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Kelley Lab

The research laboratory of Mark R. Kelley, MS, PhD focuses on translational research in DNA damage and repair as well as redox signaling pathways in tumor and normal cells. The lab has focused specifically on the enzyme apurinic/apyrimidinic endonuclease 1/ Redox effector factor-1 (APE1/Ref-1)—both mechanistically and as a therapeutic target in cancers and other diseases that are related to APE1/Ref-1 signaling node.

APE1/Ref-1 is unique to the base excision repair (BER) pathway with dual repair and redox signaling functions that are crucial to cellular viability. The laboratory has also focused on the latter function of APE1/Ref-1 as a signaling node in cancer cells and by blocking its interactions with the downstream transcription factors (e.g. HIF, STAT3, NFkB, AP-1, etc.) it regulates in tumor cells making them more susceptible to cancer therapeutics.

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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.

Active Research

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.

Areas of focus

  • APE1/Ref-1
    Regulation and function of AP endonuclease (APE1/Ref-1) DNA repair activity 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.

    Identification and development of small molecule inhibitors of both APE1/Ref-1’s redox signaling and DNA repair functions.

  • DNA damage and repair
    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

    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.

    Molecular and cellular biology, biochemistry and translational applications of eukaryotic DNA base excision repair (BER).

    Identification and development of small molecule inhibitors of both APE1/Ref-1’s redox signaling and DNA repair functions.

  • Drug Development
    Continued development of APX3330, and analogues that blocks APE1/Ref-1’s redox function for Phase I

    and eventual Phase II trials in multiple cancers.

    Phase I trials for APX3330 opened January 2018: NCT03375086 – A Study of APX3330 in Patients with Advanced Solid Tumors (APX3330)

    Advancement of second generation APE1/Ref-1 redox inhibitor compounds through preclinical studies and into additional phase I clinical trials.

Research Funding

  • NIH RO1 CA205166 (Kelley / Fehrenbacher, MPIs)
    (PQ9) Mechanistic Role of APE1 and BER in chemotherapy-induced peripheral neuropathy
  • NIH R01 CA167291-06 (Kelley / Fishel, MPIs)
    Exploiting the Ref-1 node in pancreatic cancer: tailoring new pancreatic cancer therapy using multi-target combinations
  • NIH R01 CA167291-06S1 (Kelley/Fishel, MPIs)
    Supplement to: Exploiting the Ref-1 node in pancreatic cancer: tailoring new pancreatic cancer therapy  using multi-targeted combinations- Role of Ref-1 in cancer cachexia.
  • NIH R01 CA231267 (Kelley/Fehrenbacher, MPIs)
    (PQ12) Enhancement of DNA repair in neurons via a targeted APE1 small molecule modifier to decrease and reverse chemotherapy-induced peripheral neuropathy (CIPN)
  • Apexian Pharmaceuticals Contract (Kelley, PI)
    Testing Apexian compounds for efficacy in cancer models
  • American Cancer Society IRG-84-002-28-IRG (Kelley, PI)
    IU Simon Comprehensive Cancer Center Institutional Research Grant – Director of training grant
  • NIH/NCI P30 CA08270914 (Loehrer, PI)
    Cancer Center Support Grant – Associate Director of Basic Science
  • 4UL1TRR001108 (Mentor; Shekhar PI)
    Indiana Clinical and Translational Sciences Institute – T32 Program

Recent Publications

Discoveries made throughout Dr. Kelley’s career have culminated in 21 patents, more than 183 articles in peer-reviewed journals and 31 review articles/book chapters. Collectively, these works attest to his contributions to the field of DNA repair, redox signaling and advancing findings from bench to clinic.

For a full list of Dr. Kelley’s publications, find him on PubMed.

  • 2018

    Logsdon DP, Shah F, Carta F, Supuran CT, Kamocka M, Jacobsen MH, Sandusky GE, Kelley MR*, Fishel ML*. (2018) Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival. Nature Scientific Reports. Sep 13;8(1):13759. PMID: 30214007. *co-senior authors.

    Cai Z, Kotzin JJ, Ramdas B, Chen S, Nelanuthala S, Palam LR, Pandey R, Mali RS, Liu Y, Kelley MR, Sandusky G, Mohseni M, Williams A, Henao-Mejia J, Kapur R. (2018) Downregulation of Morrbid in Tet2-deficient preleukemic cells overcomes resistance to inflammatory stress and mitigates clonal hematopoiesis. Cell Stem Cell, published online Dec 6, 2018

  • 2017

    D.W McIlwain, M.L. Fishel, A Boos, M.R. Kelley, and T.J. Jerde. (2017) APE1/Ref-1 Redox-Specific Inhibition Decreases Survivin Protein Levels and Induces Cell Cycle Arrest in Prostate Cancer Cells. Oncotarget. Dec 13;9(13):10962-10977. PMCID: PMC58342255.

    Shah, E. Goossens, N.M. Atallah, M. Grimard. M.R. Kelley, and M.L Fishel. (2017) Characterizing gene expression changes and identifying novel pathways following APE1/Ref-1 knockdown in Pancreatic Ductal Adenocarcinoma using Single-cell RNA Sequencing. Mol Oncol. 2017 Dec;11(12):1711-1732. PMCID: PMC5709621.

    J.C. Fehrenbacher, C. Guo, M.R. Kelley, and M.R. Vasko. (2017) DNA damage mediates changes in neuronal sensitivity induced by the inflammatory mediators, MCP-1 and LPS, and can be reversed by enhancing the DNA repair function of APE1. Neuroscience. 2017 Dec 16:366:23-25. PMID: 28965839.

  • 2016

    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. Nov;359(2):300-309. PMCID: PMC5074487.

Faculty Research Team

13975-Kelley, Mark

Mark R. Kelley, PhD

Betty and Earl Herr Professor of Pediatric Oncology Research

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Additional Research Team Members

Additional research team members in the Kelley Lab include Randy Wireman (technical analyst).