PHILADELPHIA (June 9, 2021)—There’s growing evidence that statins can offer an effective treatment for medulloblastoma, a childhood brain cancer, without the severe side effects of other chemotherapy drugs. Now a new study by researchers at Fox Chase Cancer Center explains why.
Specifically, the researchers demonstrated in mouse and cell models that statins successfully penetrate brain and plasma tissue, but do not penetrate bone. This explains why statins do not seem to cause the same bone deformities caused by other treatments.
“We’ve demonstrated that this exhibited very promising efficacy in treatment of medulloblastoma, but the question I kept getting from colleagues in the field is, ‘Why are there no side effects in bone development?’” said lead author Zeng-jie Yang, MD, PhD, an associate professor in the Cancer Signaling and Epigenetics Program.
“Now we’ve answered that question—it’s because it cannot penetrate into the bone,” added Yang, who conducted the study with colleagues at Fox Chase and at other centers.
Medulloblastoma is a rare cancer overall, affecting only around 500 children nationally each year, but it’s the most common form of childhood brain cancer.
Around 30% of medulloblastomas are caused by mutations in a cell signaling mechanism called the hedgehog pathway, which tells cells how to divide and grow. This pathway plays an important role in bone development, but when it becomes overactivated it can cause tumors to grow in the brain. Drugs that block the hedgehog pathway are an effective treatment, but they can lead to irreversible defects in bone growth in young children.
“The major challenge in medulloblastoma management right now is the toxicity of the treatment. Hedgehog pathway inhibitors such as vismodegib inhibit tumor growth but also severely disrupt bone development in patients with medulloblastoma,” Yang said.
Statins work by controlling cholesterol, an essential key to activating the hedgehog pathway. While previous studies showed statins could be an effective treatment, it was not clear why they did not cause the same side effects in bone development.
For the new study, the researchers used mice that were genetically engineered to block cholesterol biosynthesis in the bone and observed that the animals’ bone development was disrupted. This confirmed that both the hedgehog pathway and cholesterol biosynthesis were important for bone development.
They then studied two kinds of treatment in young mice with tumors. Some were treated with statins, while others were treated with hedgehog pathway inhibitors. The inhibitor group developed bone deformities, but the statin-treated mice did not.
Finally, they examined the mice a half hour after treatment and found that the statins could be detected in the brain and plasma, but not in the bone.
“I think all this evidence provides a strong rationale to include statins in the clinical management of medulloblastoma,” Yang said. “People are excited, because we don’t need to worry about the safety of the drug.” Yang is preparing a clinical trial to follow up on this research.
The paper, “Statins Repress Hedgehog Signaling in Medulloblastoma With No Bone Toxicities,” was published in Oncogene.