Circulating tumor cells as a biomarker of response to treatment in patient-derived xenograft mouse models of pancreatic adenocarcinoma

PLoS One. 2014 Feb 19;9(2):e89474. doi: 10.1371/journal.pone.0089474. eCollection 2014.

Abstract

Circulating tumor cells (CTCs) are cells shed from solid tumors into circulation and have been shown to be prognostic in the setting of metastatic disease. These cells are obtained through a routine blood draw and may serve as an easily accessible marker for monitoring treatment effectiveness. Because of the rapid progression of pancreatic ductal adenocarcinoma (PDAC), early insight into treatment effectiveness may allow for necessary and timely changes in treatment regimens. The objective of this study was to evaluate CTC burden as a biomarker of response to treatment with a oral phosphatidylinositol-3-kinase inhibitor, BKM120, in patient-derived xenograft (PDX) mouse models of PDAC. PDX mice were randomized to receive vehicle or BKM120 treatment for 28 days and CTCs were enumerated from whole blood before and after treatment using a microfluidic chip that selected for EpCAM (epithelial cell adhesion molecule) positive cells. This microfluidic device allowed for the release of captured CTCs and enumeration of these cells via their electrical impedance signatures. Median CTC counts significantly decreased in the BKM120 group from pre- to post-treatment (26.61 to 2.21 CTCs/250 µL, p = 0.0207) while no significant change was observed in the vehicle group (23.26 to 11.89 CTCs/250 µL, p = 0.8081). This reduction in CTC burden in the treatment group correlated with tumor growth inhibition indicating CTC burden is a promising biomarker of response to treatment in preclinical models. Mutant enriched sequencing of isolated CTCs confirmed that they harbored KRAS G12V mutations, identical to the matched tumors. In the long-term, PDX mice are a useful preclinical model for furthering our understanding of CTCs. Clinically, mutational analysis of CTCs and serial monitoring of CTC burden may be used as a minimally invasive approach to predict and monitor treatment response to guide therapeutic regimens.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / blood
  • Adenocarcinoma / drug therapy*
  • Aminopyridines / therapeutic use
  • Animals
  • Antigens, Neoplasm / metabolism
  • Biomarkers / blood*
  • Cell Adhesion Molecules / metabolism
  • DNA Mutational Analysis
  • DNA Primers / genetics
  • Epithelial Cell Adhesion Molecule
  • Fluorescent Antibody Technique
  • Humans
  • Mice
  • Microfluidic Analytical Techniques
  • Morpholines / therapeutic use
  • Neoplastic Cells, Circulating*
  • Pancreatic Neoplasms / blood
  • Pancreatic Neoplasms / drug therapy*
  • Statistics, Nonparametric

Substances

  • Aminopyridines
  • Antigens, Neoplasm
  • Biomarkers
  • Cell Adhesion Molecules
  • DNA Primers
  • Epithelial Cell Adhesion Molecule
  • Morpholines
  • NVP-BKM120