Transport properties of pancreatic cancer describe gemcitabine delivery and response
Open accessAbstract
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).
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Radiomics and quantitative imaging studies have shown that enhancement and morphology of primary pancreatic tumours have biological underpinnings and clinical relevance.
“Other applications of radiomics and quantitative imaging approaches have shown that the enhancement and morphology of the primary tumours have biological underpinnings and clinical relevance,113–115”
From Early detection of pancreatic cancer (2020) · cites this paper as [115]
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- Authors
- Koay, E. J., Truty, M. J., Cristini, V., Thomas, R. M., Chen, R., Chatterjee, D., Kang, Y., Bhosale, P. R., Tamm, E. P., Crane, C. H., Javle, M., Katz, M. H., Gottumukkala, V. N., Rozner, M. A., Shen, H., Lee, J. E., Wang, H., Chen, Y., Plunkett, W., Abbruzzese, J. L., Wolff, R. A., Varadhachary, G. R., Ferrari, M., & Fleming, J. B.
- Affiliations
- Houston Methodist (US)
- University of Florida (US)
- The University of Texas MD Anderson Cancer Center (US)
- Duke University (US)
- Corresponding author
- Fleming, Jason B.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-03-10
- Volume
- 124
- Issue
- 4
- Pages
- 1525-1536
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3973100
- OpenAlex
- W2070252009
- Cited by
- 184
- References
- 42
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 4 · 2023: 10 · 2022: 13 · 2021: 22 · 2020: 17 · 2019: 15 · 2018: 17 · 2017: 26 · 2016: 17 · 2015: 21 · 2014: 8 · 2013: 1
- FWCI
- 11.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (1263742)
- U.S. Department of Defense (W81XWH, W81XWH0910212)
- Lustgarten Foundation (989161)
- National Institutes of Health (W81XWH)
- U.S. Public Health Service (K12 KCA088084)
- National Cancer Institute (U54CA151668, U54CA149196, U54CA143837, P30CA016672, K12CA088084)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › MRI in cancer diagnosis
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Keywords
- pancreatic ductal adenocarcinoma, gemcitabine, mass transport properties, contrast-enhanced CT, tumor stroma, hENT1, chemotherapy delivery, chemoradiotherapy, neoadjuvant chemoradiotherapy, pathological response, treatment response prediction
- MeSH terms
- Gemcitabine, Aged, Antimetabolites, Antineoplastic, Biological Transport, Active, Deoxycytidine, DNA, Neoplasm, Female, Humans, Male, Middle Aged, Models, Biological, Pancreatic Neoplasms, Prognosis, Prospective Studies, Tomography, X-Ray Computed, DNA Adducts, Carcinoma, Pancreatic Ductal, Equilibrative Nucleoside Transporter 1, Kaplan-Meier Estimate
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