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Τίτλος: Tumor response to a mastermind inhibitor protein
Συγγραφείς: Epenetos, Agamemnon 
Prokopi, Marianna 
Pitsillides, Costas 
Kapnisis, Konstantinos 
Deonarain, Mahendra 
Kousparou, Christina 
Anayiotos, Andreas 
Major Field of Science: Medical and Health Sciences
Ημερομηνία Έκδοσης: 20-Μαΐ-2020
Πηγή: Journal of Clinical Oncology, 2020, vol.38 no.15
Volume: 38
Issue: 15_suppl
Start page: e17601
Περιοδικό: Journal of Clinical Oncology 
Περίληψη: Notch 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.
Description: Presented in American Society of Clinical Oncology Annual Meeting, 2020
URI: https://hdl.handle.net/20.500.14279/19914
DOI: 10.1200/JCO.2020.38.15_suppl.e17601
Type: Article
Affiliation: St Bartholomew's Hospital 
Theramir Ltd 
Cyprus University of Technology 
Antikor Ltd 
Novartis 
Publication Type: Peer Reviewed
Εμφανίζεται στις συλλογές:Άρθρα/Articles

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