The DOI matches its Crossref record; 73 of the 73 references it cites were found in a registry or an index.
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 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]
In the citing paper
“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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Cites
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PD-1 blockade induces responses by inhibiting adaptive immune resistance
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“the tumor improves response to anti-PD1 therapy (65).”
BackgroundOlive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., Madhu, B., Goldgraben, M. A., Caldwell, M. E., Allard, D., et al. (2009) · Science · doi:10.1126/science.1171362 · Cited by 3,170
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Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma
Rhim, A. D., Oberstein, P. E., Thomas, D. H., Mirek, E. T., Palermo, C. F., Sastra, S. A., Dekleva, E. N., Saunders, T., Becerra, C. P., Tattersall, I. W., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.04.021 · Cited by 2,085
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043
Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway
Son, J., Lyssiotis, C. A., Ying, H., Wang, X., Hua, S., Ligorio, M., Perera, R. M., Ferrone, C. R., Mullarky, E., Shyh-Chang, N., et al. (2013) · Nature · doi:10.1038/nature12040 · Cited by 1,990
Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
Weinberg, F., Hamanaka, R., Wheaton, W. W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G. M., Budinger, G. R. S., & Chandel, N. S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003428107 · Cited by 1,742
Glutamine and cancer: cell biology, physiology, and clinical opportunities
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Cited by
Sorted by citations
Items 201–204 of 204
Piao, J., Yang, J., Li, Y., Yi, Y. A. N. G., Li, Z., Jin, G., Chai, J., & Wang, C. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2026.151492
Wei, C., Sun, H., Long, J., Liu, X., Li, Q., & Cao, B. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.117308
Metadata
- 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
- 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
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