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


METHODS
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.
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.
Maite
M
Verreault
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.
Charlotte
C
Schmitt
Laboratoire de Pharmacologie Biologique, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, Paris, France.
Lauriane
L
Goldwirt
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.
Kristine
K
Pelton
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.
Samer
S
Haidar
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.
Camille
C
Levasseur
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.
Jeremy
J
Guehennec
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.
David
D
Knoff
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.
Marianne
M
Labussière
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.
Yannick
Y
Marie
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.
Azra H
AH
Ligon
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.
Karima
K
Mokhtari
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.
Khê
K
Hoang-Xuan
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.
Marc
M
Sanson
Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts.
Brian M
BM
Alexander
Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Patrick Y
PY
Wen
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.
Jean-Yves
JY
Delattre
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.
Keith L
KL
Ligon
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.
Ahmed
A
Idbaih
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D048288:Imidazolines / Q000008:administration & dosage*; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D048288:Imidazolines; C579783:RG7112; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2