James Abbruzzese

Overview:

My research interests include the clinical study and treatment of pancreatic cancer.

Positions:

D. C. I. Professor of Medical Oncology

Medicine, Medical Oncology
School of Medicine

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Chief, Division of Medical Oncology

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1978

University of Chicago

Intern, Internal Medicine

Johns Hopkins University School of Medicine

Resident, Internal Medicine

Johns Hopkins University School of Medicine

Grants:

Preclinical and Human Correlative Studies of a Novel Bruton Tyronsine Kinase Inhibitor in Pancreatic Cancer

Administered By
Medicine, Medical Oncology
Awarded By
Department of Defense
Role
Co Investigator
Start Date
End Date

Topic Refinement, Task order 9 Topic Briefs

Administered By
Duke Clinical Research Institute
Awarded By
Patient Centered Outcomes Research Institute
Role
Co Investigator
Start Date
End Date

Publications:

Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet.

BACKGROUND & AIMS: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. METHODS: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. RESULTS: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression-a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival-only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. CONCLUSIONS: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.
Authors
Luo, Y; Yang, Y; Liu, M; Wang, D; Wang, F; Bi, Y; Ji, J; Li, S; Liu, Y; Chen, R; Huang, H; Wang, X; Swidnicka-Siergiejko, AK; Janowitz, T; Beyaz, S; Wang, G; Xu, S; Bialkowska, AB; Luo, CK; Pin, CL; Liang, G; Lu, X; Wu, M; Shroyer, KR; Wolff, RA; Plunkett, W; Ji, B; Li, Z; Li, E; Li, X; Yang, VW; Logsdon, CD; Abbruzzese, JL; Lu, W
MLA Citation
Luo, Yongde, et al. “Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet..” Gastroenterology, July 2019. Pubmed, doi:10.1053/j.gastro.2019.07.030.
URI
https://scholars.duke.edu/individual/pub1401549
PMID
31352001
Source
pubmed
Published In
Gastroenterology
Published Date
DOI
10.1053/j.gastro.2019.07.030

Measurement of Reactive Oxygen Species by Fluorescent Probes in Pancreatic Cancer Cells.

Pancreatic cancer is a highly lethal disease and is projected to become the second leading cause of cancer-related death by 2020. Among the different subtypes, pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. The genetic landscape of PDAC shows nearly ubiquitous mutations of KRAS. However, expression of KRAS somatic mutants alone is insufficient to drive PDAC. Redox deregulation may contribute significantly to KRAS-mediated PDAC. Thus, measurement of cellular reactive oxygen species (ROS) levels is essential to determine how oxidative stress affects mutant KRAS and modulates intracellular signaling pathways leading to the change of cellular functions and the development of PDAC. Here we describe the protocol for comparative measurement of several key forms of ROS, including intracellular and mitochondrial levels of superoxide as well as extracellular H2O2 and general cellular ROS, with oxidation-sensitive fluorescent probes using flow cytometry in pancreatic cancer cells or mutant KRAS transformed cells.
Authors
Luo, Y; Wang, D; Abbruzzese, JL; Lu, W
MLA Citation
Luo, Yongde, et al. “Measurement of Reactive Oxygen Species by Fluorescent Probes in Pancreatic Cancer Cells..” Methods Mol Biol, vol. 1882, 2019, pp. 207–19. Pubmed, doi:10.1007/978-1-4939-8879-2_19.
URI
https://scholars.duke.edu/individual/pub1357301
PMID
30378057
Source
pubmed
Published In
Methods Mol Biol
Volume
1882
Published Date
Start Page
207
End Page
219
DOI
10.1007/978-1-4939-8879-2_19

Interim Acute Toxicity Analysis and Surgical Outcomes of Neoadjuvant Gemcitabine/nab-Paclitaxel and Hypofractionated Image Guided Intensity Modulated Radiation Therapy in Resectable and Borderline Resectable Pancreatic Cancer (ANCHOR) Study

Authors
Palta, M; Czito, B; Abbruzzese, J; Uronis, H; Duffy, EA; Blazer, DT; Willett, CG
URI
https://scholars.duke.edu/individual/pub1236325
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Published Date
Start Page
S204
End Page
S205

Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer.

