13975-Kelley, Mark
Faculty

Mark R. Kelley, PhD

Betty and Earl Herr Professor of Pediatric Oncology Research

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R4-302
PHMB
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Indianapolis, IN
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Bio

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

Key Publications

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
  • Education
    1987 FEL Postdoctoral Fellowship, The Rockefeller University
    1984 PhD Louisiana State University
    1981 MS Louisiana State University
    1979 BA DePauw University
  • Research

    A brief overview of my research includes:

    1.   Comprehensive molecular characterization of the APE1/Ref-1 enzyme and its functions

    The Base Excision Repair (BER) pathway is the body’s main defense in repairing oxidative damage to DNA. The most singular BER protein that has no “backup” or equivalent is APE1/Ref-1. Its dual name alludes to its unique dual functions as an AP endonuclease and as a redox effector factor (the “Ref” part of its name). Since 1987, I have studied BER extensively and was the first to fully characterize APE1/Ref-1’s translational and clinical relevance and differentiate its functions using chemical molecules (findings published in 1995, 2001, and more recently). While the fully folded protein performs its endonuclease function a locally unfolded configuration of the protein performs redox activities at its amino terminus. Unlike other redox proteins, APE1/Ref-1’s cysteine residues are buried. Also, unlike other redox proteins that require two cysteine residues, APE1/Ref-1 requires three to perform its complex redox functions (published in 2012 and 2013). My efforts in these areas have given me an unprecedented advantage in developing a new class of therapeutics that can selectively modify one function or the other (detailed further in Contribution 4).

    ·       Kelley, M.R., Cheng, L., Foster, R., Tritt, R., Broshears, J., & Koch, M. (2001). Elevated and altered expression of the multifunctional DNA base excision repair and redox enzyme Ape1/ref-1 in prostate cancer. Clin Cancer Res, 7(4), 824-830. PMID: 11309329

    ·       Su, D., Delaplane, S., Luo, M., Rempel, D., Vu, B., Kelley, M. R., Gross, M. L., & Georgiadis, M. (2011). Interactions of APE1with a redox inhibitor: Evidence for an alternate conformation of the enzyme. Biochemistry, 50(1), 82-92. PMCID: PMC3070192

    ·       Luo, M., Zhang, J., He. H., Su, D., Chen, Q., Gross, M., Kelley, M. R., & Georgiadis, M. (2012).  Characterization of the Redox Activity and Disulfide Bond Formation in Apurinic / Apyrimidinic Endonuclease. Biochemistry, 51(2), 695-705. PMCID: PMC3293223

    ·       Zhang, J., Luo, M., Marascot, D., Logsdon, D., LaFavers, K. A., Chen, Q., Reed, A., Kelley, M. R., Gross, M. L., & Georgiadis, M. M. (2013). Inhibition of Apurinic/apyrimidinic endonuclease I’s redox activity revisited. Biochemistry, 52(17), 2955-66. PMCID: PMC3706204

    2. Discoveries that APE1/Ref-1’s redox activities help maintain the DNA-binding capability of numerous transcription factors (Fos, Jun, HIF-1α, PAX, NF-kB, STAT3, as well as p53), and the therapeutic value of modulating that redox activity

    APE1/Ref-1 is a master regulator of oxidative stress; and, as such, its redox activity maintains many transcription factors by keeping them in their active (reduced) state. Many of those factors are involved in cell growth, progression, proliferation, apoptosis, angiogenesis, and inflammation. I have shown that upregulation of APE1 occurs in many solid cancers (GBM, neuroblastoma, ovarian, etc), contributing to therapeutic resistance. This is especially true with pancreatic cancer (PDAC). Inhibition of APE1’s redox activity blocks their proliferation and migration: by (1) decreasing the transcription activity of NF-κB, AP-1, HIF-1α and STAT3— key factors involved survival, invasion, and metastasis—and by (2) cell cycle arrest at G2 and increased p53-induced apoptosis. More details of those discoveries are listed in Contribution 5. Another recent finding is that APE1 inhibition also activates nuclear factor erythroid-related factor 2 (NRF2) in a dose-dependent fashion, regardless of whether abnormally high ROS are present or not. This has therapeutic implications for stimulating the NRF2 pathway to treat diseases caused by oxidative stress.

    ·       Jiang, Y., Zhou, S., Sandusky, G. E., Kelley, M. R., & Fishel, M. L. (2010). Reduced expression of DNA repair and redox signaling protein APE1/Ref-1 impairs human pancreatic cancer cell survival, proliferation, and cell cycle progression. Cancer Invest, 28(9): 885-895. PMCID: PMC2966714

    ·       Fishel, M. L, Jiang, Y., Rajeshkumar, N. V., Scandura, G., Sinn, A. L, He, Y., Shen, C., Jones, D. R., Pollok, K. E., Ivan, M., Maitra, A., & Kelley, M. R. (2011). Impact of APE1/Ref-1 Redox Inhibition on Pancreatic Tumor Growth. Mol Cancer Ther, 10(9), 1698-708. PMCID: PMC3170439

    ·       Kelley, M. R., Georgiadis, M. M., & Fishel, M. L. (2012). APE1/Ref-1 Role in Redox Signaling: Translational Applications of Targeting the Redox Function of the DNA Repair/Redox Protein APE1/Ref-1. Current Mol Pharmacol, 5(1), 36-53. PMCID: PMC3319314.

