James Abbruzzese

Overview:

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

Positions:

D. C. I. Distinguished 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

The 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

Pfizer - C4201002 - PF-07265807

Administered By
Duke Cancer Institute
Awarded By
Pfizer, Inc.
Role
Principal Investigator
Start Date
End Date

Publications:

A case report of microsatellite instability (MSI)-high, HER2 amplified pancreatic adenocarcinoma with central nervous system metastasis.

Pancreatic adenocarcinoma commonly presents as metastatic disease and harbors a dire prognosis due to its aggressive behavior, propensity for resistance to therapies, and lack of targetable driver mutations. Additionally, despite advances in other cancers, immunotherapy has been ineffective in this disease thus far and treatment remains centered around cytotoxic chemotherapy. Here, we present a case of a patient with pancreatic adenocarcinoma harboring both high microsatellite instability (MSI-H) and HER2 amplification. After an initial response to standard-of-care chemotherapy with FOLFIRINOX followed by progression, she was treated with dual immune checkpoint blockade, which resulted in a period of disease control. This was complicated by the development of autoimmune hypophysitis and an incidental finding of brain metastasis on magnetic resonance imaging (MRI). Her extracranial disease progressed while receiving stereotactic radiosurgery, with findings of lymphangitic spread in her lungs, and her treatment was changed to gemcitabine/nab-paclitaxel with trastuzumab. This resulted in a degree of extracranial disease control, though she experienced progressive brain metastases despite radiation and therapeutic switch to lapatinib and trastuzumab. Ultimately, the patient developed leptomeningeal disease which was not controlled by intrathecal trastuzumab. Given the rarity of central nervous system metastasis, HER2 amplification, and MSI in pancreatic cancer, this patient's presentation represents a confluence of multiple unique features. This case highlights the clinical value of up-front next-generation sequencing in metastatic pancreatic cancer and the ability of pancreatic cancer with actionable molecular variants to develop atypical sites of disease and adaptive resistance.
MLA Citation
DeVito, Nicholas C., et al. “A case report of microsatellite instability (MSI)-high, HER2 amplified pancreatic adenocarcinoma with central nervous system metastasis.Ame Case Rep, vol. 5, 2021, p. 14. Pubmed, doi:10.21037/acr-20-154.
URI
https://scholars.duke.edu/individual/pub1481212
PMID
33912803
Source
pubmed
Published In
Ame Case Rep
Volume
5
Published Date
Start Page
14
DOI
10.21037/acr-20-154

Targeting the IL-2 inducible kinase in melanoma; a phase 2 study of ibrutinib in systemic treatment-refractory distant metastatic cutaneous melanoma: preclinical rationale, biology, and clinical activity (NCI9922).

BACKGROUND: IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and its inhibition suppresses melanoma cell proliferation. We hypothesize that ibrutinib has a direct antitumor effect in melanoma cell lines and that treatment of metastatic melanomas with ibrutinib induces antitumor responses. METHODS: We assessed the ibrutinib effect on melanoma cell proliferation, apoptosis, and motility. Patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors (if BRAFV600-mutant) were treated with ibrutinib, 840 mg PO QD, as part of a phase II clinical trial (clinicaltrials.gov NCT02581930). RESULTS: Melanoma cell lines frequently express ITK, YES1, and EGFR. Ibrutinib suppressed cell motility and proliferation in most cell lines. Eighteen patients (13 male; median age 63.5 years, range 37-82; 12 with ipilimumab resistance) were enrolled. The most frequent side effects were fatigue (61%), anorexia (50%), hyponatremia (28%), nausea, and vomiting (22% each). No antitumor responses were seen. At a median follow-up of 6 months (0.3-35.8 months), the median progression-free survival was 1.3 months (range 0.2-5.5 months). Fifteen patients were discontinued from the study due to progression, and 14 patients had died from metastatic melanoma. All archived tumors expressed ITK, 41% had no expression of p16 and PTEN, and 61% had absent tumor-infiltrating lymphocytes (TILs). Ibrutinib significantly suppressed proliferating (Ki67+) CD19+ peripheral blood mononuclear cells and had no significant effect on other lymphocyte subsets. CONCLUSION: Ibrutinib did not induce any meaningful clinical benefit. ITK expression may not be clinically relevant. Treatment-refractory metastatic melanomas have other fundamental defects (i.e. absent PTEN and p16 expression, absent TILs) that may contribute to an adverse prognosis.
Authors
Moschos, SJ; Eroglu, Z; Khushalani, NI; Kendra, KL; Ansstas, G; In, GK; Wang, P; Liu, G; Collichio, FA; Googe, PB; Carson, CC; McKinnon, K; Wang, H-H; Nikolaishvilli-Feinberg, N; Ivanova, A; Arrowood, CC; Garrett-Mead, N; Conway, KC; Edmiston, SN; Ollila, DW; Serody, JS; Thomas, NE; Ivy, SP; Agrawal, L; Dees, EC; Abbruzzese, JL
MLA Citation
URI
https://scholars.duke.edu/individual/pub1476134
PMID
33661190
Source
pubmed
Published In
Melanoma Res
Volume
31
Published Date
Start Page
162
End Page
172
DOI
10.1097/CMR.0000000000000726

Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.

