Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on the one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-l-norleucine [DON]). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cells. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM and an increased infiltration of CD8+ T cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy, resulting in tumor regression and prolonged survival.
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Recent advances have optimized DON as a pro-drug with pharmacokinetic properties that increase tumor targeting, including an orally available analog with promising preclinical results in murine PDAC models.
“recent advances have optimized DON as a pro-drug with pharmacokinetic properties that increase tumor targeting203, including an orally available analog with promising pre-clinical results in murine PDAC models204”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [204]
DON or its analogs in murine PDAC models appear to have immunomodulatory effects.
“recent studies have shown that the use of DON or analogs in murine PDAC models also appear to have immunomodulatory effects204,205”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [204]
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- Authors
- Sharma, N. S., Gupta, V. K., Garrido, V. T., Hadad, R., Durden, B. C., Kesh, K., Giri, B., Ferrantella, A., Dudeja, V., Saluja, A., & Banerjee, S.
- Affiliations
- University of Miami (US)
- Corresponding author
- Banerjee, Sulagna
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2019-12-03
- Volume
- 130
- Issue
- 1
- Pages
- 451-465
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6934212
- OpenAlex
- W2980538229
- Cited by
- 203
- References
- 73
- Citations by year
- 2026: 11 · 2025: 27 · 2024: 22 · 2023: 50 · 2022: 39 · 2021: 37 · 2020: 14 · 2019: 1 · 2018: 1
- FWCI
- 9.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH (R01-CA170946,to AS, R01-CA124723,to AS, R01- CA184274,to SB)
- Katherine and Robert Goodale foundation support (NA)
- Minneamrita Therapeutics LLC (NA)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Keywords
- pancreatic ductal adenocarcinoma, hexosamine biosynthetic pathway, 6-diazo-5-oxo-L-norleucine, anti-PD-1 therapy, immune checkpoint inhibitor resistance, hyaluronic acid, extracellular matrix remodeling, tumor microenvironment, CD8+ T cell infiltration, tumor self-renewal, metastasis, glutamine metabolism
- MeSH terms
- Animals, Diazooxonorleucine, Female, Hexosamines, Humans, Mice, Nude, Neoplasm Metastasis, Neoplasm Proteins, Pancreatic Neoplasms, CD8-Positive T-Lymphocytes, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Programmed Cell Death 1 Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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