Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex.

Amino Acid Sequence Apoptosis / drug effects Cell Line, Tumor Endocytosis / drug effects Endpoint Determination Gene Expression Regulation, Neoplastic / drug effects Humans Oleic Acids / chemistry Peptides / chemistry Placebos Protein Conformation Proton Magnetic Resonance Spectroscopy Thermodynamics Urinary Bladder Neoplasms / drug therapy

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
08 06 2021
Historique:
received: 08 04 2020
accepted: 15 04 2021
entrez: 9 6 2021
pubmed: 10 6 2021
medline: 16 6 2021
Statut: epublish

Résumé

Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.

Identifiants

DOI: 10.1038/s41467-021-23748-y PMID: 34103518 PMC: PMC8187399
pubmed: 34103518
doi: 10.1038/s41467-021-23748-y
pii: 10.1038/s41467-021-23748-y
pmc: PMC8187399
doi:

Substances chimiques

Oleic Acids 0
Peptides 0
Placebos 0

Banques de données

ClinicalTrials.gov
['NCT03560479']

Types de publication

Clinical Trial, Phase I Clinical Trial, Phase II Journal Article Randomized Controlled Trial Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3427

Commentaires et corrections

Type : CommentIn

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Auteurs

Antonín Brisuda (A)

Department of Urology, Motol University Hospital, 2nd Faculty of Medicine, Charles University Praha, Prague, Czech Republic.

James C S Ho (JCS)

Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden.
Centre for Biomimetic Sensor Science, Nanyang Technological University, Singapore, Singapore.
ORCID: 0000-0002-6131-1297

Pancham S Kandiyal (PS)

Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin, Ireland.

Justin T-Y Ng (JT)

School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.

Ines Ambite (I)

Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden.
ORCID: 0000-0003-1470-671X

Daniel S C Butler (DSC)

Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden.
ORCID: 0000-0002-6717-545X

Jaromir Háček (J)

Department of Pathology and Molecular Medicine, Motol University Hospital, 2nd Faculty of Medicine, Charles University Praha, Prague, Czech Republic.

Murphy Lam Yim Wan (MLY)

Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden.

Thi Hien Tran (TH)

Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden.

Aftab Nadeem (A)

Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden.

Tuan Hiep Tran (TH)

Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden.

Anna Hastings (A)

Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin, Ireland.
ORCID: 0000-0002-2236-1232

Petter Storm (P)

Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden.

Daniel L Fortunati (DL)

Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin, Ireland.

Parisa Esmaeili (P)

Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden.

Hana Novotna (H)

Department of Urology, Motol University Hospital, 2nd Faculty of Medicine, Charles University Praha, Prague, Czech Republic.

Jakub Horňák (J)

Department of Urology, Motol University Hospital, 2nd Faculty of Medicine, Charles University Praha, Prague, Czech Republic.

Y G Mu (YG)

School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
ORCID: 0000-0002-2499-026X

K H Mok (KH)

Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin, Ireland.
ORCID: 0000-0003-3663-2002

Marek Babjuk (M)

Department of Urology, Motol University Hospital, 2nd Faculty of Medicine, Charles University Praha, Prague, Czech Republic.

Catharina Svanborg (C)

Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden. catharina.svanborg@med.lu.se.
ORCID: 0000-0001-8145-0553

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Classifications MeSH

questionsmedicales.fr › Sciences de l'information › Sources d'information › Services d'information › Documentation › Données de séquences moléculaires › Séquence d'acides aminés › Bladder cancer therapy using a...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Bladder cancer therapy using a...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Bladder cancer therapy using a...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Endocytose › Bladder cancer therapy using a...
questionsmedicales.fr › Techniques d'investigation › Détermination du point final › Bladder cancer therapy using a...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Bladder cancer therapy using a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Bladder cancer therapy using a...
questionsmedicales.fr › Lipides › Acides gras › Acides gras insaturés › Acides gras monoinsaturés › Acides oléiques › Bladder cancer therapy using a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Bladder cancer therapy using a...
questionsmedicales.fr › Thérapeutique › Placebo › Bladder cancer therapy using a...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Bladder cancer therapy using a...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Analyse spectrale › Spectroscopie par résonance magnétique › Spectroscopie par résonance magnétique du proton › Bladder cancer therapy using a...
questionsmedicales.fr › Phénomènes physiques › Thermodynamique › Bladder cancer therapy using a...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Tumeurs urologiques › Tumeurs de la vessie urinaire › Bladder cancer therapy using a...