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Early Research Offers Hope for Better Medulloblastoma Drugs
Research in the lab and in mice finds drugs aimed at a new molecular target may reduce the risk of relapse of certain deadly brain cancers in children.
The Challenge
Medulloblastomas are the most common type of malignant brain tumor in children, though it is still considered rare, with fewer than 500 new cases diagnosed a year. They can occur at any age but most often occur in babies and young children. These tumors are fast growing and tend to spread through the cerebrospinal fluid, mostly to the spinal cord.
The 5-year survival rate for medulloblastoma is about 70%. But for the around 30% of children whose cancer recurs, the 5-year survival is close to zero. With recurrence, there aren’t any other effective treatment options.
Medulloblastomas are divided into 4 molecular groups based on how the tumor looks under a microscope and on which gene mutations the cells have.
Some types have better outlooks than others. Researchers are now trying to find out how to use what they know about these molecular subgroups to improve treatment.
The Research
Jezabel Rodriguez-Blanco, PhD, at the Medical University of South Carolina, focuses some of her research on one of the four molecular groups of medulloblastoma, known as the SHH subgroup. She was supported by an American Cancer Society (ACS) Institutional Research Grant (IRG) and recently published a study about a new potential way to fight recurrent (relapsed) medulloblastoma.
The SHH group was named for the sonic hedgehog pathway that is mutated in these medulloblastoma tumor cells. SHH is the gene that provides instructions for making the sonic hedgehog protein. This protein functions as a chemical signal, and it’s key in the development of the brain and spinal cord, eyes, and many other parts of the body.
When I work with doctors who treat brain cancers in children, I hear stories from them and from patients’ families firsthand. The toxicity these children receive is devastating. We need to have better treatments for these kids. We need treatments to be more targeted so they will be less toxic and more effective. That’s what my lab is working on.”
The SHH protein’s signal is relayed inside the cell like a game of telephone, with the “players” being chains of molecules that pass the message across the SHH signaling pathway. Errors along that pathway have been linked with cancer and birth defects. In fact, 30% of all medulloblastoma cases are due to errors in this SHH signaling pathway.
Two promising new drugs to treat medulloblastoma, vismodegib and sonidegib, are being studied in clinical trials. These compounds are more targeted, and, therefore, less toxic than the current chemotherapy. Unfortunately, they seem to only temporarily halt the growth of the cancer. Many patients eventually had their tumors recur, and they were untreatable.
Rodriguez-Blanco’s team discovered that the target for these drugs promoted a problem that led to treatment resistance and allowed the tumor to start growing again. They specifically found a subset of tumor cells that has the ability to escape targeted therapeutics and allow the growth of aggressive, recurrent disease.
When they tested moving the drug target further away from the signal’s starting point, they discovered that the tumor not only became smaller, but also less aggressive. Therefore, in mice, the tumors were no longer able to regrow.
Why Does It Matter?
Due to the very low survival of children with recurrent brain tumors, understanding biological mechanisms that cause medulloblastoma relapse will pave the way for the development of improved treatments. We need treatments that are less toxic, and we want to make sure that they are longer lasting. In the future, that could mean renewed hope for children with this type of medulloblastoma.