Pancreatic Tumor Transport Properties Affect Gemcitabine Uptake and Efficacy

Structural abnormalities in solid tumors, including disorganized or leaky blood vessels, increased stromal density, or dysfunctional transport proteins, can alter mass transport properties and thereby impair delivery of therapeutic agents. Hypothesizing that such physical features may negatively affect the delivery and effectiveness of the nucleoside analogue gemcitabine in patients with pancreatic ductal adenocarcinoma (PDAC), Koay and colleagues developed a computed tomography (CT)–based mathematical model describing mass transport based on properties of the pancreatic tissue and surrounding vasculature in 176 pretherapy pancreatic CT scans and determined whether tumor transport properties were associated with gemcitabine incorporation in a first-in-kind prospective clinical trial in which 12 patients with PDAC received gemcitabine intravenously during curative surgical resection. Overall, tumors showed reduced transport compared with normal pancreatic tissues, and among 110 patients who had received gemcitabine-based therapy and had evaluable pretherapy CT scans, decreased transport was associated with poor response to therapy and reduced overall survival. In the 12 patients enrolled in the trial, gemcitabine incorporation in both normal and malignant pancreatic tissue was highly variable, with structural features at both the cellular and molecular levels influencing gemcitabine uptake; after controlling for expression of equilibrative nucleoside transporter 1 (ENT1), which transports gemcitabine across the cell membrane, gemcitabine incorporation inversely correlated with the amount of stroma. Moreover, as predicted, the mass transport parameters derived by applying the mathematical model to the patients' pretherapy CT scans were correlated with the tumor stromal score and inversely correlated with gemcitabine incorporation. Although further studies are needed to assess whether CT-determined transport parameters are predictive of gemcitabine incorporation and efficacy, these results suggest that the structural features and transport properties of PDAC determine gemcitabine effectiveness and provide a rationale for integration of mass transport analysis into diagnostic testing.

Koay EJ, Truty MJ, Cristini V, Thomas RM, Chen R, Chatterjee D, et al. Transport properties of pancreatic cancer describe gemcitabine delivery and response. J Clin Invest 2014;124:1525–36.

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