title: Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma.
abstract: BACKGROUND
  Curative therapy for childhood sarcoma presents challenges when complete resection is not possible. Ionizing radiation (XRT) is used as a standard modality at diagnosis or recurrence for childhood sarcoma; however, local recurrence is still problematic. Most childhood sarcomas are TP53 wild type at diagnosis, although approximately 5-10% have MDM2 amplification or overexpression.
  
  
  METHODS
  The MDM2 inhibitor, RG7388, was examined alone or in combination with XRT (20Gy given in 2 Gy daily fractions) to immune-deficient mice bearing Rh18 (embryonal) or a total of 30 Gy in 2 Gy fractions to mice bearing Rh30 (alveolar) rhabdomyosarcoma xenografts. RG7388 was administered by oral gavage using two schedules (daily ×5; schedule 1 or once weekly; schedule 2). TP53-responsive gene products (p21, PUMA, DDB2, and MIC1) as well as markers of apoptosis were analyzed.
  
  
  RESULTS
  RG7388 showed no significant single agent antitumor activity. Twenty Grays XRT induced complete regressions (CR) of Rh18 with 100 percent tumor regrowth by week 7, but no tumor regrowth at 20 weeks when combined with RG7388. RG7388 enhanced time to recurrence combined with XRT in Rh30 xenografts compared to 30 Gy XRT alone. RG7388 did not enhance XRT-induced local skin toxicity. Combination treatments induced TP53 responsive genes more rapidly and to a greater magnitude than single agent treatments.
  
  
  CONCLUSIONS
  RG7388 enhanced the activity of XRT in both rhabdomyosarcoma models without increasing local XRT-induced skin toxicity. Changes in TP53-responsive genes were consistent with the synergistic activity of RG7388 and XRT in the Rh18 model.
authors.affiliation: Center for Childhood Cancer & Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio, 43205.
authors.forename: Doris
authors.initials: D
authors.lastname: Phelps
authors.affiliation: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute, Columbus, Ohio.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Bondra
authors.affiliation: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute, Columbus, Ohio.
authors.forename: Star
authors.initials: S
authors.lastname: Seum
authors.affiliation: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute, Columbus, Ohio.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chronowski
authors.affiliation: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute, Columbus, Ohio.
authors.forename: Justin
authors.initials: J
authors.lastname: Leasure
authors.affiliation: Center for Childhood Cancer & Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio, 43205.
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.affiliation: Hoffmann-La Roche, Inc., New York.
authors.forename: Steven
authors.initials: S
authors.lastname: Middleton
authors.affiliation: Department of Radiation Oncology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Dian
authors.initials: D
authors.lastname: Wang
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Center for Childhood Cancer & Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio, 43205.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011759:Pyrrolidines / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000532:radiotherapy*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D062366:para-Aminobenzoates / Q000627:therapeutic use*
chemical_list: D051017:Apoptosis Regulatory Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C496850:Ddb2 protein, mouse; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; C488588:PUMA protein, mouse; D011759:Pyrrolidines; C586849:RG7388; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D062366:para-Aminobenzoates; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2 inhibitor; childhood sarcoma; radiation treatment
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