HemOnc Today's PharmAnalysis

HemOnc Today's PharmAnalysis

March 23, 2018
3 min read

Statins may reduce pediatric medulloblastoma tumor growth

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Zeng-jie Yang

Cholesterol may be required for medulloblastoma tumors to grow, study results showed.

This finding suggests statins may be an effective therapy, according to researchers in the laboratory of Zeng-jie Yang, MD, PhD, associate professor in the cancer biology program at Fox Chase Cancer Center.

Prior research suggested that drug resistance and safety signals are common with medulloblastoma treatments.

However, this study revealed that statins — widely used anti-cholesterol drugs, inhibit medulloblastoma growth. Moreover, statins in combination with vismodegib (Erivedge, Genentech) — an oral inhibitor of the hedgehog pathway — have demonstrated an impressive synergistic effect for repressing tumor progression.

Renata Gordon

HemOnc Today spoke with Yang and Renata Gordon, a PhD student and first author on the paper, about the rationale behind the study, whether this approach will prove effective, and the key questions subsequent research must address.


Question: What prompted you to study the association between cholesterol and medulloblastoma growth?

Answer: Medulloblastoma is the most common malignant brain tumor among children. Approximately 30% of medulloblastomas arise from the aberrant activation of the hedgehog pathway. Our goal is to identify novel therapeutic targets to treat medulloblastoma by repressing the hedgehog pathway. Although it’s known that cholesterol is involved in the regulation of hedgehog pathway activation during normal development, its role in medulloblastoma tumorigenesis had not been well established. Our preliminary studies noted elevated cholesterol biosynthesis in hedgehog group medulloblastoma in contrast to non-hedgehog-associated medulloblastoma. This led us to further investigate the role of cholesterol biosynthesis in medulloblastoma tumorigenesis.


Q: Is it certain that statins will be an effective treatment option?

A: In our studies, we demonstrated cholesterol requirement for activation of a protein called Smoothened, which is an effector of hedgehog pathway and a main target for anticancer therapeutics. Consistent with the revealed mechanism, statin-induced cholesterol deficiency inhibited Smoothened activity. We further validated the efficacy of statins with a well-established mouse medulloblastoma model. In tumors, statins effectively blocked hedgehog signal transduction, which subsequently led to suppression of medulloblastoma cell proliferation. Statins — alone or combined with FDA-approved Smoothened antagonists — demonstrated significant decrease of tumor burden, offering a novel avenue for therapy.


Q: Are there any safety signals associated with the use of statins by pediatric patients?

A: Statins are considered safe and reliable drugs for managing plasma cholesterol levels and have been approved for use in pediatric populations, indicating that statins represent a safe treatment option for medulloblastoma patients. Nevertheless, we will continue to examine the possible effects of statin-induced cholesterol deficiency on tissue development, which has been the major concern for utilizing hedgehog inhibitors in the pediatric population.


Q: How does this approach compare to other treatment options for these patients?

A: Strategies for treating medulloblastoma include a combination of surgery, craniospinal radiation and chemotherapy. Although survival rates have increased over the past decades, conventional treatment options result in severe long-term effects. Because medulloblastoma affects mostly infants and children — a patient population in which developmental processes are active — cognitive and endocrine disorders are prone to develop as a result of aggressive therapy. Therefore, targeted therapies to treat medulloblastoma are urgently needed. Selective hedgehog antagonists vismodegib and sonidegib (Odomzo, Sun Pharma) received approval for the treatment of malignant basal cell carcinoma. Despite a dramatic response to these inhibitors in initial clinical trials for medulloblastoma, severe toxicity and drug resistance arise among patients. Irreversible developmental toxicities in preclinical studies hampered FDA approval of vismodegib for use among pediatric patients. In our studies, commonly used cholesterol-lowering statins demonstrated effective inhibition of medulloblastoma growth. Compared with vismodegib and sonidegib, statins have an excellent safety profile, are readily available, and have been extensively studied for over 4 decades.


Q: Where does the research need to go next?

A: The blood-brain barrier effectively prevents penetration of cholesterol from the bloodstream into the brain, so cholesterol in the central nervous system is produced solely by brain cells. We need to further investigate the characteristics of cholesterol metabolisms and homeostasis in the brain compared with other parts of the body. These studies will help us to develop more brain-specific antagonists to treat medulloblastoma.


Q: What do physicians need to communicate to their patients about this treatment option?

A: Conventional medulloblastoma therapies cause severe side effects, including nausea, vomiting and hair loss, as well as long-term developmental, cognitive and endocrine disorders, in an already vulnerable pediatric population. Compared with existing therapeutic approaches for medulloblastoma, statins represent a safe treatment option for children, as no major side effects have been reported. It should be noted that the potential efficacy of statins in hedgehog-driven medulloblastoma will depend on which underlying mutation the tumor harbors in the hedgehog pathway. Approximately 80% of adult medulloblastomas, together with 50% of infant and childhood patients, harbor mutations in the upstream of Smoothened, and are the most likely to respond to statins. However, patients with medulloblastoma who carry mutations in the downstream of Smoothened are predicted to be resistant to cholesterol inhibitors. by Rob Volansky



Gordon RE, et al. Clin Cancer Res. 2018; doi:10.1158/1078-0432.CCR-17-2923.


For more information:

Renata Gordon can be reached at Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111; email: renata.gordon@fccc.edu.

Zeng-jie Yang, MD, PhD, can be reached at Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111; email: zeng-jie.yang@fccc.edu.


Disclosures: Gordon and Yang report no relevant financial disclosures.