title: A rationale for mTOR inhibitors as chemoprevention agents in Peutz-Jeghers syndrome.
abstract: Peutz-Jeghers patients frequently develop clinically significant complications, namely hemorrhage and bowel obstruction, from small intestinal hamartomatous polyps that frequently require surgery. In addition, many PJS patients develop epithelial malignancies in a variety of organs. The vast majority of PJS is due to germline alterations in the STK11 gene that encodes a protein that modulates PI3-kinase signaling, a key regulator of cell survival and growth. One of the major downstream mediators of PI3-kinase signaling is mTOR, the mammalian target of rapamycin. Several drugs that inhibit the PI3-kinase signal transduction pathway are in development and one, RAD001 (everolimus), an mTOR inhibitor, was recently approved for the treatment of renal cell carcinoma. Effective chemoprevention of intestinal polyps would be a first step in simplifying and improving the management of PJS patients. We present here, the rationale for the first human PJS chemoprevention trial using an mTOR inhibitor.
authors.affiliation: University of Hawaii, John A. Burns School of Medicine, Honolulu, HI, USA. skkuwada@hawaii.edu
authors.forename: Scott K
authors.initials: SK
authors.lastname: Kuwada
authors.forename: Randall
authors.initials: R
authors.lastname: Burt
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D010580:Peutz-Jeghers Syndrome / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases