esRAGE-expressing oHSV enhances anti-tumor efficacy by inhibition of endothelial cell activation

Swanner, Jessica; Shim, Ji Seon; Rivera-Caraballo, Kimberly; Vázquez-Arreguín, Karina; Hong, Bangxing; Bueso-Perez, Alberto J.; Lee, Tae Jin; Banasavadi-Siddegowda, Yeshavanth; Kaur, Balveen; Yoo, Ji Young

doi:10.1016/j.omto.2023.01.003

Cited by 3 publications

(1 citation statement)

References 47 publications

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“…The esRAGE have the same sequence as that of the sRAGE and have similar roles in the trapping of the AGEs, thereby attenuating the toxicity effects of the AGEs. esRAGE, as the decoy ligands for AGEs, regulate the endothelial permeability, and it was shown that the esRAGE-expressed oncolytic herpes simplex virus 1 (osHV), when released into the endothelial cells, enhanced the therapeutic efficacy in glioblastoma-bearing mice [ 57 ]. The sRAGE and esRAGE, because they lack the transmembrane region, act as decoy receptors for AGEs and various other ligands to the RAGE, and thereby attenuate the toxic effects of AGEs [ 58 ].…”

Section: Receptors For Advanced Glycation Endproducts (Rage)mentioning

confidence: 99%

RAGE Inhibitors in Neurodegenerative Diseases

2023

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Nonenzymatic reactions of reducing sugars with primary amino groups of amino acids, proteins, and nucleic acids, followed by oxidative degradations would lead to the formation of advanced glycation endproducts (AGEs). The AGEs exert multifactorial effects on cell damage leading to the onset of neurological disorders. The interaction of AGEs with the receptors for advanced glycation endproducts (RAGE) contribute to the activation of intracellular signaling and the expression of the pro-inflammatory transcription factors and various inflammatory cytokines. This inflammatory signaling cascade is associated with various neurological diseases, including Alzheimer’s disease (AD), secondary effects of traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and diabetic neuropathy, and other AGE-related diseases, including diabetes and atherosclerosis. Furthermore, the imbalance of gut microbiota and intestinal inflammation are also associated with endothelial dysfunction, disrupted blood–brain barrier (BBB) and thereby the onset and progression of AD and other neurological diseases. AGEs and RAGE play an important role in altering the gut microbiota composition and thereby increase the gut permeability and affect the modulation of the immune-related cytokines. The inhibition of the AGE–RAGE interactions, through small molecule-based therapeutics, prevents the inflammatory cascade of events associated with AGE–RAGE interactions, and thereby attenuates the disease progression. Some of the RAGE antagonists, such as Azeliragon, are currently in clinical development for treating neurological diseases, including AD, although currently there have been no FDA-approved therapeutics based on the RAGE antagonists. This review outlines the AGE–RAGE interactions as a leading cause of the onset of neurological diseases and the current efforts on developing therapeutics for neurological diseases based on the RAGE antagonists.

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Section: Receptors For Advanced Glycation Endproducts (Rage)mentioning

confidence: 99%

RAGE Inhibitors in Neurodegenerative Diseases

2023

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Impact of HMGB1 on cancer development and therapeutic insights focused on CNS malignancy

Patra,

Roy,

Dey

et al. 2024

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Targeting IGF2 to reprogram the tumor microenvironment for enhanced viro-immunotherapy

Noh,

Kang,

Miller

et al. 2024

Neuro-Oncology

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Background The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME). Methods RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance. Results Transcriptome analysis identified IGF2 as one of the top secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%) (p=0.0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8+cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice. Conclusion This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.

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esRAGE-expressing oHSV enhances anti-tumor efficacy by inhibition of endothelial cell activation

Cited by 3 publications

References 47 publications

RAGE Inhibitors in Neurodegenerative Diseases

RAGE Inhibitors in Neurodegenerative Diseases

Impact of HMGB1 on cancer development and therapeutic insights focused on CNS malignancy

Targeting IGF2 to reprogram the tumor microenvironment for enhanced viro-immunotherapy

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