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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 4 Pg. 1525-36 (Apr 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 24614108 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antimetabolites, Antineoplastic
• DNA Adducts
• DNA, Neoplasm
• Equilibrative Nucleoside Transporter 1
• SLC29A1 protein, human
• Deoxycytidine
• Gemcitabine

Topics

• Aged
• Antimetabolites, Antineoplastic (administration & dosage, pharmacokinetics, therapeutic use)
• Biological Transport, Active
• Carcinoma, Pancreatic Ductal (diagnostic imaging, drug therapy, metabolism)
• DNA Adducts (metabolism)
• DNA, Neoplasm (metabolism)
• Deoxycytidine (administration & dosage, analogs & derivatives, pharmacokinetics, therapeutic use)
• Equilibrative Nucleoside Transporter 1 (metabolism)
• Female
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Models, Biological
• Pancreatic Neoplasms (diagnostic imaging, drug therapy, metabolism)
• Prognosis
• Prospective Studies
• Tomography, X-Ray Computed
• Gemcitabine