iPC
Published February 3, 2021 | Version v1
Journal article Open

MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma

Creators

  • 1. Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children's Hospital, 1102 Bates Ave., Suite 460G, Houston, TX, 77030-2399, USA
  • 2. Department of Pathology and Immunology, Baylor College of Medicine, Molecular Oncology Laboratory, Texas Children's Hospital, Houston, TX, 77030, USA
  • 3. Singleton Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX, 77030, USA
  • 4. Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
  • 5. Aileron Therapeutics Inc, Cambridge, MA, 02139, USA

Description

Hepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy. MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes. Treatment with NSC207895 (XI-006), which inhibits MDM4 expression, or ATSP-7041, a stapled peptide dual inhibitor of MDM2 and MDM4, showed significant cytotoxic and antiproliferative effects in HB cells. Similar phenotypes were seen with short hairpin RNA (shRNA)-mediated inhibition of MDM4. Both NSC207895 and ATSP-7041 caused significant upregulation of p53 targets in HB cells. Knocking-down TP53 with shRNA or overexpressing MDM4 led to resistance to NSC207895-mediated cytotoxicity, suggesting that this phenotype is dependent on the MDM4-p53 axis. MDM4 inhibition also showed efficacy in a murine model of HB with significantly decreased tumor weight and increased apoptosis observed in the treatment group. This study demonstrates that inhibition of MDM4 is efficacious in HB by upregulating p53 tumor suppressor signaling.

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Funding

iPC – individualizedPaediatricCure: Cloud-based virtual-patient models for precision paediatric oncology 826121
European Commission