My work has focused on translational research in DNA damage and repair, as well as redox signaling, specifically to determine how those activities can be exploited therapeutically to treat cancers and protect normal cells from oxidative and DNA base damage. I have focused specifically on the enzyme apurinic/apyrimidinic endonuclease 1/ Redox effector factor-1 (APE1/Ref-1)—mechanistically as well as a therapeutic target in cancers and other diseases that manifest cancer-like properties. APE1/Ref-1 is unique to the Base Excision Repair Pathway (BER), withdual repair and redox signaling functions that are crucial to cellular viability. My work has been focused on teasing apart these functions and in the process we have discovered and have been developing redox-specific inhibitors of Ref-1. The main areas of my research are: 1) Comprehensive molecular characterization of the APE1/Ref-1 enzyme and its functions, 2) Discoveries that APE1/Ref-1’s redox activities help maintain the DNA-binding capability of numerous transcription factors (HIF-1α, NF-kB, STAT3, AP-1), and the therapeutic value of modulating that redox activity, 3) Anti-angiogenesis and anti-inflammatory therapeutics in cancer and non-cancer systems and impact on tumor microenvironment, 4) Studies relating to DNA damage and repair of neuronal cells resulting in chemotherapy induced peripheral neuropathy (CIPN), and 5) Identification and development of small-molecule inhibitors of both APE1/Ref-1’s redox signaling and DNA repair functions, including development of APX3330 for Phase 1/2 trials in cancer and other indications. This work was the impetus for becoming a Founder and Chief Scientific Officer of Apexian Pharmaceutical (https://apexianpharma.com/) targeting Ref-1 to produce new therapeutics for some of the deadliest and hardest-to-treat cancers. Apexian recently completed a phase I clinical trial using oral APX3330 in solid tumor patients (NCT03375086). This trial established safety, expected PK, target engagement, and responses in patients in the trial. Phase II trials are being developed in cancer and other indications (IBD), including licensing our compounds for Phase II trials in diabetic retinopathy and diabetic macular edema to Ocuphire Pharma. In broader terms, all the academic chairs I have held and the program leader and director positions he currently holds are dedicated to fast-tracking collaboration and translational research to find more effective cancer treatments as well as treatments for other indications.. In my Associate Director positions, he also helps equip the next generation of researchers by training and mentoring junior faculty, postdoctorates, fellows, MD students and others.
All of the discoveries during my career have culminated in 19 patents and over 196 articles in peer reviewed journals as well as 36 review articles/book chapters, attesting to my contributions to the field of DNA repair, redox signaling and drug development. I am a recent AAAS Science Fellow (2022). Current h index is 76.
I serve on numerous consulting/scientific boards of several biotechnology companies and have and still serves on various NIH/NCI study sections and Cancer Center review panels. I was chair of the Cancer Etiology Study Section at NIH and reviews for numerous international agencies. I am a member of American Association for the Advancement of Science, American Association for Cancer Research, Society for Pediatric Research, and American Society of Clinical Oncology. I also serve on the editorial board of Frontiers in Bioscience, Journal of Pharmacology and Experimental Therapeutics, Mutation Research; Molecular and Fundamental Mechanisms (Assoc Editor) and Current Molecular Pharmacology.
1993 - 1998 Associate Professor, Department of Pediatrics, Section of Pediatric Endocrinology, and Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
1994 – Present Indiana University SimonComprehensive Cancer Center (IUSCCC) member
1995 - 2017 Associate Director, Herman B Wells Center for Pediatric Research, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
1999 – Present Professor, Department of Pediatrics, Section of Hematology/Oncology, and Department of Biochemistry & Molecular Biology, Indiana University School of Medicine
2001 – 2005 Co-Program Leader, Experimental Therapeutics Research Program, IU Simon Cancer Center, Indiana University School of Medicine
2001 – 2008 Jonathan and Jennifer Simmons Professor of Pediatrics, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202
2003 – Present Professor, Department of Pharmacology and Toxicology, Indiana University School of Medicine
2005 – Present Associate Director of Basic Science Research, IU Simon Cancer Center
2008 – Present Director, Program in Molecular Oncology and Experimental Therapeutics, Department of Pediatrics, Indiana University School of Medicine
2008 – 2012 Chair, Indiana CTSI Preclinical Project Development Team (TRAC1)
2008 – Present Betty and Earl Herr Chair in Pediatric Oncology Research, Indiana University School of Medicine
2010 – 2013 NCI Initial Review Group, Subcommittee F Manpower and Training
2008 – Present Chief Scientific Officer and Founder, Apexian Pharmaceuticals, Inc., Indianapolis, IN
2017 Education Board Member, American Health Council
2017 - 2018 Member, Basic Mechanisms of Cancer Therapeutics (BMCT) Study Section, NIH
2018 – 2019 Member, Mechanisms of Cancer Therapeutics (MCT – reorganization of BMCT) Study Section, NIH
2020 –present Member, Eugene and Marilyn Glick Eye Institute, Professor of Ophthalmology
2019 – 2022 Interim co-leader Experimental and Developmental Therapeutics Program, IUSCCC
2020—present Member, Indiana University Ventures Investment Committee
2020 – present co-Director, Cancer Drug Discovery and Development program, IUSCCC
2021—present Member, CTSI Preclinical Innovation “Think-Tank” Program, IUSM
2022—present AAAS Science Fellow
Recent Highlighted Publications
Sahakian L, Filippone R, Stavely R, Robinson A, Yan X, Abalo R, Eri R, Bornstein J, Kelley MR, Nurgali K. (2021) Inhibition of APE1/Ref-1 redox signalling alleviates intestinal dysfunction and enteric nervous system damage in a mouse model of chronic colitis, Inflammatory Bowel Disease Feb 16;27(3):388-406. PMID: 32618996
Gampala S, Shah F, Zhang C, Rhodes SD, Babb O, Grimard M, Wireman RS, Rad E, Calver B, Bai RY, Staedtke V, Hulsey EL, Saadatzadeh MR, Pollok KE, Tong Y, Smith AE, Clapp DW, Tee AR, Kelley MR, Fishel ML. (2021) Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumors. Br J Cancer. Apr;124(9):1566-1580. doi: 10.1038/s41416-021-01270-8. Epub 2021 Mar 3. PMID: 33658640; PMCID: PMC8076291.
Caston RA, Shah F, Starcher CL, Wireman R, Babb O, Grimard M, McGeown J, Armstrong L, Tong Y, Pili R, Rupert J, Zimmers TA, Elmi AN, Pollok KE, Motea EA, Kelley MR, Fishel ML. (2021) Combined inhibition of Ref-1 and STAT3 leads to synergistic tumor inhibition in multiple cancers using 3D and in vivo tumour co-culture models. J Cell Mol Med. Jan;25(2):784-800. PMID: 33274592; PMCID: PMC7812272.
Gampala S, Shah F, Lu X, Moon HR, Babb O, Umesh Ganesh N, Sandusky G, Hulsey E, Armstrong L, Mosely AL, Han B, Ivan M, Yeh JJ, Kelley MR, Zhang C, Fishel ML. (2021) Ref-1 redox activity alters cancer cell metabolism in pancreatic cancer: Exploiting this novel finding as a potential target. J Exp Clin Cancer Res. 2021 Aug 10;40(1):251. PMID: 34376225
Mijit M, Wireman R, Armstrong L, Gampala S, Hassan Z, Schneeweis C, Schneider G, Zhang C, Fishel ML and Kelley MR (2022) RelA Is an Essential Target for Enhancing Cellular Responses to the DNA Repair/Ref-1 Redox Signaling Protein and Restoring Perturbated Cellular Redox Homeostasis in Mouse PDAC Cells. Front. Oncol. 12:826617. doi: 10.3389/fonc.2022.826617
Complete Bibliography at https://www.ncbi.nlm.nih.gov/myncbi/mark.kelley.1/bibliography/public/
Titles & Appointments
- Betty and Earl Herr Professor of Pediatric Oncology Research
- Professor of Pediatrics
- Professor of Biochemistry & Molecular Biology
- Professor of Pharmacology & Toxicology
- Professor of Ophthalmology