title: eRapa restores a normal life span in a FAP mouse model.
abstract: Mutation of a single copy of the adenomatous polyposis coli (APC) gene results in familial adenomatous polyposis (FAP), which confers an extremely high risk for colon cancer. Apc(Min/+) mice exhibit multiple intestinal neoplasia (MIN) that causes anemia and death from bleeding by 6 months. Mechanistic target of rapamycin complex 1 (mTORC1) inhibitors were shown to improve Apc(Min/+) mouse survival when administered by oral gavage or added directly to the chow, but these mice still died from neoplasia well short of a natural life span. The National Institute of Aging Intervention Testing Program showed that enterically targeted rapamycin (eRapa) extended life span for wild-type genetically heterogeneous mice in part by inhibiting age-associated cancer. We hypothesized that eRapa would be effective in preventing neoplasia and extend survival of Apc(Min/+) mice. We show that eRapa improved survival of Apc(Min/+) mice in a dose-dependent manner. Remarkably, and in contrast to previous reports, most of the Apc(Min/+) mice fed 42 parts per million eRapa lived beyond the median life span reported for wild-type syngeneic mice. Furthermore, chronic eRapa did not cause detrimental immune effects in mouse models of cancer, infection, or autoimmunity, thus assuaging concerns that chronic rapamycin treatment suppresses immunity. Our studies suggest that a novel formulation (enteric targeting) of a well-known and widely used drug (rapamycin) can dramatically improve its efficacy in targeted settings. eRapa or other mTORC1 inhibitors could serve as effective cancer preventatives for people with FAP without suppressing the immune system, thus reducing the dependency on surgery as standard therapy.
authors.affiliation: 15355 Lambda Drive, San Antonio, TX 78145. Phone: 210-567-7226; Fax: 210-562-4161; E-mail: sharp@uthscsa.edu; Tyler J. Curiel, E-mail: curielt@uthscsa.edu; Paul Hasty, hastye@uthscsa.edu; Carolina B. Livi, Agilent Technologies, 5301 Stevens Creek Boulevard, Santa Clara, CA 95051. carolina.livi@Agilent.com, cblivi@gmail.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Hasty
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Livi
authors.forename: Sherry G
authors.initials: SG
authors.lastname: Dodds
authors.forename: Diane
authors.initials: D
authors.lastname: Jones
authors.forename: Randy
authors.initials: R
authors.lastname: Strong
authors.forename: Martin
authors.initials: M
authors.lastname: Javors
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Fischer
authors.forename: Lauren
authors.initials: L
authors.lastname: Sloane
authors.forename: Kruthi
authors.initials: K
authors.lastname: Murthy
authors.forename: Gene
authors.initials: G
authors.lastname: Hubbard
authors.forename: Lishi
authors.initials: L
authors.lastname: Sun
authors.forename: Vincent
authors.initials: V
authors.lastname: Hurez
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
authors.forename: Zelton Dave
authors.initials: ZD
authors.lastname: Sharp
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000517:prevention & control*; D000818:Animals; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D017491:Genes, APC; D007413:Intestinal Mucosa / Q000378:metabolism; D008136:Longevity; D000076222:Mechanistic Target of Rapamycin Complex 1; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D009368:Neoplasm Transplantation; D020123:Sirolimus / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus