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

Michael Müller1,2,3, Lisa Rösch1,2,4, Sara Najafi1,2,5

  • 1Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany.

Cancers
|September 10, 2021
PubMed

Insights

APR-246 (Eprenetapopt) shows potent anti-cancer activity, particularly in neuroblastoma. A new gene signature predicts treatment effectiveness, and combining APR-246 with HDAC-inhibitors enhances its efficacy, offering a novel targeted therapy option.

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.
Keywords:
ROSTP53histone deacetylasespediatric tumors of the nervous systemprecision medicineresponse prediction biomarkersmall molecule inhibitors

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