Selective EGLN Inhibition Enables Ablative Radiotherapy and Improves Survival in Unresectable Pancreatic Cancer

Fujimoto, Tara N.; Colbert, Lauren E.; Huang, Yanqing; Molkentine, Jessica M.; Deorukhkar, Amit; Baseler, Laura; Bonilla, Marimar de la Cruz; Yu, Meifang; Lin, Daniel; Gupta, Sonal; Cabeceiras, Peter K.; Kingsley, Charles V.; Tailor, Ramesh; Sawakuchi, Gabriel O.; Koay, Eugene J.; Piwnica‐Worms, Helen; Maitra, Anirban; Taniguchi, Cullen M.

doi:10.1158/0008-5472.can-18-1785

Cited by 28 publications

(21 citation statements)

References 45 publications

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“…However, recent studies showed an antitumor action of FG-4592 in macrophage-abundant tumors ( Nishide et al., 2019 ), and in human ovarian clear cell carcinoma ES2 cells ( Price et al., 2019 ). In another study, FG-4592 could selectively protect the intestinal tract from radiation toxicity without affecting pancreatic cancer ( Fujimoto et al., 2019 ). In our present study, we treated DOX-sensitive cells of HepG2 and MCF-7 with FG-4592 in combination with DOX for 24 h and found FG-4592 had no further effect on the reduced cell viability induced by DOX.…”

Section: Discussionmentioning

confidence: 99%

Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways

Long

Chen

et al. 2020

Front. Pharmacol.

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Doxorubicin (DOX) is broadly used in treating various malignant tumors. However, its cardiotoxicity limits its clinical use. Roxadustat (FG-4592) is a new hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor and has been approved for treating anemia in chronic kidney diseases (CKD) patients. However, the role of FG-4592 in DOX-induced cardiotoxicity remains unknown. In this study, mouse cardiac function was evaluated by echocardiography, plasma LDH/CK-MB, and heart HE staining. Cell viability, apoptosis, oxidative stress, inflammation, and HIF-target genes were evaluated in mouse cardiac tissue and cardiac cells exposed to DOX with FG-4592 pretreatment. DOX-sensitive HepG2 and MCF-7 cell lines were used to evaluate FG-4592 effect on the anticancer activity of DOX. We found that FG-4592 alleviated DOX-induced cardiotoxicity shown by the protection against cardiac dysfunction, cardiac apoptosis, and oxidative stress without the effect on inflammatory response. FG-4592 alone did not change the cardiac function, cardiomyocyte morphology, oxidative stress, and inflammation in vivo. FG-4592 could protect cardiomyocytes against DOX-induced apoptosis and ROS production in line with the upregulation of HIF-1a and its target genes of Bcl-2 and SOD2. Importantly, FG-4592 displayed anticancer property in cancer cells treated with or without DOX. These findings highlighted the protective effect of FG-4592 on DOX-induced cardiotoxicity possibly through upregulating HIF-1a and its target genes antagonizing apoptosis and oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways

Long

Chen

et al. 2020

Front. Pharmacol.

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“…Orthotopic pancreas injection. Orthotopic pancreatic injections were performed as previously described (49). Before surgery, animals were shaved around the surgical site to remove excess fur; 0.1 mg/kg extended release buprenorphine was given as an analgesic.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer

et al. 2019

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“…HIF-1a, the master regulator of hypoxia, modulates pathways that are vital to PDA carcinogenesis and has been correlated with poor patient survival (22)(23)(24)(25)(26). While the pro-tumorigenic effect of hypoxia in PDA cannot be contended, some studies have highlighted a tumor suppressor role for HIFs, implicating them in having a protective function against tumor formation (27)(28)(29)(30). It is important to note that such studies have focused on epithelial HIF expression, giving little credit to the impact of HIF signaling within the TME (31).…”

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confidence: 99%

An Eight-Gene Hypoxia Signature Predicts Survival in Pancreatic Cancer and Is Associated With an Immunosuppressed Tumor Microenvironment

et al. 2021

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Intratumoral hypoxia is a widely established element of the pancreatic tumor microenvironment (TME) promoting immune escape, tumor invasion, and progression, while contributing to treatment resistance and poor survival. Despite this critical role, hypoxia is underrepresented in molecular signatures of pancreatic ductal adenocarcinoma (PDA) and concurrent investigations into the hypoxia-immune status are lacking. In this work a literature-based approach was applied to derive an eight-gene hypoxia signature that was validated in fourteen cancer cell lines and in a cohort of PDA. The eight-gene hypoxia signature was significantly associated with overall survival in two distinct PDA datasets and showed independent prognostic value in multivariate analysis. Comparative analysis of tumors according to their hypoxia score (high versus low) determined that tumors with high hypoxia were significantly less enriched in cytotoxic T-cells, and cytolytic activity. In addition, they had lower expression of cytokines and tumor inflammatory markers, pointing to the signature’s ability to discern an immune “cold”, hypoxic TME. Combining the signature with an immune metric highlighted a worse survival probability in patients with high hypoxia and low immune reactivity, indicating that this approach could further refine survival estimates. Hypoxia as determined by our signature, was significantly associated with certain immune checkpoint inhibitors (ICI) biomarkers, suggesting that the signature reflects an aspect of the TME that is worth pursuing in future clinical trials. This is the first work of its kind in PDA, and our findings on the hypoxia-immune tumor contexture are not only relevant for ICI but could also guide combinatorial hypoxia-mediated therapeutic strategies in this cancer type.

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Selective EGLN Inhibition Enables Ablative Radiotherapy and Improves Survival in Unresectable Pancreatic Cancer

Abstract: The EGLN inhibitor FG-4592 reduces radiation toxicity to the GI tract, which enables definitive radiation treatments for pancreatic cancer.

Cited by 28 publications

References 45 publications

Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways

Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways

Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer

An Eight-Gene Hypoxia Signature Predicts Survival in Pancreatic Cancer and Is Associated With an Immunosuppressed Tumor Microenvironment

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