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.
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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

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Figure 2

Clinical trial of intraoperative gemcitabine.

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Clinical trial of intraoperative gemcitabine. (A) Trial design. Patients...
(A) Trial design. Patients were evaluated for appropriateness for resection before infusion of gemcitabine. Gemcitabine infusion was initiated at the start of resection (asterisk; 50–100 minutes prior to specimen removal, with time dependent on drug dose) and infused at a fixed rate (see Methods). Pathological analysis and quantitative assessment of gemcitabine incorporation were then performed. (B) Immediately after tumor resection, specimens were collected using standard surgical pathology techniques, and punch biopsies of the tumor and normal pancreas were taken to measure gemcitabine incorporation into DNA. (C) Blood samples were collected at regular intervals during the intraoperative infusion of gemcitabine, so that drug concentration could be measured by HPLC and intravascular pharmacokinetics could be analyzed. The similar slopes of the lines and the tight distribution of serum gemcitabine concentrations at each time point indicate that the infusion conditions were similar for all 12 trial patients. (D) DNA was extracted from tumor biopsy samples and analyzed for gemcitabine incorporation (measured relative to deoxyguanosine) into the DNA of pancreatic tumor cells. A positive value indicates more gemcitabine incorporation into the tumor compared with normal pancreas; a negative value indicates less. Marked variability was observed in the amount of gemcitabine incorporated for the 12 trial patients.