Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.14279/19914
DC FieldValueLanguage
dc.contributor.authorEpenetos, Agamemnon-
dc.contributor.authorProkopi, Marianna-
dc.contributor.authorPitsillides, Costas-
dc.contributor.authorKapnisis, Konstantinos-
dc.contributor.authorDeonarain, Mahendra-
dc.contributor.authorKousparou, Christina-
dc.contributor.authorAnayiotos, Andreas-
dc.date.accessioned2021-02-16T09:03:27Z-
dc.date.available2021-02-16T09:03:27Z-
dc.date.issued2020-05-20-
dc.identifier.citationJournal of Clinical Oncology, 2020, vol.38 no.15en_US
dc.identifier.urihttps://hdl.handle.net/20.500.14279/19914-
dc.descriptionPresented in American Society of Clinical Oncology Annual Meeting, 2020en_US
dc.description.abstractNotch signalling is implicated in tumorigenesis prompting scientists to research and develop anti-Notch therapeutics. Drugging the Notch pathway has been a challenge due to severe G-I toxicity seen by many small-molecule inhibitors. Mastermind is a key nuclear factor that mediates Notch activity. We generated a novel protein drug, Syntana-4, that inhibits the Notch pathway at the Mastermind transcriptional level. Syntana-4 consists of the cell penetrating domain of Antennapedia, fused to a truncated peptide from Mastermind-like (MAML) that behaves in a dominant-negative fashion inhibiting Notch. Syntana-4 translocates into the cell nucleus, suppressing Notch activity and inducing apoptosis in Notch-driven cancer cells. Methods: We have conducted pharmacokinetics (PK), pharmacodynamics (PD) and toxicology studies, in combination with innovative imaging including in vivo flow cytometry and whole-body fluorescence reflectance imaging to define the behaviour of Syntana-4, determine its mode of action and establish a safety and efficacy profile in an orthotopic model of breast cancer in SCID mice based on the implantation of MDA-MB-231 cells into mammary fat pads. Samples of blood and tissues were examined for toxicity, apoptosis and immunogenicity. Results: We found that Syntana-4 was well-tolerated by normal cells and organs and was not immunogenic. Also, it was shown that free, non-internalized drug was rapidly cleared from the circulation. Whole body imaging showed that the drug in tissues was cleared within 24 hrs. Assessment of tumor growth demonstrated a reduction in tumor growth as evidenced by an overall increase of less than 50% in the intensity of fluorescence signal in the treated group compared to a 3-fold increase in signal and thus tumour size in untreated group by day 14. Conclusions: Syntana-4, a Mastermind inhibitor, was found to be well-tolerated and non-immunogenic in healthy animals. This drug targets the oncogenic Notch mechanism and can be applied across tumours with genetic defects in Notch signalling including breast, prostate, etc. We have demonstrated the utility of an innovative molecular imaging system emulating a clinical ‘phase I/II’ study in an orthotopic cancer model in order to measure the biodistribution, PK, PD, mode of action, toxicity and efficacy of a first-in-class biological therapy prior to entering the clinic. This innovative approach could be useful for accurate selection of lead drug candidates prior to entering clinical development.en_US
dc.formatpdfen_US
dc.language.isoenen_US
dc.relation.ispartofJournal of Clinical Oncologyen_US
dc.titleTumor response to a mastermind inhibitor proteinen_US
dc.typeArticleen_US
dc.collaborationSt Bartholomew's Hospitalen_US
dc.collaborationTheramir Ltden_US
dc.collaborationCyprus University of Technologyen_US
dc.collaborationAntikor Ltden_US
dc.collaborationNovartisen_US
dc.journalsSubscriptionen_US
dc.countryUnited Kingdomen_US
dc.countryCyprusen_US
dc.subject.fieldMedical and Health Sciencesen_US
dc.publicationPeer Revieweden_US
dc.identifier.doi10.1200/JCO.2020.38.15_suppl.e17601en_US
dc.relation.issue15_supplen_US
dc.relation.volume38en_US
cut.common.academicyear2020-2021en_US
dc.identifier.spagee17601en_US
item.grantfulltextnone-
item.openairecristypehttp://purl.org/coar/resource_type/c_6501-
item.fulltextNo Fulltext-
item.languageiso639-1en-
item.cerifentitytypePublications-
item.openairetypearticle-
crisitem.journal.journalissn1527-7755-
crisitem.journal.publisherAmerican Society of Clinical Oncology-
crisitem.author.deptDepartment of Mechanical Engineering and Materials Science and Engineering-
crisitem.author.deptDepartment of Mechanical Engineering and Materials Science and Engineering-
crisitem.author.deptDepartment of Mechanical Engineering and Materials Science and Engineering-
crisitem.author.deptDepartment of Mechanical Engineering and Materials Science and Engineering-
crisitem.author.facultyFaculty of Engineering and Technology-
crisitem.author.facultyFaculty of Engineering and Technology-
crisitem.author.facultyFaculty of Engineering and Technology-
crisitem.author.facultyFaculty of Engineering and Technology-
crisitem.author.orcid0000-0003-4123-3065-
crisitem.author.orcid0000-0002-4999-0231-
crisitem.author.orcid0000-0003-4471-7604-
crisitem.author.parentorgFaculty of Engineering and Technology-
crisitem.author.parentorgFaculty of Engineering and Technology-
crisitem.author.parentorgFaculty of Engineering and Technology-
crisitem.author.parentorgFaculty of Engineering and Technology-
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