    ·       Fishel, M. L., Devlin, C. M., Jiang, Y., Luo, M., He, Y., Yu, Z., Tong, Y., Lipking, K. P., Maitra, A., Rejeshkumar, N. V., Wu, X., Scandura, G., Kelley, M. R., & Ivan, M. (2015). Apurinic/Apyrimidinic Endonuclease/Redox Factor-1 (APE1/Ref-1) redox function negatively regulates NRF2. J Biol Chem, 290(5), 3057-68. PMCID: PMC4317024

    3. Anti-angiogenesis and anti-inflammatory therapeutics in cancer and non-cancer systems and impact on tumor microenvironment

    I was the first to demonstrate a new role of APE1 with its involvement in angiogenesis and show that inhibition of APE1’s redox function abrogates that role. This discovery holds great promise for treating any condition characterized by abnormal neovascularization, including cancers and many diseases of the eye (AMD, diabetic retinopathy, ROP). Regarding the latter, APE1 is highly expressed in the retina, choroid, and retinal pigment epithelium. Using mouse models we demonstrated that APE1’s redox activity is required for cellular proliferation, migration, and tube formation. My lab was the first to show that redox-specific APE1 inhibition regulates RPEs’ response to oxidative stress and accumulation of intracellular ROS, while reducing a broad panel of stress- and toxicity-responsive transcription factors that are otherwise upregulated in retinal disease. APE1 inhibition could augment the results of today’s most advanced anti-angiogenic treatments, including anti-VEGF therapy. Additionally, I’ve shown that APE1 inhibition suppresses inflammatory response in activated human macrophages—downregulating TNF-α, IL-6, IL-12, and other molecules and inhibiting transcription of AP-1 and NF-κB. Thus, APE1 inhibition holds promise as a novel therapeutic strategy for inhibiting tumor-associated macrophages and impacting the tumor-microenvironment as well as tumor-immunotherapy.

    ·       Luo, M., Delaplane, S., Jiang, A., Reed, A., He, Y., Fishel, M., Nyland II, R., Borch, R. F., Qiao, X., Georgiadis, M. M., & Kelley, M. R. (2008). Role of the multifunctional DNA repair and redox signaling protein Ape1/Ref-1 in cancer and endothelial cells: Small molecule inhibition of Ape1’s redox function. Antiox Redox Signal, 10(11), 1853-1867. PMCID: PMC2587278

    ·       Jedinak, A., Dudhgaonkara, S., Kelley, M. R., & Sliva, D. (2011). Apurinic/apyrimidinic endonuclease 1 regulates inflammatory response in macrophages. Anticancer Res, 31(2), 379-85. PMCID: PMC3256557

    ·       Jiang, A., Gao, H., Kelley, M. R., & Qiao, X. (2011). Inhibition of APE1/Ref-1 Redox Activity with APX3330 Blocks Retinal Angiogenesis In Vitro and In Vivo. Vision Res, 51, 93-100. PMCID: PMC3010438

    ·       Li, Y., Liu, X., Zhou, T., Kelley, M. R., Edwards, P., Gao, H., & Qiao, X. (2014). Inhibition of APE1/Ref-1 redox activity rescues human retinal pigment epithelial cells from oxidative stress and reduces choroidal neovascularization. Redox Biol, 21(2), 485-494. PMCID: PMC3949093

     

    4. Studies relating to DNA damage and repair of neuronal cells resulting in chemotherapy induced peripheral neuropathy (CIPN)

    A perennial problem in treating cancer with platinating agents, microtubule stabilizers, and ionizing radiation is the development of cancer-induced peripheral neuropathy (CIPN). The nerves’ high metabolic activity and high gene transcription rates make them very susceptible to DNA damage. Anticancer agents not only cause damage by forming adducts, but also by producing ROS. My lab was the first to identify that the repair function of APE1 contributes to the survival of nondividing post-mitotic cells following oxidative DNA damage. I further showed that overexpression of the repair function of APE1 can protect hippocampal and DRG neurons after irradiation and can attenuate CIPN after administration of platinating agents. Serendipitously, inhibition of APE1’s redox function enhances APE1’s repair function in this milieu. Currently no effective treatments exist for CIPN; therefore my lab’s discoveries hold promise for a breakthrough therapy that could significantly improve patients’ quality of life after anticancer treatment both for prevention and reversal of CIPN.

