Chemoprevention and treatment of experimental Cowden's disease by mTOR inhibition with rapamycin
- PMID: 18757421
- DOI: 10.1158/0008-5472.CAN-08-0922
Chemoprevention and treatment of experimental Cowden's disease by mTOR inhibition with rapamycin
Abstract
Cowden's disease is an autosomal dominant disorder characterized by the development of multiple mucocutaneous lesions and benign tumors, and enhanced cancer predisposition. Most Cowden's disease patients harbor inactivating mutations in the PTEN tumor suppressor gene which encodes a lipid phosphatase, PTEN, which restrains the phosphatidylinositol 3-kinase-Akt signaling pathway. We observed that the epithelial-specific deletion of Pten in mice causes multiple hyperproliferative and tumor lesions that strikingly resemble Cowden's disease. This animal model system provided an opportunity to explore novel therapeutic approaches in Cowden's disease. Indeed, we show here that rapamycin administration, which inhibits a key downstream _target of Akt, mammalian _target of rapamycin (mTOR), promotes the rapid regression of advanced mucocutaneous lesions. Furthermore, when administered before disease manifestation, rapamycin can halt the development of Cowden's disease-like lesions, thereby prolonging animal survival. These findings suggest that mTOR inhibition with rapamycin may represent a suitable therapeutic option for the chemoprevention and treatment of Cowden disease patients and others tumor syndromes that involve defective PTEN function.
Similar articles
-
Cowden's syndrome with immunodeficiency.J Med Genet. 2015 Dec;52(12):856-9. doi: 10.1136/jmedgenet-2015-103266. Epub 2015 Aug 5. J Med Genet. 2015. PMID: 26246517 Free PMC article.
-
Hamartoma-like lesions in the mouse retina: an animal model of Pten hamartoma tumour syndrome.Dis Model Mech. 2018 May 21;11(5):dmm031005. doi: 10.1242/dmm.031005. Dis Model Mech. 2018. PMID: 29716894 Free PMC article.
-
Primary lung adenocarcinoma occurring in a PTEN related syndrome (Cowden's disease): routine EGFR sequencing also highlights two rare somatic mutations S768I and V769L.Lung Cancer. 2013 Mar;79(3):318-20. doi: 10.1016/j.lungcan.2012.11.020. Epub 2012 Dec 20. Lung Cancer. 2013. PMID: 23261230
-
Mucocutaneous papillomatous papules in Cowden's syndrome.Clin Exp Dermatol. 2008 Mar;33(2):151-3. doi: 10.1111/j.1365-2230.2007.02602.x. Epub 2007 Nov 15. Clin Exp Dermatol. 2008. PMID: 18021272 Review.
-
Dysregulation of the mTOR pathway secondary to mutations or a hostile microenvironment contributes to cancer and poor wound healing.J Invest Dermatol. 2009 Mar;129(3):529-31. doi: 10.1038/jid.2008.441. J Invest Dermatol. 2009. PMID: 19209152 Review.
Cited by
-
PI3K/mTOR inhibitor PF-04691502 antitumor activity is enhanced with induction of wild-type TP53 in human xenograft and murine knockout models of head and neck cancer.Clin Cancer Res. 2013 Jul 15;19(14):3808-19. doi: 10.1158/1078-0432.CCR-12-2716. Epub 2013 May 2. Clin Cancer Res. 2013. PMID: 23640975 Free PMC article.
-
Chemoprevention in hereditary digestive neoplasia: A comprehensive review.Therap Adv Gastroenterol. 2023 Dec 1;16:17562848231215585. doi: 10.1177/17562848231215585. eCollection 2023. Therap Adv Gastroenterol. 2023. PMID: 38050626 Free PMC article. Review.
-
_targeting the biology of aging with mTOR inhibitors.Nat Aging. 2023 Jun;3(6):642-660. doi: 10.1038/s43587-023-00416-y. Epub 2023 May 4. Nat Aging. 2023. PMID: 37142830 Free PMC article. Review.
-
The skin: a mirror to the gut.Int J Colorectal Dis. 2013 Jul;28(7):889-913. doi: 10.1007/s00384-012-1637-x. Epub 2013 Jan 18. Int J Colorectal Dis. 2013. PMID: 23329214 Review.
-
Spatially distinct roles of class Ia PI3K isoforms in the development and maintenance of PTEN hamartoma tumor syndrome.Genes Dev. 2013 Jul 15;27(14):1568-80. doi: 10.1101/gad.216069.113. Genes Dev. 2013. PMID: 23873941 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous