Mark R. Kelley PhD Associate Director, Herman B Wells Center for Pediatric Research

Betty and Earl Herr Professor of Pediatric Oncology Research: Department of Pediatrics

Professor, Departments of Pediatrics, Biochemistry & Molecular Biology, and Pharmacology & Toxicology

Associate Director for Basic Science Research: IU Simon Cancer Center

Director, Program in Molecular Pediatric Oncology

Co-Director, Chemical Biology and Drug Discovery Initiative

Basic Science Joint Appointments: Biochemistry and Molecular Biology, Pharmacology and Toxicology

Assistant Professor: Loyola University Medical School, Chicago, IL

Postdoctoral Fellowship: The Rockefeller University, New York, NY

PhD: Louisiana State University, Baton Rouge, LA, 1984




Pub Med Search

Current Research Interests:

  • 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 (Fos, Jun, HIF-1, PAX, NFkB, STAT3) 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 and other indications.



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. Recently, 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 as both a DNA repair and redox signaling factor for normal and cancer cells.

Ongoing projects include:

  1. Regulation, of AP endonuclease (Ape1/ref-1) in normal and cancer cells. The multifunctional mammalian APE is responsible for the repair of AP (abasic) sites in DNA. In addition, this enzyme has been shown to function as a redox factor facilitating the DNA-binding capability of numerous transcription factors (Fos, Jun, HIF-1, PAX, NFkB, STAT3) as well as p53. We are determining the relationship of the Ape1/ref-1 DNA repair enzyme to apoptosis, differentiation and redox control utilizing a variety of cells, tissues, cell lines and patient derived cell lines, both in vitro and in vivo using current animal models.
  2. Another avenue of study with APE/ref-1 involves its use as a cancer therapeutic target and understanding its role in tumor cells. We and others have shown that the Ape1/ref-1 protein is significantly and dramatically elevated in pediatric and adult brain tumors, osteosarcomas and rhabdomyosarcomas, ALL, pancreatic cancer, ovarian, prostate, cervical and germ cell tumors. 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, siRNA, dominant-negative mutants). Our primary focus is currently directed toward pediatric and adult gliomas, pediatric promyelocytic leukemia, ALL, multiple myeloma, ovarian and pancreatic cancers.
  3. Among the numerous side effects of cancer treatments, neurotoxicity which includes both neurocognitive dysfunction commonly called "chemobrain" and peripheral neuropathy, occurs frequently and has not been effectively studied at the cellular or molecular level. Some salient new studies reveal short and long-term effects of both IR and chemotherapy on a variety of neurocognitive deficits. Peripheral neuropathy which refers to damage to peripheral nerves and particularly sensory neurons is also quite common following chemotherapy and IR treatment. However, while patients with these neurocognitive and peripheral neuropathy manifestations have been documented, the underlying mechanism behind these neural effects has not been well studied. Consequently, understanding mechanisms by which cancer therapies produce neurotoxicity are critical to the successful management of this side effect. Indeed, both IR and chemotherapy can produce DNA damage and DNA repair mechanisms play a critical role in preventing toxicity to the neuronal tissue. Given Ape1's known role in the repair of alkylation and oxidative DNA damage following ROS production, it is a prime candidate for mechanistic studies and intervention. Additionally, Ape1's second function as a redox signaling molecule is important for regulating the function of a variety of transcription factors such as AP-1, NFkB, p53, CREB and others. It has been shown that these targets of Ape1 are essential for proper neuronal function. Therefore, we are studying Ape1's role in both central and peripheral neural cells as well as other members of the DNA BER pathway.

Dr. Kelley's Laboratory