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Transport properties of pancreatic cancer describe gemcitabine delivery and response.

ABSTRACT: 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.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.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.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.Clinicaltrials.gov NCT01276613.Lustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).

SUBMITTER: Koay EJ

PROVIDER: S-EPMC3973100 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Transport properties of pancreatic cancer describe gemcitabine delivery and response.

Koay Eugene J EJ Truty Mark J MJ Cristini Vittorio V Thomas Ryan M RM Chen Rong R Chatterjee Deyali D Kang Ya'an Y Bhosale Priya R PR Tamm Eric P EP Crane Christopher H CH Javle Milind M Katz Matthew H MH Gottumukkala Vijaya N VN Rozner Marc A MA Shen Haifa H Lee Jeffery E JE Wang Huamin H Chen Yuling Y Plunkett William W Abbruzzese James L JL Wolff Robert A RA Varadhachary Gauri R GR Ferrari Mauro M Fleming Jason B JB

The Journal of clinical investigation 20140310 4

<h4>Background</h4>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.<h4>Methods</h4>We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemci ...[more]

PMID: 24614108

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Project description:There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.

Project description:A clear contradiction exists between cytotoxic in-vitro studies demonstrating effectiveness of Gemcitabine to curtail pancreatic cancer and in-vivo studies failing to show Gemcitabine as an effective treatment. The outcome of chemotherapy in metastatic stages, where surgery is no longer viable, shows a 5-year survival <5%. It is apparent that in-vitro experiments, no matter how well designed, may fail to adequately represent the complex in-vivo microenvironmental and phenotypic characteristics of the cancer, including cell proliferation and apoptosis. We evaluate in-vitro cytotoxic data as an indicator of in-vivo treatment success using a mathematical model of tumor growth based on a dimensionless formulation describing tumor biology. Inputs to the model are obtained under optimal drug exposure conditions in-vitro. The model incorporates heterogeneous cell proliferation and death caused by spatial diffusion gradients of oxygen/nutrients due to inefficient vascularization and abundant stroma, and thus is able to simulate the effect of the microenvironment as a barrier to effective nutrient and drug delivery. Analysis of the mathematical model indicates the pancreatic tumors to be mostly resistant to Gemcitabine treatment in-vivo. The model results are confirmed with experiments in live mice, which indicate uninhibited tumor proliferation and metastasis with Gemcitabine treatment. By extracting mathematical model parameter values for proliferation and death from monolayer in-vitro cytotoxicity experiments with pancreatic cancer cells, and simulating the effects of spatial diffusion, we use the model to predict the drug response in-vivo, beyond what would have been expected from sole consideration of the cancer intrinsic resistance. We conclude that this integrated experimental/computational approach may enhance understanding of pancreatic cancer behavior and its response to various chemotherapies, and, further, that such an approach could predict resistance based on pharmacokinetic measurements with the goal to maximize effective treatment strategies.

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Transport properties of pancreatic cancer describe gemcitabine delivery and response.

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Transport properties of pancreatic cancer describe gemcitabine delivery and response.

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