2. Academic Validation
  3. 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. [email protected] [email protected].
  • 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. [email protected] [email protected].
PMID: 26482041 DOI: 10.1158/1078-0432.CCR-15-1015
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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