Source: Johns Hopkins University
