Browsing by Author "Kpenu, Eyram K."

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    Combating PDAC Drug Resistance: The Role of Ref-1 Inhibitors in Accelerating Progress in Pancreatic Cancer Research
    (Elsevier, 2024) Kpenu, Eyram K.; Kelley, Mark R.; Pediatrics, School of Medicine
    Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most lethal solid tumor diagnoses given its limited treatment options and dismal prognosis. Its complex tumor microenvironment (TME), heterogeneity, and high propensity for drug resistance are major obstacles in developing effective therapies. Here, we highlight the critical role of Redox effector 1 (Ref-1) in PDAC progression and drug resistance, focusing on its redox regulation of key transcription factors (TFs) such as STAT3, HIF1α, and NF-κB, which are pivotal for tumor survival, proliferation, and immune evasion. We discuss the development of novel Ref-1 inhibitors, including second-generation compounds with enhanced potency and improved pharmacokinetic profiles, which have shown significant promise in preclinical models. These inhibitors disrupt Ref-1’s redox function, leading to decreased TF activity and increased chemosensitivity in PDAC cells. We further detail our utilization of advanced preclinical models, such as 3D spheroids, organoids, and Tumor-Microenvironment-on-Chip (T-MOC) systems, which better simulate the complex conditions of the PDAC TME and improve the predictive power of therapeutic responses. By targeting Ref-1 and its associated pathways, in conjunction with improved models, more replicative of PDAC’s TME, we are focused on approaches which hold the potential to overcome current therapeutic limitations and advance the development of more effective treatments for PDAC. Our findings suggest that integrating Ref-1 inhibitors into combination therapies could disrupt multiple survival mechanisms within the tumor, offering new hope for improving outcomes in this challenging cancer.
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    Ref‐1 redox activity regulates retinal neovascularization by modulating transcriptional activation of HIF‐1α
    (Wiley, 2025) Hartman, Gabriella D.; Muniyandi, Anbukkarasi; Sishtla, Kamakshi; Kpenu, Eyram K.; Miller, William P.; Kaplan, Bryan A.; Kim, Leo A.; Liu, Sheng; Wan, Jun; Qi, Xiaoping; Boulton, Michael E.; Kelley, Mark R.; Corson, Timothy W.; Ophthalmology, School of Medicine
    Retinal neovascularization impairs visual function and is a hallmark of several neovascular eye diseases, including retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Current treatments include intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, but these therapeutics are often accompanied by high treatment burden and resistance to therapy. Prior studies indicate that APE1/Ref-1, a multifunctional protein with both endonuclease (APE1) and redox-mediated transcriptional regulatory activity (Ref-1), activates multiple pro-angiogenic and pro-inflammatory signaling pathways by chemically reducing key cysteine residues in transcription factors, thereby activating them. Here, we investigated the previously unexplored role of Ref-1 in retinal neovascularization. We demonstrate that Ref-1 is highly expressed in endothelial cells in human PDR and in the oxygen-induced retinopathy (OIR) mouse model of retinal neovascularization. Ref-1 is also highly expressed in microglia and astrocytes in OIR. A small molecule Ref-1 redox inhibitor, APX2009, decreased retinal neovascularization in OIR after systemic delivery. In vitro, hypoxic endothelial cells did not exhibit upregulation of Ref-1 but rather increased Ref-1 nuclear localization. APX2009 decreased hypoxic endothelial cell proliferation and HIF-1α transcriptional activation. Thus, Ref-1 redox activity may be a novel therapeutic target for the treatment of retinal neovascularization, making APX2009 a promising systemic therapeutic approach for the treatment of vascular retinopathies such as ROP and PDR.