Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

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 su...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research

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CONCLUSIONS: Our results indicated that miR-497 may serve as a predictor for PDAC and could be a novel target of PDAC treatment. PMID: 31957824 [PubMed - in process]
Source: European Review for Medical and Pharmacological Sciences - Category: Drugs & Pharmacology Tags: Eur Rev Med Pharmacol Sci Source Type: research
In this study, we showed that Laminin Subunit Beta 3 (LAMB3) was aberrantly overexpressed in PDAC and was closely associated with the overall survival rate of patients with PDAC. Functional studies demonstrated that LAMB3 played important roles in cell proliferation, the cell cycle, and invasion capacity. Using bioinformatics analysis, we determined that miR-24-3p was an upstream miRNA of LAMB3, and further experiments verified that miR-24-3p regulated LAMB3 expression in PDAC cells. A dual-luciferase reporter system demonstrated that miR-24-3p directly targeted the LAMB3 3'UTR, and FISH assay confirmed that miR-24-3p and ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions: These findings uncover a novel effect and mechanism of action of the antiplatelet drug ticagrelor in PDAC cells and suggest a multi-functional role for ADP-P2Y12 signalling in the tumour microenvironment.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Conditions:   Metastatic Pancreatic Adenocarcinoma;   Stage IV Pancreatic Cancer AJCC v8 Interventions:   Drug: Fluorouracil;   Drug: Gemcitabine;   Drug: Gemcitabine Hydrochloride;   Drug: Leucovorin;   Drug: Leucovorin Calcium;   Drug: Liposomal Irinotecan;   Drug: Nab-paclitaxel;   Other: Quality-of-Life Assessment;   Other: Questionnaire Administration Sponsors:   ECOG-ACRIN Cancer Research Group;   National Cancer Institute&nb...
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
rts Next-generation sequencing has led to the recent discovery of several novel pancreatic cancer susceptibility genes. These genes include ataxia telangiectasia mutated (ATM), a serine/threonine kinase that is an integral component of DNA repair. Pathogenic germline ATM variants are frequently identified in patients with pancreatic ductal adenocarcinoma (PDAC) with and without a family history of the disease. Loss of ATM is also a frequent somatic event in the development of PDAC. These discoveries have advanced our understanding of the genetic basis of pancreatic cancer risk and will impact patient care through appro...
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Review Source Type: research
Source: Cancer Management and Research - Category: Cancer & Oncology Tags: Cancer Management and Research Source Type: research
ConclusionsThe findings of this study provide evidence that FUT8 plays a pivotal role in PDAC invasion and metastasis and might be a therapeutic target for this disease.
Source: Surgery Today - Category: Surgery Source Type: research
I. E. Bruce Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to standard treatments leading to poor patient survival. The expression of plasma membrane calcium ATPase-4 (PMCA4) is reported to modulate key cancer hallmarks including cell migration, growth, and apoptotic resistance. Data-mining revealed that PMCA4 was over-expressed in pancreatic ductal adenocarcinoma (PDAC) tumors which correlated with poor patient survival. Western blot and RT-qPCR revealed that MIA PaCa-2 cells almost exclusively express PMCA4 making these a suitable cellular model of PDAC with poor patient survival. Knockdown of PMCA4 in ...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
CONCLUSIONS: Thus, these results indicated that SNHG14 expression acts as a prognostic maker for PDAC and potential target of PDAC treatment. PMID: 31929143 [PubMed - as supplied by publisher]
Source: Cancer Biomarkers - Category: Cancer & Oncology Tags: Cancer Biomark Source Type: research
Authors: Shang M, Zhang L, Chen X, Zheng S Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies without effective screening strategy during the early stage. Therefore, a novel screening panel was identified based on potential biomarkers associated with PDAC using the gene expression profile. The dataset GSE15471, which was downloaded from the Gene Expression Omnibus (GEO) database, included matching pairs of normal and tumor tissue samples from the resected pancreas of 39 pancreatic cancer patients. We used the online tool GEO2R to screen and pick out the differentially expressed ...
Source: Discovery Medicine - Category: Research Tags: Discov Med Source Type: research
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