Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma

Area of Science:

• Oncology
• Pharmacology
• Genomics

Background:

• APR-246 (Eprenetapopt) is an anti-cancer drug investigated as a p53 refolding agent and for its role in elevating reactive oxygen species (ROS).
• Previous research identified SLC7A11 as a predictive biomarker for APR-246 responsiveness.

Purpose of the Study:

• To investigate cancer cell line responses to APR-246 using in silico analysis.
• To identify a gene signature predicting APR-246 effectiveness.
• To evaluate the combination of APR-246 with HDAC-inhibitors.

Main Methods:

• In silico analysis of approximately 800 cancer cell lines from the Cancer Therapeutics Response Portal (CTRP).
• Analysis of gene expression data from the Cancer Cell Line Encyclopedia (CCLE) and the INFORM registry study.
• Validation of predicted APR-246 sensitivity in cell lines and ex vivo patient samples.
• In vitro and in vivo studies using zebrafish neuroblastoma xenograft models to assess combination therapy.

Main Results:

• Neuroblastoma, lymphoma, and acute lymphocytic leukemia cells showed high responsiveness to APR-246.
• Low SLC7A11 expression correlated with APR-246 responsiveness.
• A novel gene signature predicted APR-246 effectiveness with 90% sensitivity and 94% specificity.
• Combining APR-246 with HDAC-inhibitors significantly increased sensitivity in cell cultures and in vivo models.

Conclusions:

• APR-246 demonstrates potent anti-cancer activity, with specific cancer types showing higher sensitivity.
• A validated gene signature can predict APR-246 treatment efficacy.
• The combination of APR-246 and HDAC-inhibitors represents a promising targeted treatment strategy, particularly for neuroblastoma.