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:

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:

Imaging & Biomarker Correlates on Outcomes in a Phase II Trial of Neoadjuvant Gemcitabine/Nab-Paclitaxel and Hypofractionated Image-Guided Radiotherapy (HIGRT) in Potentially Resectable Pancreas Cancer

Authors
Kent, CL; Marin, D; Niedzwiecki, D; Stephens, SJ; Duffy, E; Malicki, M; Abbruzzese, J; Uronis, H; Blobe, G; Blazer, DG; Czito, B; Willett, CG; Palta, M
MLA Citation
Kent, C. L., et al. “Imaging & Biomarker Correlates on Outcomes in a Phase II Trial of Neoadjuvant Gemcitabine/Nab-Paclitaxel and Hypofractionated Image-Guided Radiotherapy (HIGRT) in Potentially Resectable Pancreas Cancer.” International Journal of Radiation Oncology*Biology*Physics, vol. 105, no. 1, Elsevier BV, 2019, pp. E238–39. Crossref, doi:10.1016/j.ijrobp.2019.06.2014.
URI
https://scholars.duke.edu/individual/pub1415201
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
105
Published Date
Start Page
E238
End Page
E239
DOI
10.1016/j.ijrobp.2019.06.2014

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, vol. 157, no. 5, Nov. 2019, pp. 1413-1428.e11. Pubmed, doi:10.1053/j.gastro.2019.07.030.
URI
https://scholars.duke.edu/individual/pub1401549
PMID
31352001
Source
pubmed
Published In
Gastroenterology
Volume
157
Published Date
Start Page
1413
End Page
1428.e11
DOI
10.1053/j.gastro.2019.07.030

Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk.

The liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) pathway has been identified as a new target for cancer therapy, because it controls the glucose and lipid metabolism in response to alterations in nutrients and intracellular energy levels. In the present study, we aimed to identify genetic variants of the LKB1-AMPK pathway genes and their associations with pancreatic cancer (PanC) risk using 15 418 participants of European ancestry from two previously published PanC genome-wide association studies. We found that six novel tagging single-nucleotide polymorphisms (SNPs) (i.e, MAP2 rs35075084 T > deletion, PRKAG2 rs2727572 C > T and rs34852782 A > deletion, TP53 rs9895829 A > G, and RPTOR rs62068300 G > A and rs3751936 G > C) were significantly associated with an increased PanC risk. The multivariate logistic regression model incorporating the number of unfavorable genotypes (NUGs) with adjustment for age and sex showed that carriers with five to six NUGs had an increased PanC risk (odds ratio = 1.24, 95% confidence interval = 1.16-1.32 and P < 0.0001), compared to those with zero to four NUGs. Subsequent expression quantitative trait loci (eQTL) analysis further revealed that these SNPs were associated with significantly altered mRNA expression levels either in 373 normal lymphoblastoid cell lines (TP53 SNP rs9895829, P < 0.05) or in whole blood cells of 369 normal donors from the genotype-tissue expression project (GTEx) database [RPTOR SNP rs60268947 and rs28434589, both in high linkage disequilibrium (r2  > 0.9) withRPTOR rs62068300, P < 0.001]. Collectively, our findings suggest that these novel SNPs in the LKB1-AMPK pathway genes may modify susceptibility to PanC, possibly by influencing gene expression.
Authors
Xu, X; Qian, D; Liu, H; Cruz, D; Luo, S; Walsh, KM; Abbruzzese, JL; Zhang, X; Wei, Q
MLA Citation
Xu, Xinyuan, et al. “Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk..” Mol Carcinog, vol. 58, no. 8, Aug. 2019, pp. 1338–48. Pubmed, doi:10.1002/mc.23018.
URI
https://scholars.duke.edu/individual/pub1381281
PMID
30997723
Source
pubmed
Published In
Molecular Carcinogenesis
Volume
58
Published Date
Start Page
1338
End Page
1348
DOI
10.1002/mc.23018

Preoperative Therapy and Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma: a 25-Year Single-Institution Experience.

