Transport properties of pancreatic cancer describe gemcitabine delivery and response
Eugene J. Koay, … , Mauro Ferrari, Jason B. Fleming
Eugene J. Koay, … , Mauro Ferrari, Jason B. Fleming
Published March 10, 2014
Citation Information: J Clin Invest. 2014;124(4):1525-1536. https://doi.org/10.1172/JCI73455.
View: Text | PDF
Clinical Research and Public Health

Transport properties of pancreatic cancer describe gemcitabine delivery and response

Abstract

Background. The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy.

Methods. We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC.

Results. Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival.

Conclusion. Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints.

Trial registration. Clinicaltrials.gov NCT01276613.

Funding. Lustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).

Authors

Eugene J. Koay, Mark J. Truty, Vittorio Cristini, Ryan M. Thomas, Rong Chen, Deyali Chatterjee, Ya’an Kang, Priya R. Bhosale, Eric P. Tamm, Christopher H. Crane, Milind Javle, Matthew H. Katz, Vijaya N. Gottumukkala, Marc A. Rozner, Haifa Shen, Jeffery E. Lee, Huamin Wang, Yuling Chen, William Plunkett, James L. Abbruzzese, Robert A. Wolff, Gauri R. Varadhachary, Mauro Ferrari, Jason B. Fleming

×

Figure 3

Correlations between transport properties and gemcitabine incorporation.

Options: View larger image (or click on image) Download as PowerPoint
Correlations between transport properties and gemcitabine incorporation....
(A) Normalized gemcitabine incorporation for each patient on the clinical trial of intraoperative gemcitabine infusion during PDAC resection, measured using specimens obtained directly from the tumor (see Figure 2B). Surgical specimens were scored for hENT1 staining (see Supplemental Table 6). A significant difference was observed in the normalized gemcitabine incorporation when divided by hENT1 score (2-tailed t test; mean and SD indicated by short and long lines, respectively). (B) Stroma amount was scored independently by a pathologist, and gemcitabine incorporation in the tumor and normal pancreas were measured. After accounting for hENT1 score, a significant inverse correlation was seen with normalized gemcitabine incorporation (linear regression). (C) Pretherapy CTs of each patient in the clinical trial of intraoperative gemcitabine infusion during PDAC resection were derived, and the normalized CT-derived parameter AUC was plotted against the stromal scores from surgical pathology for the corresponding patient. A direct linear correlation was observed. (D) Normalized AUC was plotted against the measured gemcitabine (dFdC) incorporation into pancreatic tumor cell DNA (expressed relative to deoxyguanosine [dG]). A significant inverse correlation was observed (linear regression), in agreement with the inverse correlation found for the stromal score (B), which directly correlated with the normalized CT parameter AUC (C). The equation indicates how the CT parameter may be used to predict gemcitabine incorporation in future clinical trials.