title: Mechanistic evaluation of the novel HSP90 inhibitor NVP-AUY922 in adult and pediatric glioblastoma.
abstract: The dismal prognosis of glioblastoma (GB) indicates the urgent need for new therapies for these tumors. Heat shock protein 90 (HSP90) inhibitors induce the proteasome-mediated degradation of many oncogenic client proteins involved in all of the hallmark characteristics of cancer. Here, we explored the mechanistic potential of the potent synthetic diarylisoxazole amide resorcinol HSP90 inhibitor, NVP-AUY922, in adult and pediatric GB. In vitro antiproliferative potency (nanomolar range) was seen in both adult and pediatric human GB cell lines with different molecular pathologies. A cytostatic effect was observed in all GB lines; more apoptosis was observed at lower concentrations in the SF188 pediatric GB line and at 144 hours in the slower growing KNS42 pediatric GB line, as compared with the adult GB lines U87MG and SF268. In vitro combination studies with inhibitors of phosphoinositide 3-kinase/mammalian target of rapamycin (PI-103) or mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (PD-0325901) supported the hypothesis that sustained inhibition of ERK up to 72 hours and at least temporary inhibition of AKT were necessary to induce apoptosis in GB lines. In athymic mice bearing established s.c U87MG GB xenografts, NVP-AUY922 (50 mg/kg i.p x 3 days) caused the inhibition of ERK1/2 and AKT phosphorylation and induced apoptosis, whereas 17-AAG used at maximum tolerated dose was less effective. NVP-AUY922 antitumor activity with objective tumor regression resulted from antiproliferative, proapoptotic, and antiangiogenic effects, the latter shown by decreased microvessel density and HIF1alpha levels. Our results have established a mechanistic proof of concept for the potential of novel synthetic HSP90 inhibitors in adult and pediatric GB, alone or in combination with phosphoinositide 3-kinase/mammalian target of rapamycin and mitogen-activated protein/ERK kinase inhibitors.
authors.affiliation: Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaspar
authors.forename: Swee Y
authors.initials: SY
authors.lastname: Sharp
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Sharon
authors.initials: S
authors.lastname: Gowan
authors.forename: Sergey
authors.initials: S
authors.lastname: Popov
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.forename: Andrew
authors.initials: A
authors.lastname: Pearson
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D012118:Resorcinols / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols
references.citation: J Biol Chem. 2005 Apr 8;280(14):14349-55
references.pmid: 15699047
references.citation: Science. 2007 Oct 12;318(5848):287-90
references.pmid: 17872411
references.citation: Cell Cycle. 2004 Jan;3(1):51-60
references.pmid: 14657666
references.citation: J Cell Physiol. 2004 Dec;201(3):374-84
references.pmid: 15389545
references.citation: J Clin Oncol. 2007 Apr 1;25(10):1196-208
references.pmid: 17401009
references.citation: Assay Drug Dev Technol. 2007 Jun;5(3):391-401
references.pmid: 17638539
references.citation: Clin Cancer Res. 2009 Jun 15;15(12):4046-57
references.pmid: 19509149
references.citation: J Natl Cancer Inst. 1999 Nov 17;91(22):1940-9
references.pmid: 10564678
references.citation: Mol Carcinog. 2006 May;45(5):288-301
references.pmid: 16550610
references.citation: J Clin Oncol. 2005 Jun 20;23(18):4152-61
references.pmid: 15961763
references.citation: Bioorg Med Chem Lett. 2005 Jul 15;15(14):3338-43
references.pmid: 15955698
references.citation: J Cell Physiol. 2003 Aug;196(2):394-402
references.pmid: 12811834
references.citation: PLoS One. 2009;4(4):e5209
references.pmid: 19365568
references.citation: Cancer Res. 2001 May 15;61(10):4010-6
references.pmid: 11358819
references.citation: Oncologist. 2004;9(2):197-206
references.pmid: 15047924
references.citation: Biochem Biophys Res Commun. 2005 Sep 30;335(3):900-5
references.pmid: 16099423
references.citation: Cancer Res. 2002 Jan 1;62(1):200-7
references.pmid: 11782378
references.citation: Neuro Oncol. 2009 Apr;11(2):109-21
references.pmid: 18682579
references.citation: Mol Cancer Ther. 2006 Mar;5(3):522-32
references.pmid: 16546966
references.citation: Oncogene. 2005 May 26;24(23):3697-707
references.pmid: 15782129
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11318-22
references.pmid: 16844778
references.citation: Mol Cancer Ther. 2007 Jul;6(7):1909-19
references.pmid: 17620423
references.citation: Clin Cancer Res. 2007 Mar 15;13(6):1789-93
references.pmid: 17363534
references.citation: J Med Chem. 2008 Jan 24;51(2):196-218
references.pmid: 18020435
references.citation: Neoplasia. 2008 May;10(5):501-10
references.pmid: 18472967
references.citation: Br J Cancer. 1998;77(1):1-10
references.pmid: 9459138
references.citation: Bioessays. 2004 Mar;26(3):262-9
references.pmid: 14988927
references.citation: Cancer Res. 2009 Mar 1;69(5):1966-75
references.pmid: 19244114
references.citation: Cancer Res. 2008 Apr 15;68(8):2850-60
references.pmid: 18413753
references.citation: Lancet Oncol. 2009 May;10(5):459-66
references.pmid: 19269895
references.citation: Mol Cancer Ther. 2009 Dec;8(12):3369-78
references.pmid: 19952119
references.citation: Cell Cycle. 2009 Feb 1;8(3):443-53
references.pmid: 19177002
references.citation: Cancer Res. 2007 Apr 1;67(7):3239-53
references.pmid: 17409432
references.citation: Leukemia. 2008 Aug;22(8):1604-12
references.pmid: 18480838
references.citation: Ann N Y Acad Sci. 2007 Oct;1113:202-16
references.pmid: 17513464
references.citation: Biochem Pharmacol. 2007 May 15;73(10):1528-36
references.pmid: 17324379
references.citation: Curr Opin Pharmacol. 2008 Aug;8(4):370-4
references.pmid: 18644253
references.citation: Mol Cancer Ther. 2007 Apr;6(4):1198-211
references.pmid: 17431102
references.citation: Microvasc Res. 2009 Mar;77(2):96-103
references.pmid: 19118564
references.citation: Clin Cancer Res. 2008 Apr 15;14(8):2512; author reply 2513-4
references.pmid: 18413847
references.citation: Mol Carcinog. 2006 Jan;45(1):47-59
references.pmid: 16267832
references.citation: J Clin Oncol. 2005 Apr 1;23(10):2411-22
references.pmid: 15800333
references.citation: Int J Cancer. 2008 Jul 1;123(1):209-16
references.pmid: 18386816
references.citation: Pharmacol Rev. 2006 Sep;58(3):621-81
references.pmid: 16968952
references.citation: Cancer Res. 2002 Oct 1;62(19):5551-8
references.pmid: 12359767
references.citation: J Med Chem. 2005 Jun 30;48(13):4212-5
references.pmid: 15974572
references.citation: N Engl J Med. 2005 Nov 10;353(19):2012-24
references.pmid: 16282176
references.citation: Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25
references.pmid: 14685170
references.citation: Cancer Res. 2003 Jan 1;63(1):236-41
references.pmid: 12517803
references.citation: Cancer Res. 2001 May 15;61(10):4003-9
references.pmid: 11358818