1. Academic Validation
  2. Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

  • Clin Cancer Res. 2016 Mar 1;22(5):1185-96. doi: 10.1158/1078-0432.CCR-15-1015.
Maite Verreault 1 Charlotte Schmitt 2 Lauriane Goldwirt 3 Kristine Pelton 4 Samer Haidar 4 Camille Levasseur 2 Jeremy Guehennec 2 David Knoff 4 Marianne Labussière 2 Yannick Marie 2 Azra H Ligon 5 Karima Mokhtari 6 Khê Hoang-Xuan 6 Marc Sanson 7 Brian M Alexander 8 Patrick Y Wen 9 Jean-Yves Delattre 7 Keith L Ligon 4 Ahmed Idbaih 10
Affiliations

Affiliations

  • 1 Inserm, U 1127, Paris, France. CNRS, UMR 7225, Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Paris, France. Institut du Cerveau et de la Moëlle épinière, ICM, 47, Bd de l'Hôpital, Paris, France. Institut du Cerveau et de la Moëlle épinière, Centre de neuroimagerie de recherche, CHU Pitié-Salpêtrière, 47, Bd de l'Hôpital, Paris, France.
  • 2 Inserm, U 1127, Paris, France. CNRS, UMR 7225, Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Paris, France. Institut du Cerveau et de la Moëlle épinière, ICM, 47, Bd de l'Hôpital, Paris, France.
  • 3 Laboratoire de Pharmacologie Biologique, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, Paris, France.
  • 4 Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. Department of Pathology, Harvard Medical School, Boston, Massachusetts. Boston Children's Hospital, Boston, Massachusetts.
  • 5 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. Department of Pathology, Harvard Medical School, Boston, Massachusetts. ahmed.idbaih@gmail.com Keith_Ligon@dfci.harvard.edu.
  • 6 Inserm, U 1127, Paris, France. CNRS, UMR 7225, Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Paris, France. Institut du Cerveau et de la Moëlle épinière, ICM, 47, Bd de l'Hôpital, Paris, France. AP-HP, Hôpital universitaire Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, 47, Bd de l'Hôpital, Paris, France. AP-HP, Hôpital de la Pitié-Salpêtrière, Service de Neuropathologie R Escourolle, 47, Bd de l'Hôpital, Paris, France.
  • 7 Inserm, U 1127, Paris, France. CNRS, UMR 7225, Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Paris, France. Institut du Cerveau et de la Moëlle épinière, ICM, 47, Bd de l'Hôpital, Paris, France. AP-HP, Hôpital universitaire Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, 47, Bd de l'Hôpital, Paris, France. AP-HP, Hôpital de la Pitié-Salpêtrière, Service de Neuropathologie R Escourolle, 47, Bd de l'Hôpital, Paris, France. OncoNeuroThèque biobank, Institut du Cerveau et de la Moëlle épinière, ICM, 47, Bd de l'Hôpital, Paris, France.
  • 8 Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts.
  • 9 Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 10 Inserm, U 1127, Paris, France. CNRS, UMR 7225, Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Paris, France. Institut du Cerveau et de la Moëlle épinière, ICM, 47, Bd de l'Hôpital, Paris, France. AP-HP, Hôpital universitaire Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, 47, Bd de l'Hôpital, Paris, France. AP-HP, Hôpital de la Pitié-Salpêtrière, Service de Neuropathologie R Escourolle, 47, Bd de l'Hôpital, Paris, France. ahmed.idbaih@gmail.com Keith_Ligon@dfci.harvard.edu.
Abstract

Purpose: p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM.

Experimental design: We performed a preclinical evaluation of RG7112 MDM2 Inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCL), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models.

Results: MDM2-amplified PDCLs were 44 times more sensitive than TP53-mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 μmol/L vs. 21.9 μmol/L). MDM4-amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 μmol/L), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 μmol/L). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and Apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival.

Conclusions: These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2-amplified models suggests that additional markers of response to MDM2 inhibitors must be identified.

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