# Repurposing statins and phenothiazines to treat chemoresistant neuroblastoma

## TL;DR

This study repurposes two approved drugs, statins and phenothiazines, to improve treatment outcomes in chemoresistant neuroblastoma in children.

## Contribution

The novel contribution is identifying a drug combination of statins and phenothiazines that enhances chemotherapy in chemoresistant neuroblastoma.

## Key findings

- The combination of prochlorperazine and pitavastatin showed synergistic effects in neuroblastoma organoids and reduced tumor growth in xenograft models.
- The drug combination induced a phenotypic change in neuroblastoma cells, increasing their sensitivity to chemotherapy.
- Adding the drug combination to standard chemotherapy improved outcomes in chemoresistant patient-derived xenografts.

## Abstract

Relapse and treatment resistance are common in children with high-risk neuroblastoma, and novel therapies are needed. Conventional drug discovery is slow, expensive, often fails in practice, and consequently falls short in addressing pediatric and rare conditions. In such instances, drug repurposing is a promising strategy. Here, we used two independent in silico prediction tools including machine learning to identify approved drugs for repurposing against neuroblastoma. The combination of statins and phenothiazines showed strong synergistic effects in human neuroblastoma organoids, decreased tumor growth, and prolonged survival in MYCN-amplified neuroblastoma patient-derived xenografts. The drug combination altered cholesterol metabolism through two different mechanisms and induced a phenotypic change toward an adrenergic state in vitro, which was associated with enhanced chemosensitivity. Integration of the drug combination into standard-of-care chemotherapy regressed tumors and prolonged survival in chemoresistant patient-derived xenografts. Thus, a combination of safe and approved medications added to standard-of-care chemotherapy outperforms chemotherapy alone in chemoresistant neuroblastoma.

Over half of children with high-risk neuroblastoma (NB) exhibit treatment resistance to current therapies. Combining two clinically approved drugs, prochlorperazine (PCZ) and pitavastatin (PIT), with standard-of-care chemotherapy was shown to enhance treatment efficacy in chemoresistant NB.

In silico predictions, including machine-learning analyses, of NB gene expression profiles identified PCZ and PIT for drug repurposing.The PCZ + PIT combination led to drug synergy, NB cell death, and cholesterol deficiency in NB organoids.The combination of PCZ + PIT induced NB cell state changes in vitro leading to enhanced sensitivity to chemotherapy.In vivo treatment with PCZ + PIT in addition to standard-of-care chemotherapy led to decreased tumor size and extended survival in a chemoresistant patient-derived xenograft model of high-risk NB.

In silico predictions, including machine-learning analyses, of NB gene expression profiles identified PCZ and PIT for drug repurposing.

The PCZ + PIT combination led to drug synergy, NB cell death, and cholesterol deficiency in NB organoids.

The combination of PCZ + PIT induced NB cell state changes in vitro leading to enhanced sensitivity to chemotherapy.

In vivo treatment with PCZ + PIT in addition to standard-of-care chemotherapy led to decreased tumor size and extended survival in a chemoresistant patient-derived xenograft model of high-risk NB.

Over half of children with high-risk neuroblastoma (NB) exhibit treatment resistance to current therapies. Combining two clinically approved drugs, prochlorperazine (PCZ) and pitavastatin (PIT), with standard-of-care chemotherapy was shown to enhance treatment efficacy in chemoresistant NB.