title: Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097.
abstract: The tumor suppressor p53 is a key regulator of apoptosis and functions upstream in the apoptotic cascade by both indirectly and directly regulating Bcl-2 family proteins. In cells expressing wild-type (WT) p53, the HDM2 protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell-cycle arrest. Here, we investigated the ability of the novel HDM2 inhibitor CGM097 to potently and selectively kill WT p53-expressing AML cells. The antileukemic effects of CGM097 were studied using cell-based proliferation assays (human AML cell lines, primary AML patient cells, and normal bone marrow samples), apoptosis, and cell-cycle assays, ELISA, immunoblotting, and an AML patient-derived in vivo mouse model. CGM097 potently and selectively inhibited the proliferation of human AML cell lines and the majority of primary AML cells expressing WT p53, but not mutant p53, in a target-specific manner. Several patient samples that harbored mutant p53 were comparatively unresponsive to CGM097. Synergy was observed when CGM097 was combined with FLT3 inhibition against oncogenic FLT3-expressing cells cultured both in the absence as well as the presence of cytoprotective stromal-secreted cytokines, as well as when combined with MEK inhibition in cells with activated MAPK signaling. Finally, CGM097 was effective in reducing leukemia burden in vivo. These data suggest that CGM097 is a promising treatment for AML characterized as harboring WT p53 as a single agent, as well as in combination with other therapies targeting oncogene-activated pathways that drive AML.
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. ellen_weisberg@dfci.harvard.edu james_griffin@dfci.harvard.edu.
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.affiliation: Novartis Institutes of Biomedical Research, Cambridge, Massachusetts.
authors.forename: Ensar
authors.initials: E
authors.lastname: Halilovic
authors.affiliation: Novartis Institutes of Biomedical Research, Cambridge, Massachusetts.
authors.forename: Vesselina G
authors.initials: VG
authors.lastname: Cooke
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nonami
authors.affiliation: National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Diseases Research, Harvard Medical School, Boston, Massachusetts.
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Sanda
authors.affiliation: Molecular Genetics Core, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Irene
authors.initials: I
authors.lastname: Simkin
authors.affiliation: Novartis Institutes of Biomedical Research, Cambridge, Massachusetts.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Novartis Institutes of Biomedical Research, Cambridge, Massachusetts.
authors.forename: Brandon
authors.initials: B
authors.lastname: Antonakos
authors.affiliation: Novartis Institutes of Biomedical Research, Basel, Switzerland.
authors.forename: Louise
authors.initials: L
authors.lastname: Barys
authors.affiliation: Novartis Institutes of Biomedical Research, Basel, Switzerland.
authors.forename: Moriko
authors.initials: M
authors.lastname: Ito
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kristen
authors.initials: K
authors.lastname: Cowens
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Erik
authors.initials: E
authors.lastname: Nelson
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Martin
authors.initials: M
authors.lastname: Sattler
authors.affiliation: Novartis Institutes of Biomedical Research, Basel, Switzerland.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jeay
authors.affiliation: Novartis Institutes of Biomedical Research, Basel, Switzerland.
authors.forename: Jens U
authors.initials: JU
authors.lastname: Wuerthner
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sean M
authors.initials: SM
authors.lastname: McDonough
authors.affiliation: Novartis Institutes of Biomedical Research, Basel, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. ellen_weisberg@dfci.harvard.edu james_griffin@dfci.harvard.edu.
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010671:Phenylurea Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D007546:Isoquinolines; C000602644:NVP-CGM097; D010671:Phenylurea Compounds; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C544967:quizartinib; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019311:Staurosporine; C059539:midostaurin