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Burgenske DM, Monsma DJ, Dylewski D, et al. Establishment of genetically diverse patient-derived xenografts of colorectal cancer. Am J Cancer Res. 2014;4(6):824-37
Burgenske, D. M., Monsma, D. J., Dylewski, D., Scott, S. B., Sayfie, A. D., Kim, D. G., Luchtefeld, M., Martin, K. R., Stephenson, P., Hostetter, G., Dujovny, N., & MacKeigan, J. P. (2014). Establishment of genetically diverse patient-derived xenografts of colorectal cancer. American journal of cancer research, 4(6), 824-37.
Burgenske, Danielle M, et al. "Establishment of genetically diverse patient-derived xenografts of colorectal cancer." American journal of cancer research vol. 4,6 (2014): 824-37.
Burgenske DM, Monsma DJ, Dylewski D, Scott SB, Sayfie AD, Kim DG, Luchtefeld M, Martin KR, Stephenson P, Hostetter G, Dujovny N, MacKeigan JP. Establishment of genetically diverse patient-derived xenografts of colorectal cancer. Am J Cancer Res. 2014 Nov 19;4(6):824-37. eCollection 2014. PMID: 25520871; PMCID: PMC4266715.
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Am J Cancer Res. 2014 Nov 19;4(6):824-37. eCollection 2014.

Establishment of genetically diverse patient-derived xenografts of colorectal cancer.

American journal of cancer research

Danielle M Burgenske, David J Monsma, Dawna Dylewski, Stephanie B Scott, Aaron D Sayfie, Donald G Kim, Martin Luchtefeld, Katie R Martin, Paul Stephenson, Galen Hostetter, Nadav Dujovny, Jeffrey P MacKeigan

Affiliations

  1. Laboratory of Systems Biology, Van Andel Research Institute Grand Rapids, MI 49503, USA ; Van Andel Institute Graduate School Grand Rapids, MI 49503, USA.
  2. Preclinical Therapeutics, Van Andel Research Institute Grand Rapids, MI 49503, USA.
  3. Laboratory of Systems Biology, Van Andel Research Institute Grand Rapids, MI 49503, USA.
  4. Ferguson-Blodgett Digestive Disease Institute, Spectrum Health Medical Group Grand Rapids, MI 49503, USA.
  5. Department of Statistics, Grand Valley State University Allendale, MI 49401, USA.
  6. Laboratory of Analytical Pathology, Van Andel Research Institute Grand Rapids, MI 49503, USA.

PMID: 25520871 PMCID: PMC4266715

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.

Keywords: AZD8055; BEZ235; PD0325901; Targeted therapies; colorectal cancer; patient-derived xenograft; translational models

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