title: Establishment of genetically diverse patient-derived xenografts of colorectal cancer.
abstract: Preclinical compounds tested in animal models often show limited efficacy when transitioned into human clinical trials. As a result, many patients are stratified into treatment regimens that have little impact on their disease. In order to create preclinical models that can more accurately predict tumor responses, we established patient-derived xenograft (PDX) models of colorectal cancer (CRC). Surgically resected tumor specimens from colorectal cancer patients were implanted subcutaneously into athymic nude mice. Following successful establishment, fourteen models underwent further evaluation to determine whether these models exhibit heterogeneity, both at the cellular and genetic level. Histological review revealed properties not found in CRC cell lines, most notably in overall architecture (predominantly columnar epithelium with evidence of gland formation) and the presence of mucin-producing cells. Custom CRC gene panels identified somatic driver mutations in each model, and therapeutic efficacy studies in tumor-bearing mice were designed to determine how models with known mutations respond to PI3K, mTOR, or MAPK inhibitors. Interestingly, MAPK pathway inhibition drove tumor responses across most models tested. Noteworthy, the MAPK inhibitor PD0325901 alone did not significantly mediate tumor response in the context of a KRAS(G12D) model, and improved tumor responses resulted when combined with mTOR inhibition. As a result, these genetically diverse models represent a valuable resource for preclinical efficacy and drug discovery studies.
authors.affiliation: Laboratory of Systems Biology, Van Andel Research Institute Grand Rapids, MI 49503, USA ; Van Andel Institute Graduate School Grand Rapids, MI 49503, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Burgenske
authors.affiliation: Preclinical Therapeutics, Van Andel Research Institute Grand Rapids, MI 49503, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Monsma
authors.affiliation: Preclinical Therapeutics, Van Andel Research Institute Grand Rapids, MI 49503, USA.
authors.forename: Dawna
authors.initials: D
authors.lastname: Dylewski
authors.affiliation: Preclinical Therapeutics, Van Andel Research Institute Grand Rapids, MI 49503, USA.
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Scott
authors.affiliation: Laboratory of Systems Biology, Van Andel Research Institute Grand Rapids, MI 49503, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Sayfie
authors.affiliation: Ferguson-Blodgett Digestive Disease Institute, Spectrum Health Medical Group Grand Rapids, MI 49503, USA.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Kim
authors.affiliation: Ferguson-Blodgett Digestive Disease Institute, Spectrum Health Medical Group Grand Rapids, MI 49503, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Luchtefeld
authors.affiliation: Laboratory of Systems Biology, Van Andel Research Institute Grand Rapids, MI 49503, USA.
authors.forename: Katie R
authors.initials: KR
authors.lastname: Martin
authors.affiliation: Department of Statistics, Grand Valley State University Allendale, MI 49401, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Stephenson
authors.affiliation: Laboratory of Analytical Pathology, Van Andel Research Institute Grand Rapids, MI 49503, USA.
authors.forename: Galen
authors.initials: G
authors.lastname: Hostetter
authors.affiliation: Ferguson-Blodgett Digestive Disease Institute, Spectrum Health Medical Group Grand Rapids, MI 49503, USA.
authors.forename: Nadav
authors.initials: N
authors.lastname: Dujovny
authors.affiliation: Laboratory of Systems Biology, Van Andel Research Institute Grand Rapids, MI 49503, USA ; Van Andel Institute Graduate School Grand Rapids, MI 49503, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: MacKeigan
keywords: AZD8055; BEZ235; PD0325901; Targeted therapies; colorectal cancer; patient-derived xenograft; translational models