title: Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy.
abstract: Based on clinical presentation, glioblastoma (GBM) is stratified into primary and secondary types. The protein 53 (p53) pathway is functionally incapacitated in most GBMs by distinctive type-specific mechanisms. To model human gliomagenesis, we used a GFAP-HRas(V12) mouse model crossed into the p53ER(TAM) background, such that either one or both copies of endogenous p53 is replaced by a conditional p53ER(TAM) allele. The p53ER(TAM) protein can be toggled reversibly in vivo between wild-type and inactive conformations by administration or withdrawal of 4-hydroxytamoxifen (4-OHT), respectively. Surprisingly, gliomas that develop in GFAP-HRas(V12);p53(+/KI) mice abrogate the p53 pathway by mutating p19(ARF)/MDM2 while retaining wild-type p53 allele. Consequently, such tumors are unaffected by restoration of their p53ER(TAM) allele. By contrast, gliomas arising in GFAP-HRas(V12);p53(KI/KI) mice develop in the absence of functional p53. Such tumors retain a functional p19(ARF)/MDM2-signaling pathway, and restoration of p53ER(TAM) allele triggers p53-tumor-suppressor activity. Congruently, growth inhibition upon normalization of mutant p53 by a small molecule, Prima-1, in human GBM cultures also requires p14(ARF)/MDM2 functionality. Notably, the antitumoral efficacy of p53 restoration in tumor-bearing GFAP-HRas(V12);p53(KI/KI) animals depends on the duration and frequency of p53 restoration. Thus, intermittent exposure to p53ER(TAM) activity mitigated the selective pressure to inactivate the p19(ARF)/MDM2/p53 pathway as a means of resistance, extending progression-free survival. Our results suggest that intermittent dosing regimes of drugs that restore wild-type tumor-suppressor function onto mutant, inactive p53 proteins will prove to be more efficacious than traditional chronic dosing by similarly reducing adaptive resistance.
authors.affiliation: Department of Pathology, Neurology, Neurological Surgery, and Pediatrics, Sandler Neurosciences Center, and Brain Tumor Research Center, University of California, San Francisco, CA 94158, USA. ksenya.shchors@epfl.ch
authors.forename: Ksenya
authors.initials: K
authors.lastname: Shchors
authors.forename: Anders I
authors.initials: AI
authors.lastname: Persson
authors.forename: Fanya
authors.initials: F
authors.lastname: Rostker
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Natalya
authors.initials: N
authors.lastname: Lyubynska
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Lamorna Brown
authors.initials: LB
authors.lastname: Swigart
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D006652:Histological Techniques; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; C016601:afimoxifene; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
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