Discovery and Basic Research
Mark Kelley, PhD (he/him/his)
Professor and Associate Director
Indiana University School of Medicine
Indianapolis, Indiana
Sudip Das, PhD (he/him/his)
Professor of Pharmaceutics & Drug Delivery
Butler University, College of Pharmacy & Health Sciences
Indianapolis, Indiana
AP endonuclease-1 / Redox factor-1 (APE1/Ref-1), recognized as a crucial regulatory protein, operates upstream of various transcription factors (TFs) such as NFκB, HIF1α, STAT3, and AP-1 (Fos/Jun), facilitating their DNA binding activity. This multifaceted protein, Ref-1, boasts major functions in redox signaling and DNA repair, along with additional roles encompassing RNA processing, DNA maintenance, RNA quality control, miRNA metabolism, and mitochondrial DNA repair. However, its dysregulation in cancer cells, observed in aggressive cancers like PDAC, MPNST, breast, and prostate cancers, underscores its pivotal role in cancer signaling. Despite its expression in both stromal and tumor cells, Ref-1 exhibits higher expression levels in tumor cells. Importantly, its DNA repair function operates independently of its redox function, rendering it a promising target for cancer therapy, especially through the development of small molecules targeting its redox function alone.
Cancer progression and metastasis, shaped by altered transcriptional networks, involve dysregulation of gene expression, often through activation of TFs. Notably, aggressive cancers like pancreatic ductal adenocarcinoma (PDAC), breast cancer (BC), and malignant peripheral nerve sheath tumor (MPNST) are characterized by a hypoxic, nutrient-poor, and densely inflammatory stroma. Key TFs like NFκB, HIF-1α, AP-1, and TGFβ/SMADs contribute significantly to these characteristics and the crosstalk between the tumor and its microenvironment (TME).
APE1/Ref-1 emerges as a multifunctional protein overexpressed in most aggressive cancers, impacting various cancer cell signaling pathways. Its redox activity notably activates crucial TFs like NFκB, HIF1α, STAT3, and AP-1, contributing significantly to tumor development and metastatic growth. Consequently, the development of potent, selective inhibitors targeting Ref-1's redox function presents an appealing approach for therapeutic intervention. Encouragingly, a first-generation compound, APX3330, has shown promise in phase I clinical trials for solid tumors, exhibiting favorable response rates, pharmacokinetics, and minimal toxicity.
Shifting focus to ocular diseases, neovascular age-related macular degeneration (nAMD) presents challenges unmet by existing anti-vascular endothelial growth factor (anti-VEGF) biologics, necessitating the identification of new therapeutic targets. A promising target in this regard is APE1/Ref-1, whose redox function regulates key features of nAMD, including inflammation and angiogenesis, via transcriptional activation of HIF-1α, NF-κB, STAT3, and others. Notably, the Ref-1 inhibitor APX3330 has advanced to a Phase III clinical trial for diabetic retinopathy and diabetic macular edema, demonstrating its potential in ocular disease management. Our research showcases Ref-1's overexpression in human nAMD, correlating with the vasculature in mouse models of choroidal neovascularization and subretinal neovascularization (SRN).
In summary, this presentation aims to offer an insightful overview of a novel class of small-molecule drugs for targeted therapy, addressing diverse cancers and ocular diseases alike.