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.
Authors
Koay, EJ; Baio, FE; Ondari, A; Truty, MJ; Cristini, V; Thomas, RM; Chen, R; Chatterjee, D; Kang, Y; Zhang, J; Court, L; Bhosale, PR; Tamm, EP; Qayyum, A; Crane, CH; Javle, M; Katz, MH; Gottumukkala, VN; Rozner, MA; Shen, H; Lee, JE; Wang, H; Chen, Y; Plunkett, W; Abbruzzese, JL; Wolff, RA; Maitra, A; Ferrari, M; Varadhachary, GR; Fleming, JB
MLA Citation
Koay, Eugene J., et al. “Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer..” Phys Biol, vol. 11, no. 6, Nov. 2014. Pubmed, doi:10.1088/1478-3975/11/6/065002.
URI
https://scholars.duke.edu/individual/pub1051251
PMID
25427073
Source
pubmed
Published In
Physical Biology
Volume
11
Published Date
Start Page
065002
DOI
10.1088/1478-3975/11/6/065002

Clinicopathologic features and prognosis of duodenal adenocarcinoma and comparison with ampullary and pancreatic ductal adenocarcinoma.

Because of the rarity of duodenal adenocarcinoma (DAC), the clinicopathologic features and prognostication data for DAC are limited. There are no published studies directly comparing the prognosis of DAC to that of ampullary adenocarcinoma (AA) and of pancreatic ductal adenocarcinoma (PDA) after resection. In this study, we examined the clinicopathologic features of 68 patients with DAC, 92 patients with AA, and 126 patients with PDA who underwent resection. Patient clinicopathologic and survival information were extracted from medical records. Statistical analysis was performed using Statistical Package for the Social Sciences with 2-sided significance level of .05. Patients with DAC had higher American Joint Committee on Cancer (AJCC) stage than AA patients (P = .001). Lymph node metastasis (P = .013) and AJCC stage (P = .02) correlated with overall survival in DAC patients. Patients with DAC or AA had lower frequencies of lymph node metastasis and positive margin and better survival than those with PDA (P < .05). However, no differences in nodal metastasis, margin status, or survival were observed between DAC patients and those with AA. Our study showed that lymph node metastasis and AJCC stage are important prognostic factors for overall survival in DAC patients. Patients with DAC had less frequent nodal metastasis and better prognosis than those with PDA. There was no significant difference in prognosis between DAC and AA.
Authors
Zenali, M; Overman, MJ; Rashid, A; Broaddus, RB; Wang, H; Katz, MH; Fleming, JB; Abbruzzese, JL; Wang, H
MLA Citation
Zenali, Maryam, et al. “Clinicopathologic features and prognosis of duodenal adenocarcinoma and comparison with ampullary and pancreatic ductal adenocarcinoma..” Hum Pathol, vol. 44, no. 12, Dec. 2013, pp. 2792–98. Pubmed, doi:10.1016/j.humpath.2013.07.030.
URI
https://scholars.duke.edu/individual/pub1043369
PMID
24139211
Source
pubmed
Published In
Hum Pathol
Volume
44
Published Date
Start Page
2792
End Page
2798
DOI
10.1016/j.humpath.2013.07.030

Research Areas:

Adolescent
Adult
Age Distribution
Albumins
Animals
Blood Transfusion
Cell Differentiation
Cell Growth Processes
Cell Lineage
Cell Movement
Cell Transformation, Neoplastic
Chemotherapy, Adjuvant
Chi-Square Distribution
Child
Cisplatin
Clinical Competence
Combined Modality Therapy
Cytokines
DNA Repair
Diabetes Complications
Diabetes Mellitus, Type 2
Diagnosis, Differential
Disease Models, Animal
Disease-Free Survival
Drug Delivery Systems
Drug Therapy, Combination
Dyspnea
Epithelial Cells
False Positive Reactions
Fibrosis
Genetic Variation
Genotype
HEK293 Cells
HT29 Cells
Health Status
Homozygote
Hypothyroidism
Immunohistochemistry
Inflammation
Intercellular Signaling Peptides and Proteins
Islets of Langerhans
Isotope Labeling
Liver
Liver Neoplasms
Liver Neoplasms, Experimental
Lymph Nodes
Membrane Proteins
Mesoderm
Models, Biological
Mutation
Neoadjuvant Therapy
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplasm Proteins
Neoplasm Recurrence, Local
Neoplasm Staging
Neoplasms
Nervous System
Odds Ratio
Organoplatinum Compounds
Oxidative Stress
Pain
Pancreas
Pancreatectomy
Pancreatic Ducts
Pancreatic Neoplasms
Pancreaticoduodenectomy
Patient Care Team
Phenotype
Physicians
Polymorphism, Genetic
Probability
Prognosis
Proteolysis
Pyrimidines
Quinazolines
Radiation Tolerance
Radiotherapy, Adjuvant
Reactive Oxygen Species
Reference Values
Reproducibility of Results
Risk
Sensitivity and Specificity
Sepsis
Sex Distribution
Signal Transduction
Thiazoles
Time Factors
Treatment Outcome
Tumor Cells, Cultured
Tumor Markers, Biological
Water
Xenograft Model Antitumor Assays