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Citations to this article

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 Article has an altmetric score of 44

Transport properties of pancreatic cancer describe gemcitabine delivery and response

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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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Establishment of a human primary pancreatic cancer mouse model to examine and investigate gemcitabine resistance
YJ Zhang, CL Wen, YX Qin, XM Tang, MM Shi, BY Shen, Y Fang
Oncology reports 2017
EUS-guided fine-needle injection of gemcitabine for locally advanced and metastatic pancreatic cancer
MJ Levy, SR Alberts, WR Bamlet, PA Burch, MB Farnell, FC Gleeson, MG Haddock, ML Kendrick, AL Oberg, GM Petersen, N Takahashi, ST Chari
Gastrointestinal Endoscopy 2017
Matrix control of pancreatic cancer: New insights into fibronectin signaling
M Topalovski, RA Brekken
Cancer Letters 2016
Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer
PP Adiseshaiah, RM Crist, SS Hook, SE McNeil
Nature Reviews Clinical Oncology 2016
Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release
H Hosoya, AS Dobroff, WH Driessen, V Cristini, LM Brinker, FI Staquicini, M Cardó-Vila, S DAngelo, F Ferrara, B Proneth, YS Lin, DR Dunphy, P Dogra, MP Melancon, RJ Stafford, K Miyazono, JG Gelovani, K Kataoka, CJ Brinker, RL Sidman, W Arap, R Pasqualini
Proceedings of the National Academy of Sciences 2016
Conformity analysis to demonstrate reproducibility of target volumes for Margin-Intense Stereotactic Radiotherapy for borderline-resectable pancreatic cancer
DL Holyoake, M Robinson, D Grose, D McIntosh, D Sebag-Montefiore, G Radhakrishna, N Patel, M Partridge, S Mukherjee, MA Hawkins
Radiotherapy and Oncology 2016
Isolation of Pancreatic Cancer Cells from a Patient-Derived Xenograft Model Allows for Practical Expansion and Preserved Heterogeneity in Culture
K Pham, D Delitto, AE Knowlton, ER Hartlage, R Madhavan, DH Gonzalo, RM Thomas, KE Behrns, TJ George, SJ Hughes, SM Wallet, C Liu, JG Trevino
The American Journal of Pathology 2016
Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill
Z Wang, R Kerketta, YL Chuang, P Dogra, JD Butner, TA Brocato, A Day, R Xu, H Shen, E Simbawa, AS AL-Fhaid, SR Mahmoud, SA Curley, M Ferrari, EJ Koay, V Cristini, DD Bernardo
PLoS computational biology 2016
Redirecting Transport of Nanoparticle Albumin-Bound Paclitaxel to Macrophages Enhances Therapeutic Efficacy against Liver Metastases
T Tanei, F Leonard, X Liu, JF Alexander, Y Saito, M Ferrari, B Godin, K Yokoi
Cancer research 2016
STAT3 Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer
NS Nagathihalli, JA Castellanos, C Shi, Y Beesetty, ML Reyzer, R Caprioli, X Chen, AJ Walsh, MC Skala, HL Moses, NB Merchant
Gastroenterology 2015
Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression
J Lee, S Condello, B Yakubov, R Emerson, A Caperell-Grant, K Hitomi, J Xie, D Matei
Clinical cancer research 2015
Nicotine Reduces Survival via Augmentation of Paracrine HGF-MET Signaling in the Pancreatic Cancer Microenvironment
D Delitto, D Zhang, S Han, BS Black, AE Knowlton, AC Vlada, GA Sarosi, KE Behrns, RM Thomas, X Lu, C Liu, TJ George, SJ Hughes, SM Wallet, JG Trevino
Clinical cancer research 2015
Pancreatic cancer and FOLFIRINOX: a new era and new questions
RD Marsh, MS Talamonti, MH Katz, JM Herman
Cancer Medicine 2015
Integrated PK-PD and agent-based modeling in oncology
Z Wang, JD Butner, V Cristini, TS Deisboeck
Journal of Pharmacokinetics and Pharmacodynamics 2015
Blockade of dual-specificity phosphatase 28 decreases chemo-resistance and migration in human pancreatic cancer cells
J Lee, JH Yun, J Lee, C Choi, JH Kim
Scientific Reports 2015
Zidovudine, an anti-viral drug, resensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibition of the Akt-GSK3β-Snail pathway
T Namba, R Kodama, S Moritomo, T Hoshino, T Mizushima
Cell Death and Disease 2015
Predictive Modeling of Drug Response in Non-Hodgkin’s Lymphoma
HB Frieboes, BR Smith, Z Wang, M Kotsuma, K Ito, A Day, B Cahill, C Flinders, SM Mumenthaler, P Mallick, E Simbawa, AS AL-Fhaid, SR Mahmoud, SS Gambhir, V Cristini, C Cinti
PloS one 2015
The inflammatory milieu within the pancreatic cancer microenvironment correlates with clinicopathologic parameters, chemoresistance and survival
D Delitto, BS Black, HL Sorenson, AE Knowlton, RM Thomas, GA Sarosi, LL Moldawer, KE Behrns, C Liu, TJ George, JG Trevino, SM Wallet, SJ Hughes
BMC Cancer 2015
MicroRNA Profiling Implies New Markers of Gemcitabine Chemoresistance in Mutant p53 Pancreatic Ductal Adenocarcinoma
SA Dhayat, WA Mardin, J Seggewiß, AJ Ströse, C Matuszcak, R Hummel, N Senninger, ST Mees, J Haier, M Fernandez-Zapico
PloS one 2015
Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models
M DAronzo, M Vinciguerra, T Mazza, C Panebianco, C Saracino, SP Pereira, P Graziano, V Pazienza
Oncotarget 2015
Quantitative imaging to evaluate malignant potential of IPMNs
AN Hanania, LE Bantis, Z Feng, H Wang, EP Tamm, MH Katz, A Maitra, EJ Koay
Oncotarget 2015
Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer
EJ Koay, FE Baio, A Ondari, MJ Truty, V Cristini, RM Thomas, R Chen, D Chatterjee, Y Kang, J Zhang, L Court, PR Bhosale, EP Tamm, A Qayyum, CH Crane, M Javle, MH Katz, VN Gottumukkala, MA Rozner, H Shen, JE Lee, H Wang, Y Chen, W Plunkett, JL Abbruzzese, RA Wolff, A Maitra, M Ferrari, GR Varadhachary, JB Fleming
Physical Biology 2014
Development of a sampling-based global sensitivity analysis workflow for multiscale computational cancer models
Z Wang, V Cristini, TS Deisboeck
IET Systems Biology 2014
Development of a Diffusion-Based Mathematical Model for Predicting Chemotherapy Effects
Wang Z, Kerketta R, Chuang YL, Cristini V
2014
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2009

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