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Mini Review Open Access
Volume 5 | Issue 4 | DOI: https://doi.org/10.33696/Signaling.5.126

Combating PDAC Drug Resistance: The Role of Ref-1 Inhibitors in Accelerating Progress in Pancreatic Cancer Research

  • 1Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
  • 2Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
  • 3Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, Indianapolis, IN, USA
+ Affiliations - Affiliations

Corresponding Author

Mark R. Kelley, mkelley@iu.edu

Received Date: September 09, 2024

Accepted Date: October 14, 2024

Abstract

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.

Keywords

APE1/Ref-1, Redox regulation, PDAC, Drug development, PDAC model, Redox inhibition, Transcription factor

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