دورية أكاديمية
A Pilot Study of Sirolimus in Subjects with Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN .
| العنوان: | A Pilot Study of Sirolimus in Subjects with Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN . |
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| المؤلفون: | Komiya T; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA takefumi.komiya@parkview.com.; Parkview Cancer Institute, Wayne, Indiana, USA., Blumenthal GM; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., DeChowdhury R; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Fioravanti S; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Ballas MS; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.; GlaxoSmithKline, Philadelphia, Pennsylvania, USA., Morris J; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.; University of Cincinnati, Cincinnati, Ohio, USA., Hornyak TJ; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.; VA Medical Center, Baltimore, Maryland, USA., Wank S; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA., Hewitt SM; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Morrow B; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Memmott RM; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Rajan A; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Dennis PA; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.; AstraZeneca, Gaithersburg, Maryland, USA. |
| المصدر: | The oncologist [Oncologist] 2019 Dec; Vol. 24 (12), pp. 1510-e1265. Date of Electronic Publication: 2019 Jul 26. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Intramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 9607837 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1549-490X (Electronic) Linking ISSN: 10837159 NLM ISO Abbreviation: Oncologist Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2022- : Oxford : Oxford University Press Original Publication: Dayton, Ohio : AlphaMed Press, c1996- |
| مواضيع طبية MeSH: | Anti-Bacterial Agents/*therapeutic use , Hamartoma Syndrome, Multiple/*drug therapy , PTEN Phosphohydrolase/*genetics , Sirolimus/*therapeutic use, Adult ; Aged ; Anti-Bacterial Agents/pharmacology ; Female ; Germ-Line Mutation ; Humans ; Male ; Middle Aged ; Pilot Projects ; Sirolimus/pharmacology ; Young Adult |
| مستخلص: | Lessons Learned: This is the first human interventional study in patients with Cowden syndrome that is driven by inactivation of germline PTEN gene.Single-agent sirolimus, a mTOR inhibitor, suppressed mTOR signaling in surrogate human tissues without significant toxicity. Background: Cowden syndrome is characterized by inactivating germline PTEN mutations, which can lead to activation of the PI3K-Akt-mTOR pathway. Methods: Adult subjects with germline PTEN mutation who met international diagnostic criteria for Cowden syndrome and who had Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and adequate organ function were enrolled. Subjects were treated with a 56-day course of daily oral sirolimus. In addition to symptom assessment and physical examination, dermatologic, endoscopic, neurologic (cerebellar), and radiographic assessments were conducted. Inhibition of the mTOR pathway in benign skin and gastrointestinal (GI) lesion was assessed by immunohistochemistry. Results: A total of 18 patients and 16 families were enrolled. PTEN mutations were located at exons 1-8. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Neurological evaluation showed improvement in cerebellar function score at 1 month. Immunohistochemistry (IHC) analysis in skin and GI benign lesions showed a decrease in the ratio of phosphorylated (p)S6 to total S6 in response to sirolimus. Ratios of pS6K to total S6 at days 14 and 56 were significantly lower than at baseline ( p = .0026, p = .00391, respectively). A 56-day course of sirolimus was well tolerated. Conclusion: A 56-day course of sirolimus was well tolerated in subjects with Cowden syndrome and was associated with some evidence of improvement in symptoms, skin and GI lesions, cerebellar function, and decreased mTOR signaling. (© AlphaMed Press; the data published online to support this summary are the property of the authors.) |
| References: | Am J Hum Genet. 2011 Jan 7;88(1):42-56. (PMID: 21194675) Clin Cancer Res. 2012 Jan 15;18(2):400-7. (PMID: 22252256) Lancet Oncol. 2014 Dec;15(13):1513-1520. (PMID: 25456370) J Med Genet. 2004 May;41(5):323-6. (PMID: 15121767) N Engl J Med. 2011 Apr 28;364(17):1595-606. (PMID: 21410393) Am J Hum Genet. 2001 Oct;69(4):704-11. (PMID: 11536076) Methods. 2015 May;77-78:11-9. (PMID: 25461771) |
| سلسلة جزيئية: | ClinicalTrials.gov NCT00971789 |
| المشرفين على المادة: | 0 (Anti-Bacterial Agents) EC 3.1.3.67 (PTEN Phosphohydrolase) EC 3.1.3.67 (PTEN protein, human) W36ZG6FT64 (Sirolimus) |
| تواريخ الأحداث: | Date Created: 20190728 Date Completed: 20200901 Latest Revision: 20200901 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC6975943 |
| DOI: | 10.1634/theoncologist.2019-0514 |
| PMID: | 31350329 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1549-490X |
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| DOI: | 10.1634/theoncologist.2019-0514 |