    ·       Vasko, M. R., Guo, C., Thompson, E. L., & Kelley, M. R. (2011). The repair function of the multifunctional DNA repair/redox protein APE1 is neuroprotective after ionizing radiation. DNA Repair, 10(9), 942-952. PMCID: PMC3162094

    ·       Kelley, M. R., Jiang, Y. Guo, C., Reed, A., Meng, H., & Vasko, M. R. (2014). Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy. PloS One, 9(9), e106485. PMID: 25188410

    ·       Kim H-S, Guo C, Thompson EL, Jiang Y, Kelley MR, Vasko MR, Lee S-H. (2015) APE1, the DNA base excision repair protein, regulates the removal of platinum adducts in sensory neuronal cultures by NER. Mutation Research Sept 2015: 779:96-104. PMCID: PMC4554977

    ·       M.R. Kelley, J.H. Wikel, C. Guo, K.E. Pollok, B.J. Bailey, R. Wireman, M.L. Fishel, and M.R. Vasko. (2016) Identification and Characterization of new chemical entities targeting apurinic/apyrimidinic endonuclease 1 for the prevention of chemotherapy-induced peripheral neuropathy. J Pharmacol Exp Ther. 2016 Sept 8. pii: jpet.116.235283 (epub ahead of print). PMCID: PMC5074487

     

    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

    Others’ research efforts to inhibit APE1 yielded topoisomerase poisons or nonspecific BER inhibitors—not true APE1 inhibitors. My group was the first to isolate and develop true APE1 inhibitors, and further was able to selectively block just the endonuclease or redox function of APE1. A lead compound is ready for early clinical trials, and preclinical testing is underway for 2nd-generation compounds. Additionally, my lab recently showed, for the first time, that APE1’s redox function directly regulates STAT3 transcriptional activity and DNA binding; and, that APE1 inhibition synergistically works with STAT 3 blockage to inhibit the proliferation and viability of human PDAC cells. This has the potential to be a breakthrough technology in this difficult-to-treat cancer. APE1 redox inhibition also holds promise as a potential treatment for inflammatory-based liver diseases, as well as taxane resistant prostate cancer and in situations where anti-angiogenic agents are used (anti-VEGF or anti-VEGF-R) to enhance the effectiveness of those agents.

    ·       Bapat, A., Glass, L. S., Luo, M., Fishel, M. L., Long, E. C., Georgiadis, M. M., & Kelley, M. R. (2010). Novel small-molecule inhibitor of apurinic/apyrimidinic endonuclease 1 blocks proliferation and reduces viability of glioblastoma cells. J Pharmacol Exp Ther, 334(3), 988-98. PMCID: PMC2939666

    ·       Kelley, M. R., Luo, M., Reed, A., Su, D., Delaplane, S., Borch, R. F., Nyland II RL, Gross, M. L., & Georgiadis, M. (2011). Functional analysis of new and novel analogs of E3330 that block the redox signaling activity of the multifunctional AP endonuclease/redox signaling enzyme APE1/Ref-1. Antiox Redox Signal, 14(8), 1387-1401. PMCID: PMC3061197

    ·       Cardoso, A. A., Jiang, Y., Luo, M., Reed, A. R., He, Y., Kelley, M. R., & Fishel, M. L. (2012). APE1/Ref-1 Regulates STAT3 Transcriptional Activity and APE1/Ref-1-STAT3 Dual-Targeting Effectively Inhibits Pancreatic Cancer Cell Survival. PloS One, 7(10): e47462. PMCID: PMC3477158

    ·       Fishel ML, Devlin CM, Jiang Y, Luo M, He Y, Yu Zhangsheng, Tong Y, Lipking KP, Maitra A, Rejeshkumar NV, Wu X, Scandura G, Kelley M.R., Ivan M. (2015) Apurinic/Apyrimidinic Endonuclease/Redox Factor-1 (APE1/Ref-1) redox function negatively regulates NRF2. J Biol Chem. 2015 Jan 30;290(5):3057-68. PMCID: PMC4317024

  • Professional Organizations
    Alliance of Distinguished Rank Professors
    American Association for Cancer Research
    American Association for the Advancement of Science
    American Society for Pharmacology and Experimental Therapeutics
    American Society of Clinical Oncology
    Association for Research in Vision and Ophthalmology
    Education Board Member, American Health Council 2017 -
    Society for Redox Biology and Medicine
  • Clinical Interests

    I have been developing a redox-specific inhibitor of Ref-1, as well as second-generation analogs that are under further investigation. We launched a company, Apexian Pharmaceuticals, to advance these findings to the clinic including the 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.

  • Awards
    Org: American Association for the Advancement of Science
    Desc: Fellow (Biological Sciences)
    Scope: National
    Date: 2022-02-01

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