MTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion
| Autor: | Henry Taylor, Marta C. Cohen, Stephan Buderus, Charis Eng, Isabel Rojas, Kevin Sweet, Peter Dale, Natalia Nedelkopoulou, Victor L. Fox, Claudia Phen, Inés Loverdos, Holm H. Uhlig, Tim G. J. de Meij, Jürgen Heise, Isabel Spier, Dilay Yerlioglu, Stefan Aretz, Emmanuel Mas, Veronica Busoni, Mike Thomson, Antje Ballauff |
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| Přispěvatelé: | Imperial College London, Istanbul University, University of Texas Southwestern Medical Center [Dallas], Helios Klinikum Krefeld - Helios Klinikum Krefeld, Sheffield Children's NHS Foundation Trust, University Hospital Bonn, University of Barcelona, Italian Hospital of Buenos Aires, Helios Klinikum [Erfurt], Royal Gwent Hospital, Vrije Universiteit Amsterdam [Amsterdam] (VU), Ohio State University [Columbus] (OSU), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Case Western Reserve University [Cleveland], Cleveland Clinic, Gemeinnützige Gesellschaft der Franziskanerinnen zu Olpe mbH (GFO), University of Oxford [Oxford], NIHR Oxford Biomedical Research Centre, Pediatric surgery, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Reproduction & Development (AR&D) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
AcademicSubjects/SCI01140
03 medical and health sciences 0302 clinical medicine Neoplastic Syndromes Hereditary Genetics medicine [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] PTEN Humans Enteropathy Juvenile polyposis syndrome [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Molecular Biology Genetics (clinical) PI3K/AKT/mTOR pathway Bone Morphogenetic Protein Receptors Type I Colectomy 030304 developmental biology 0303 health sciences Everolimus biology Intestinal Polyposis TOR Serine-Threonine Kinases PTEN Phosphohydrolase General Medicine MTOR Inhibitors medicine.disease BMPR1A 3. Good health 030220 oncology & carcinogenesis Sirolimus biology.protein Cancer research General Article Haploinsufficiency Gastrointestinal Hemorrhage [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology medicine.drug |
| Zdroj: | Taylor, H, Yerlioglu, D, Phen, C, Ballauff, A, Nedelkopoulou, N, Spier, I, Loverdos, I, Busoni, V B, Heise, J R, Dale, P, de Meij, T, Sweet, K, Cohen, M C, Fox, V L, Mas, E, Aretz, S, Eng, C, Buderus, S, Thomson, M, Rojas, I & Uhlig, H H 2021, ' MTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion ', Human Molecular Genetics, vol. 30, no. 14, pp. 1273-1282 . https://doi.org/10.1093/hmg/ddab094 Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2021, 30 (14), pp.1273-1282. ⟨10.1093/hmg/ddab094⟩ Human Molecular Genetics, 30(14), 1273-1282. Oxford University Press |
| ISSN: | 0964-6906 1460-2083 |
| Popis: | Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07–0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase–AKT–mTOR pathway mitigates the detrimental synergistic effects of combined PTEN–BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome. Graphical Abstract Graphical Abstract |
| Databáze: | OpenAIRE |
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