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IP1867B suppresses the insulin-like growth factor 1 receptor (IGF1R) ablating epidermal growth factor receptor inhibitor resistance in adult high grade gliomas

2019Journal article Open access
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dc.contributor.authorMihajluk, K.
dc.contributor.authorSimms, C.
dc.contributor.authorReay, M.
dc.contributor.authorMadureira, Patricia A
dc.contributor.authorHowarth, A.
dc.contributor.authorMurray, P.
dc.contributor.authorNasser, S.
dc.contributor.authorDuckworth, C. A.
dc.contributor.authorPritchard, D. M.
dc.contributor.authorPilkington, G. J.
dc.contributor.authorHill, R.
dc.date.accessioned2020-07-24T10:53:15Z
dc.date.available2020-07-24T10:53:15Z
dc.date.issued2019
dc.description.abstractHigh grade gliomas (HGGs) are aggressive primary brain tumours with local invasive growth and poor clinical prognosis. Clinical outcome is compounded by resistance to standard and novel therapeutics. We have evaluated reformulated aspirin (IP1867B) alone and in combination with conventional and novel anti-aHGG agents. We show that recent biopsy-derived aHGG models were highly resistant to conventional therapeutics although show sensitivity to IP1867B, a reformulated "liquid" aspirin. IP186713 treatment mediated a potent suppression of the IL6/STAT3 and NF-kappa B pathways and observed a significant reduction in EGFR transcription and protein expression. We observed the loss of the insulin-like growth factor 1 and insulin-like growth factor 1 receptor expression at both the transcript and protein level post IP1867B treatment. This increased sensitivity to EGFR inhibitors. In vivo, IP1867B was very well tolerated, had little-to-no gastric lesions versus aspirin and, directed a significant reduction of tumour burden with suppression of EGFR, IGF1 and IGFR1. With EGFR inhibitors, we noted a potent synergistic response in aHGG cells. These data provide a rationale for further investigation of IP1867B with a number of anti-EGFR agents currently being evaluated in the clinic.
dc.description.sponsorshipBrain Tumour Research
dc.description.sponsorshipHeadcase Cancer Trust
dc.description.sponsorshipOllie Young Foundation
dc.description.sponsorshipFCT Investigator contract from the Foundation for Science and Technology (FCT), Portugal [IF/00614/2014]
dc.description.sponsorshipFCTPortuguese Foundation for Science and Technology [IF/00614/2014/CP12340006, UID/BIM/04773/2013CBMR1334]
dc.description.sponsorshipInnovate Pharmaceuticals
dc.identifier.doi10.1016/j.canlet.2019.05.028
dc.identifier.doi10.1016/j.canlet.2021.03.008
dc.identifier.issn0304-3835
dc.identifier.issn1872-7980
dc.identifier.urihttp://hdl.handle.net/10400.1/14471
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier
dc.relation.requireshttps://sapientia.ualg.pt/handle/10400.1/15462
dc.subjectCentral-nervous-system
dc.subjectGlioblastoma-multiforme
dc.subjectAdjuvant temozolomide
dc.subjectAspirin
dc.subjectSurvival
dc.subjectEgfr
dc.subjectConcomitant
dc.subjectRadiotherapy
dc.subjectTherapy
dc.subjectTumors
dc.titleIP1867B suppresses the insulin-like growth factor 1 receptor (IGF1R) ablating epidermal growth factor receptor inhibitor resistance in adult high grade gliomas
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage38
oaire.citation.startPage29
oaire.citation.titleCancer Letters
oaire.citation.volume458
person.familyNameMadureira
person.givenNamePatricia
person.identifier.ciencia-id6612-9A86-6929
person.identifier.orcid0000-0002-4856-3908
person.identifier.scopus-author-id10340140500
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublicationa40de6a3-d52d-45dd-8620-cb94a22ebc8f
relation.isAuthorOfPublication.latestForDiscoverya40de6a3-d52d-45dd-8620-cb94a22ebc8f

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