Repurposing statins and phenothiazines to treat chemoresistant neuroblastoma

Area of Science:

• Oncology
• Pharmacology
• Computational Biology

Background:

• High-risk neuroblastoma in children frequently involves relapse and treatment resistance.
• Conventional drug discovery is inefficient for rare and pediatric conditions like neuroblastoma.
• Drug repurposing presents a viable strategy for identifying novel neuroblastoma therapies.

Purpose of the Study:

• To identify approved drugs for repurposing against neuroblastoma using in silico prediction tools.
• To evaluate the efficacy of identified drug combinations in preclinical neuroblastoma models.
• To investigate the mechanisms underlying the therapeutic effects of the drug combination.

Main Methods:

• Utilized two independent in silico prediction tools, including machine learning, for drug repurposing.
• Tested drug combinations in human neuroblastoma organoids and patient-derived xenografts (PDX).
• Assessed tumor growth, survival rates, cholesterol metabolism, and chemosensitivity in vitro and in vivo.

Main Results:

• A combination of statins and phenothiazines demonstrated strong synergistic effects in neuroblastoma models.
• The drug combination reduced tumor growth and prolonged survival in MYCN-amplified neuroblastoma PDX.
• Altered cholesterol metabolism and induced an adrenergic phenotype, enhancing chemosensitivity.
• Integration with standard chemotherapy regressed tumors and improved survival in chemoresistant PDX.

Conclusions:

• Drug repurposing of statins and phenothiazines is a promising strategy for high-risk neuroblastoma.
• The combination therapy shows significant efficacy, particularly in chemoresistant neuroblastoma.
• This approach offers a potentially safer and more efficient therapeutic option compared to conventional drug discovery.