Office: R4 302C
Mark R. Kelley PhD
Betty and Earl Herr Chair in Pediatric Oncology Research
Professor of Pediatrics
Professor of Biochemistry & Molecular Biology
Professor of Pharmacology & Toxicology
Associate Director, Herman B Wells Center for Pediatric Research
Associate Director, Basic Science Research, IU Simon Cancer Center
Director, Program in Pediatric Molecular Oncology and
Co-Director, Chemical Biology and Drug Discovery Initiative
Associate Director, IU Pancreatic Cancer Signature Center
Associate Director, IU Pancreatic Cancer Signature Center Indiana University School of Medicine
- BA:DePauw University
- MS:Louisiana State University
- PhD:Louisiana State University
- Postdoctorate:The Rockefeller University
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. We have focused more specifically on the role of the major apurinic endonuclease DNA repair enzyme, APE1/Ref-1, in cancer both as a diagnostic and therapeutic factor and are studying the role of DNA BER and specifically APE1/Ref-1 as both a DNA repair and redox signaling factor for normal and cancer cells. We and others have shown that the Ape1/Ref-1 protein is significantly and dramatically elevated in pediatric and adult brain tumors, neuroblastoma, osteosarcomas and rhabdomyosarcomas, ALL, pancreatic cancer, ovarian, and prostate cancers. We are currently trying to understand APE1/Ref-1's role in these cancers and others, and determining how to modulate its activity for therapeutic applications (small molecule inhibitors). Our primary focus is currently directed toward pediatric and adult gliomas, pediatric leukemia/neuroblastoma, and pancreatic cancer:
- Molecular and cellular biology, biochemistry and translational applications of eukaryotic DNA base excision repair (BER).
- Regulation and function of AP endonuclease (Ape1/Ref-1) in normal and cancer cells. The multifunctional mammalian APE1 is responsible for the repair of AP (abasic) sites in DNA.
- APE1/Ref-1 is a multifunctional protein that has also been shown to function as a redox factor facilitating the DNA-binding capability of numerous transcription factors (Hif-1a, STAT3, NFkB, AP-1) as well as p53.
- Studies of DNA repair genes involved in repairing base damage that occurs from oxidative and alkylation events in normal and tumor cells.
- Studies relating to DNA damage and repair of neuronal cells resulting in chemotherapy induced peripheral neuropathy (CIPN); peripheral neuropathy and cognitive dysfunction ("chemobrain")
- Cross-talk between the BER and the NER DNA repair pathways in peripheral neurons.
- Redox signaling in mammalian cells.
- Anti-angiogenesis therapeutics in cancer and non-cancer systems including macular degeneration and neo-vascularization.
- Identification and development of small molecule inhibitor's of both APE1/Ref-1's redox signaling and DNA repair functions.
Continued development of APX3330, a small molecule that blocks APE1/Ref-1's redox function for Phase I and eventual Phase II trials in pancreatic cancer, other adult indications and pediatric cancers.