Oncogenic RAS is a critical driver for the initiation and progression of several types of cancers. However, effective therapeutic strategies by targeting RAS, in particular RASG12D and RASG12V, and associated downstream pathways have been so far unsuccessful. Treatment of oncogenic RAS-ravaged cancer patients remains a currently unmet clinical need. Consistent with a major role in cancer metabolism, oncogenic RAS activation elevates both reactive oxygen species (ROS)-generating NADPH oxidase (NOX) activity and ROS-scavenging glutathione biosynthesis. At a certain threshold, the heightened oxidative stress and antioxidant capability achieve a higher level of redox balance, on which cancer cells depend to gain a selective advantage on survival and proliferation. However, this prominent metabolic feature may irrevocably render cancer cells vulnerable to concurrent inhibition of both NOX activity and glutathione biosynthesis, which may be exploited as a novel therapeutic strategy. In this report, we test this hypothesis by treating the HRASG12V-transformed ovarian epithelial cells, mutant KRAS-harboring pancreatic and colon cancer cells of mouse and human origins, as well as cancer xenografts, with diphenyleneiodonium (DPI) and buthionine sulfoximine (BSO) combination, which inhibit NOX activity and glutathione biosynthesis, respectively. Our results demonstrate that concomitant targeting of NOX and glutathione biosynthesis induces a highly potent lethality to cancer cells harboring oncogenic RAS. Therefore, our studies provide a novel strategy against RAS-bearing cancers that warrants further mechanistic and translational investigation.
Authors
Liu, M; Wang, D; Luo, Y; Hu, L; Bi, Y; Ji, J; Huang, H; Wang, G; Zhu, L; Ma, J; Kim, E; Luo, CK; Abbruzzese, JL; Li, X; Yang, VW; Li, Z; Lu, W
MLA Citation
Liu, Muyun, et al. “Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.Cell Death Dis, vol. 12, no. 2, Feb. 2021, p. 189. Pubmed, doi:10.1038/s41419-021-03473-6.
URI
https://scholars.duke.edu/individual/pub1474663
PMID
33594044
Source
pubmed
Published In
Cell Death & Disease
Volume
12
Published Date
Start Page
189
DOI
10.1038/s41419-021-03473-6

Pancreatic Tumorigenesis: Oncogenic KRAS and the Vulnerability of the Pancreas to Obesity.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) mutations have been considered a critical driver of PDAC initiation and progression. However, the effects of mutant KRAS alone do not recapitulate the full spectrum of pancreatic pathologies associated with PDAC development in adults. Historically, mutant KRAS was regarded as constitutively active; however, recent studies have shown that endogenous levels of mutant KRAS are not constitutively fully active and its activity is still subject to up-regulation by upstream stimuli. Obesity is a metabolic disease that induces a chronic, low-grade inflammation called meta-inflammation and has long been recognized clinically as a major modifiable risk factor for pancreatic cancer. It has been shown in different animal models that obesogenic high-fat diet (HFD) and pancreatic inflammation promote the rapid development of mutant KRAS-mediated PDAC with high penetrance. However, it is not clear why the pancreas with endogenous levels of mutant KRAS is vulnerable to chronic HFD and inflammatory challenges. Recently, the discovery of fibroblast growth factor 21 (FGF21) as a novel anti-obesity and anti-inflammatory factor and as a downstream target of mutant KRAS has shed new light on this problem. This review is intended to provide an update on our knowledge of the vulnerability of the pancreas to KRAS-mediated invasive PDAC in the context of challenges engendered by obesity and associated inflammation.
Authors
Luo, Y; Li, X; Ma, J; Abbruzzese, JL; Lu, W
MLA Citation
Luo, Yongde, et al. “Pancreatic Tumorigenesis: Oncogenic KRAS and the Vulnerability of the Pancreas to Obesity.Cancers (Basel), vol. 13, no. 4, Feb. 2021. Pubmed, doi:10.3390/cancers13040778.
URI
https://scholars.duke.edu/individual/pub1474557
PMID
33668583
Source
pubmed
Published In
Cancers
Volume
13
Published Date
DOI
10.3390/cancers13040778

A randomized multi-center phase 2 study of combined PD-L1/CTLA-4 inhibition with or without radiation in non-small cell lung cancer patients who progressed on PD-(L)1 directed therapy: ETCTN 10021

Authors
Monjazeb, A; Giobbie-Hurder, A; Lako, A; Awad, M; Gentzler, R; Lee, C; Hubbard, J; Abbruzzese, J; Jabbour, S; Uboha, N; Stephans, K; Johnson, J; Park, H; Villaruz, L; Kao, K; Sharon, E; Raben, D; Mak, R; Streicher, H; Chen, H; Ahmed, M; Rodig, S; Hodi, FS; Schoenfeld, J
URI
https://scholars.duke.edu/individual/pub1422595
Source
wos
Published In
Journal for Immunotherapy of Cancer
Volume
7
Published Date

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