The laboratory was the first to tease apart those functions, not only to fully characterize them but also to determine how to manipulate each function individually for therapeutic benefit and drug development. In doing the latter, the group discovered and has been developing a redox-specific inhibitor of Ref-1 and second-generation analogs. This original work led to the formation of Apexian Pharmaceutical, an integrated drug development company that is leveraging the APE1/Ref-1 target platform to produce new therapeutics for some of the deadliest and hardest-to-treat cancers.
The lead compound, APX3330 has entered phase 1 clinical trials for safety and recommended phase II dose (RP2D) in cancer patients (NCT03375086). The laboratory is also exploring APE1/Ref-1 and BER for mechanistic and therapeutic opportunities in chemotherapy-induced peripheral neuropathy (CIPN), age-related macular degermation (AMD), diabetic macular edema (DME), inflammatory bowel disease (IBD) and other indications such as tuberous sclerosis complex (TSC), malignant peripheral nerve sheath tumors (MPNST) and more.
The inherent chemical instability of DNA, the production of reactive oxygen species during normal cellular metabolism, and the continuous exposure to environmental mutagens and extraneous agents (such as during cancer therapy) all represent a potential threat to the integrity of the DNA of cells. The Kelley Lab focuses specifically on the role of the major apurinic endonuclease DNA repair enzyme, apurinic/apyrimidinic endonuclease-reduction-oxidation (redox) factor 1 (APE1/ref-1), in cancer – both as a diagnostic and therapeutic factor. Recent studies have identified APE1/Ref-1 as a critical node in tumor cells as a redox regulator of transcription factor activation and as part of the DNA damage response.
As a redox signaling protein, APE1/Ref-1 enhances the transcriptional activity of STAT3, HIF-1a, NF-κB, AP-1 and other transcription factors (TFs) to promote growth, migration and survival in tumor cells as well as inflammation and angiogenesis in the tumor microenvironment. Since TFs downstream of APE1/Ref-1 are key contributors to many cancers, inhibition of APE1/Ref-1 redox signaling slows growth and progression in a number of tumor types. APE1/Ref-1 is activated and elevated in a variety of cancers, including pediatric and adult brain tumors; osteosarcomas and rhabdomyosarcomas; pancreatic, ovarian, prostate, bladder, colon, lung and leukemias, leading to increased aggressiveness. APE1/Ref-1 inhibition is also highly effective when paired with other drugs, including standard-of-care therapies and therapies targeting pathways affected by APE1/Ref-1 redox signaling.
Additionally, APE1/Ref-1 plays a role in a variety of other indications, such as retinopathy, inflammation, and neuropathy. The laboratory is currently trying to understand APE1/Ref-1’s role in these cancers, and other indications, and determining how to modulate its activity for therapeutic applications (small molecule inhibitors). The primary focus is currently directed toward pediatric sarcomas, neuroblastoma and adult cancers such as pancreatic, bladder, and colon. The group is also investigating the MOA of chemotherapy-induced peripheral neuropathy (CIPN) and potential treatments as well as ocular diseases such as AMD.