ERapa restores a normal life span in a FAP mouse model

Paul Hasty, Carolina B. Livi, Sherry G. Dodds, Diane Jones, Randy Strong, Martin Javors, Kathleen E. Fischer, Lauren Sloane, Kruthi Murthy, Gene Hubbard, Lishi Sun, Vincent Hurez, Tyler J. Curiel, Zelton Dave Sharp

Research output: Contribution to journalArticle

39 Scopus citations

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. ApcMin/+ 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 ApcMin/+ 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 ApcMin/+ mice. We show that eRapa improved survival of ApcMin/+ 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.

Original languageEnglish (US)
Pages (from-to)169-178
Number of pages10
JournalCancer Prevention Research
Volume7
Issue number1
DOIs
StatePublished - Jan 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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