Mark R. Kelley

Mark R. Kelley, MS, PhD

Betty and Earl Herr Professor of Pediatric Oncology Research

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Bio

My work has focused on translational research in DNA damage and repair, specifically, to determine how those activities can be exploited therapeutically to treat cancers and protect normal cells from oxidative and DNA base damage. Since 1993, 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), with dual repair and redox signaling functions that are crucial to cellular viability. My work has been the first to tease apart those functions, not only to fully characterize them, but to also determine how to manipulate each function individually for therapeutic benefit. In doing the latter, I discovered and have been developing a redox-specific inhibitor of Ref-1, as well as second-generation analogs that are under further investigation. This original work was the impetus for becoming Chief Scientific Founder and Officer of Apexian Pharmaceutical, an integrated drug development company that’s leveraging the APE1/Ref-1 target platform to produce new therapeutics for some of the deadliest and hardest-to-treat cancers. Apexian recently submitted and received a treatment IND (IND125360) for a new drug that targets Ref-1; its potential indications include ovarian, colon, pancreatic cancer, leukemias as well as other adult and pediatric cancers. APX3330 is completing a phase 1 clinical trial for safety and recommended Phase II dose (RP2D) in cancer patients (NCT03375086). I am also exploring APE1/Ref-1 and BER for mechanistic and therapeutic opportunities in chemotherapy-induced peripheral neuropathy (CIPN) and other diseases. In broader terms, all the academic chairs I’ve held and the program leader and director positions I currently hold are dedicated to fast-tracking collaboration and translational research to find more effective cancer treatments. In my Associate Director positions, I also help equip the next generation of researchers by training and mentoring junior faculty, postdoctorates, fellows, MD students and others. My expertise in Ref-1 functions, drug development, such as taking APX3330 to clinical trials and development of second generation compounds, as well as years of studies centering on Ref-1 and its role as a node in cancer cells will augment this application.

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 of Pediatrics, Section of Pediatric Endocrinology and Dept. of Biochemistry and Molecular Biology, Indiana University School of Medicine (IUSM)

1995– 2017      Associate Director, Wells Center for Pediatric Research, IUSM

1997–present   Professor of Pediatrics and Dept. of Biochemistry and Molecular Biology, IUSM

2001–2006        Program Leader, Experimental and Developmental Therapeutics Research, IUSCC, IUSM

2002–2006        Chemical Pathology Study Section Member & Cancer Etiology Study Section Member

2004–2006        Cancer Etiology Study Section Chairperson

2008–2012        NCI-F Manpower and Training: T32 Training grant and K99/R00 Career development Awards

2001–2008        Jonathan and Jennifer Simmons Professor of Pediatrics, Dept. of Pediatrics, IUSM

2002–present   Professor, Dept. of Pharmacology and Toxicology, Indiana University School of Medicine

2005–present   Associate Director of Basic Science Research, Indiana University Simon Cancer Center

2006–present   Chair, IU Simon Cancer Center Translational Research Acceleration Collaboration (ITRAC)

2008–present   Director, Program in Pediatric Molecular Oncology and Experimental Therapeutics, IUSM

2008–present   Betty and Earl Herr Chair in Pediatric Oncology Research

2008–present   Chief Scientific Founder and Officer, Apexian Pharmaceuticals, Indianapolis, IN

2012–2016        Co-Director, Chemical Biology and Drug Discovery Initiative, IU Simon Cancer Center

2012–2016        NCI-F Grant Review SEP: Cancer Health Disparities/Diversity in Basic Cancer Research

2013–2016        Chair, NCI Omnibus Special Emphasis Panel: drug discovery reviews

2017—present  Member, Basic Mechanisms of Cancer Therapeutics (BMCT) Study Section, NIH

2004-- 2018      75 NIH study section review panels over 14 years.

Key Publications

 

Ref-1/APE1 inhibition with novel small molecules blocks ocular neovascularization. Sardar Pasha SPB, Sishtla K, Sulaiman RS, Park B, Shetty T, Shah F, Fishel ML, Wikel JH, Kelley MR, Corson TW. J Pharmacol Exp Ther. 2018 Aug 3. PMID:30076264

APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats.  Yan T, Venkat P, Chopp M, Zacharek A, Yu P, Ning R, Qiao X, Kelley MR, Chen J. Aging Dis. 2018 Jun 1;9(3):453-466. 2018. PMID:29896433

 APE1/Ref-1 redox-specific inhibition decreases survivin protein levels and induces cell cycle arrest in prostate cancer cells. McIlwain DW, Fishel ML, Boos A, Kelley MR, Jerde TJ.  Oncotarget. 2017 Dec 13;9(13):10962-10977. 2018 Feb 16. PMID:29541389

APE1/Ref-1 knockdown in pancreatic ductal adenocarcinoma: Characterizing gene expression changes and identifying novel pathways using single-cell RNA sequencing. Shah F, Goossens E, Atallah NM, Grimard M, Kelley MR, Fishel ML. Mol Oncol. 2017 Sep 18. doi: 10.1002/1878-0261.12138. PMID:28922540

Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. Shah F, Logsdon D, Messmann RA, Fehrenbacher JC, Fishel ML, Kelley MR. NPJ Precis Oncol. 2017;1. Epub 2017 Jun 8. PMID:28825044

Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia. Ding J, Fishel ML, Reed AM, McAdams E, Czader MB, Cardoso AA, Kelley MR. Mol Cancer Ther. 2017 Jul;16(7):1401-1411. Epub 2017 Apr 26. MID:28446640

Challenges and opportunities identifying therapeutic targets for chemotherapy-induced peripheral neuropathy resulting from oxidative DNA damage.  Kelley MR, Fehrenbacher JC. Neural Regen Res. 2017 Jan;12(1):72-74. PMID:28250749

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models. Logsdon DP, Grimard M, Luo M, Shahda S, Jiang Y, Tong Y, Yu Z, Zyromski N, Schipani E, Carta F, Supuran CT, Korc M, Ivan M, Kelley MR, Fishel ML.  Mol Cancer Ther. 2016 Nov;15(11):2722-2732. Epub 2016 Aug 17. PMID:  27535970

Identification and Characterization of New Chemical Entities Targeting Apurinic/Apyrimidinic Endonuclease 1 for the Prevention of Chemotherapy-Induced Peripheral Neuropathy. Kelley MR, Wikel JH, Guo C, Pollok KE, Bailey BJ, Wireman R, Fishel ML, Vasko MR. J Pharmacol Exp Ther. 2016 Nov;359(2):300-309. Epub 2016 Sep 8. PMID:27608656 

Connect


mkelley@iu.edu 


(317) 274-2755 


Ped-Heme/Onc Basic Research
R4-302 PHMB
Indianapolis, IN


  

Cancer
Pediatrics
Translational Research

Titles & Appointments

  • Professor of Pediatrics
  • Professor of Biochemistry & Molecular Biology
  • Professor of Pharmacology & Toxicology