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

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

Treatment sequencing for resectable pancreatic cancer: influence of early metastases and surgical complications on multimodality therapy completion and survival.

Barriers to multimodality therapy (MMT) completion among patients with resectable pancreatic adenocarcinoma include early cancer progression and postoperative major complications (PMC). We sought to evaluate the influence of these factors on MMT completion rates of patients treated with neoadjuvant therapy (NT) and surgery-first (SF) approaches. We evaluated all operable patients treated for clinically resectable pancreatic head adenocarcinoma at our institution from 2002 to 2007. Rates of MMT completion, 90-day PMC, and overall survival (OS) were evaluated. Ninety-five of 115 (83 %) NT and 29/50 (58 %) SF patients completed MMT. Patients who completed MMT lived longer than those who did not (36 vs. 11 months, p < 0.001). The most common reason that NT (11 %) and SF (26 %) patients failed to complete MMT was early disease progression. The rates of PMC among NT and SF patients were similar. Among SF patients, 69 % with no PMC completed MMT versus 29 % after PMC (p = 0.040). PMC were associated with decreased OS in SF patients but not in NT patients. The impact of early cancer progression and PMC upon completion of MMT is reduced by delivery of nonoperative therapies prior to pancreaticoduodenectomy. NT sequencing is a practical treatment strategy, particularly for patients at high biological or perioperative risk.
Authors
Tzeng, C-WD; Tran Cao, HS; Lee, JE; Pisters, PWT; Varadhachary, GR; Wolff, RA; Abbruzzese, JL; Crane, CH; Evans, DB; Wang, H; Abbott, DE; Vauthey, J-N; Aloia, TA; Fleming, JB; Katz, MHG
MLA Citation
Tzeng, Ching-Wei D., et al. “Treatment sequencing for resectable pancreatic cancer: influence of early metastases and surgical complications on multimodality therapy completion and survival..” J Gastrointest Surg, vol. 18, no. 1, Jan. 2014, pp. 16–24. Pubmed, doi:10.1007/s11605-013-2412-1.
URI
https://scholars.duke.edu/individual/pub1043368
PMID
24241967
Source
pubmed
Published In
J Gastrointest Surg
Volume
18
Published Date
Start Page
16
End Page
24
DOI
10.1007/s11605-013-2412-1

Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells.

PURPOSE: The most common genetic lesions in pancreatic ductal adenocarcinoma (PDAC) have been identified. However, significant gaps still exist in our understanding of how such genetic alterations act in concert to induce PDAC development. In this study, we investigated the mechanism of tumorigenic transformation in the immortalized human pancreatic ductal epithelial (HPDE) cell line by sequentially introducing PDAC signature alterations into this cell line. EXPERIMENTAL DESIGN: The phenotype for stable expression of mutant K-ras, Her2, p16/p14shRNA, and Smad4shRNA in HPDE cells was examined by assays for cell proliferation, migration, invasion, soft agar, and orthotopic tumorigenesis. The mechanisms of tumorigenic transformation were further explored by gene expression profiling and pathway analyses. RESULTS: The transformed cells exhibited enhanced proliferation, migration, and invasion, displayed anchorage-independent growth in soft agar, and grew orthotopic tumors with some histopathologic features of PDAC. We found that Smad4 played key roles in the tumorigenic transformation of HPDE cells. We further found that MDM2 and Bmi-1 were overexpressed in the tumorigenic HPDE cells and that Bmi-1 overexpression was regulated by Smad4. Ingenuity Pathway Analysis software analysis of microarray data revealed that dysregulation of integrin-linked kinase signaling and the cell cycle were the most significant changes involved in tumorigenic transformation. Altogether, this cell culture model closely recapitulated human pancreatic carcinogenesis from gene lesions, activation of specific signaling pathways, and some histopathologic features. CONCLUSION: The combination of activated K-ras and Her2 with inactivated p16/p14 and Smad4 was sufficient and essential to transform HPDE cells, thus revealing the potential tumorigenic mechanism.
Authors
Chang, Z; Li, Z; Wang, X; Kang, Y; Yuan, Y; Niu, J; Wang, H; Chatterjee, D; Fleming, JB; Li, M; Abbruzzese, JL; Chiao, PJ
MLA Citation
Chang, Zhe, et al. “Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells..” Clin Cancer Res, vol. 19, no. 3, Feb. 2013, pp. 549–59. Pubmed, doi:10.1158/1078-0432.CCR-12-0032.
URI
https://scholars.duke.edu/individual/pub1110133
PMID
23340292
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
19
Published Date
Start Page
549
End Page
559
DOI
10.1158/1078-0432.CCR-12-0032

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