BACKGROUND: The purpose of this study was to evaluate a single-institution experience with delivery of preoperative therapy to patients with pancreatic ductal adenocarcinoma (PDAC) prior to pancreatoduodenectomy (PD). METHODS: Consecutive patients (622) with PDAC who underwent PD following chemotherapy and/or chemoradiation between 1990 and 2014 were retrospectively reviewed. Preoperative treatment regimens, clinicopathologic characteristics, operative details, and long-term outcomes in four successive time periods (1990-1999, 2000-2004, 2005-2009, 2010-2014) were evaluated and compared. RESULTS: The average number of patients per year who underwent PD following preoperative therapy as well as the proportion of operations performed for borderline resectable and locally advanced (BR/LA) tumors increased over time. The use of induction systemic chemotherapy, as well as postoperative adjuvant chemotherapy, also increased over time. Throughout the study period, the mean EBL decreased while R0 margin rates and vascular resection rates increased overall. Despite the increase in BR/LA resections, locoregional recurrence (LR) rates remained similar over time, and overall survival (OS) improved significantly (median 24.1, 28.1, 37.3, 43.4 months, respectively, p < 0.0001). CONCLUSIONS: Despite increases in case complexity, relatively low rates of LR have been maintained while significant improvements in OS have been observed. Further improvements in patient outcomes will likely require disruptive advances in systemic therapy.
Authors
Cloyd, JM; Katz, MHG; Prakash, L; Varadhachary, GR; Wolff, RA; Shroff, RT; Javle, M; Fogelman, D; Overman, M; Crane, CH; Koay, EJ; Das, P; Krishnan, S; Minsky, BD; Lee, JH; Bhutani, MS; Weston, B; Ross, W; Bhosale, P; Tamm, EP; Wang, H; Maitra, A; Kim, MP; Aloia, TA; Vauthey, J-N; Fleming, JB; Abbruzzese, JL; Pisters, PWT; Evans, DB; Lee, JE
MLA Citation
Cloyd, Jordan M., et al. “Preoperative Therapy and Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma: a 25-Year Single-Institution Experience..” J Gastrointest Surg, vol. 21, no. 1, Jan. 2017, pp. 164–74. Pubmed, doi:10.1007/s11605-016-3265-1.
URI
https://scholars.duke.edu/individual/pub1150915
PMID
27778257
Source
pubmed
Published In
J Gastrointest Surg
Volume
21
Published Date
Start Page
164
End Page
174
DOI
10.1007/s11605-016-3265-1

Cyclopamine-loaded core-cross-linked polymeric micelles enhance radiation response in pancreatic cancer and pancreatic stellate cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Cyclopamine (CPA), a potent inhibitor for sonic hedgehog pathway (SHH), shows great promises in PDAC treatment, including the disruption of tumor-associated stroma, and enhancement of radiation therapy. However, CPA is insoluble in water and therefore requires a nanometric delivery platform to achieve satisfactory performance. We herein encapsulated CPA in a core-cross-linked polymeric micelle system (M-CPA). M-CPA was combined with Cs-137 radiation and evaluated in vitro in PDAC cell lines and a human pancreatic stellate cell line. The results showed that M-CPA had higher cytotoxicity than CPA, abolished Gli-1 expression (a key component of SHH), and enhanced the radiation therapy of Cs-137. M-CPA radiosensitization correlated with its ability to disrupt the repair of radiation-induced DNA damage. These findings indicate that the combination therapy of M-CPA and radiation is an effective strategy to simultaneously treat pancreatic tumors and tumor-associated stroma.
Authors
Zhao, J; Wu, C; Abbruzzese, J; Hwang, RF; Li, C
MLA Citation
Zhao, Jun, et al. “Cyclopamine-loaded core-cross-linked polymeric micelles enhance radiation response in pancreatic cancer and pancreatic stellate cells..” Mol Pharm, vol. 12, no. 6, June 2015, pp. 2093–100. Pubmed, doi:10.1021/mp500875f.
URI
https://scholars.duke.edu/individual/pub1072931
PMID
25936695
Source
pubmed
Published In
Mol Pharm
Volume
12
Published Date
Start Page
2093
End Page
2100
DOI
10.1021/mp500875f

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