Howard Donninger, Ph.D.

Education:

B.Sc, Biochemistry and Microbiology, University of Cape Town, Cape Town, South Africa, 1990
B.Sc(MED)(HONS), Medical Biochemistry, University of Cape Town, Cape Town, South Africa, 1991
Ph.D, Medical Biochemistry, University of Cape Town, Cape Town, South Africa, 2000
Postdoctoral Fellowship, National Cancer Institute, National Institutes of Health, Bestheda MD, 2006

Curriculum Vitae

Current Positions:

Assistant Professor, Department of Medicine, University of Louisville School of Medicine
Member, Experimental Therapeutics & Diagnostics Program, James Graham Brown Cancer Center

Contact Information:

Clinical Translational Research Building, Room 416
University of Louisville
505 Hancock St.
Louisville, KY 40202, USA
Phone 502-852-8414
Fax 502-852-3661

Email: howard.donninger@louisville.edu

Research Description

Although Ras is a well characterized oncogene that has been implicated in the development and progression of multiple tumor types, Ras also paradoxically has growth inhibitory effects. While the growth promoting effects of Ras are well established, the mechanisms by which Ras promotes cell death are not well characterized. Our lab is interested in the RASSF (RASSF1-6) family of Ras effectors and how they function as tumor suppressors. The best characterized member of the family is RASSF1A whose expression is frequently inactivated in numerous tumor types by promoter methylation, an epigenetic mechanism that inactivates many tumor suppressor genes and is a major contributor to the development of cancer. The RASSF proteins lack inherent enzyme activity and likely act as scaffolding molecules that facilitate the assembly of tumor suppressor complexes, thereby integrating multiple tumor suppressor pathways. Although the family members share some homology, and thus some common functions, there is significant variation in their sequences to suggest they each have unique functions. All the family members have a Ras binding domain and there is some evidence to suggest they do interact directly with the Ras oncoproteins. In fact we have shown that RASSF2 and K-Ras form an endogenous complex and K-Ras can modulate certain functions of RASSF2. Thus the RASSF proteins may link Ras to activation of pro-apoptotic pathways. Our lab is currently studying the interactions between the RASSF family members and other pro-apoptotic effectors to better understand how they impart their growth inhibitory properties on cells and how they potentially link Ras to apoptosis.

A further interest in the lab is to develop small molecule inhibitors of IL-6, a pro-inflammatory cytokine that has been linked to the development and progression of multiple tumor types. High levels of IL-6 are associated with metastasis, poor prognosis and the development of drug-resistant tumors in a variety of tumors, including lung, ovarian and prostate. Small-scale clinical trials have shown that inhibiting IL-6 activity may hold promise as a new therapeutic approach. Small molecules designed to block the interaction of IL-6 with its receptor could be an effective approach at targeting IL-6 signaling. In collaboration with a computational biologist, using in silico screening, we have identified several compounds that could potentially inhibit the IL-6/IL-6R interaction. We have shown that these compounds block IL-6 signaling and specifically inhibit anchorage-independent growth of multiple tumor cell lines without affecting 2-D growth. In addition, in collaboration with Dr. Kavitha Yaddanapudi, we are exploring the potential of using these inhibitors to block the suppressive activity of myeloid-derived suppressor cells (MDSCs), which promote a suppressive environment thereby reducing the efficacy of cancer immunotherapy. We are currently further characterizing the mode of action of these compounds with the goal of developing them into non-toxic, highly effective, small molecule inhibitors of IL-6 that may be used in combinatorial therapies for multiple cancers.

Representative Publications:

The Function of RASSF Family Members

  1. Allen NP,  Donninger H, Vos MD, Eckfeld K, Hesson L, Gordon L, Birrer MJ, Latif F, Clark GJ.  RASSF6 is a novel member of the RASSF family of tumor suppressors.  Oncogene 2007 Sep 13;26(42):6203-11. PMID: 17404571.
  2. Donninger H, Vos MD, Clark GJ.  The RASSF1A tumor suppressor.  Journal of Cell Science 2007 Sep 15;120(pt 18):3163-72. PMID: 17878233. [ www.jcs.biologists.org/content/120/18/3163.long ]
  3. Calvisi DF, Donninger H, Vos MD, Birrer MJ, Gordon L, Leaner V, Clark GJ.  NORE1A tumor suppressor candidate modulates p21CIP1 via p53.  Cancer Research 2009 Jun 1;69(11):4629-37. PMID: 19435914. [ www.cancerres.aacrjournals.org/content/69/11/4629.long ]
  4. Donninger H, Hesson L, Vos M, Beebe K, Gordon L, Sidransky M, Liu JW, Schlegel T, Payne S, Hartmann A, Latif F, Clark GJ.  The Ras effector RASSF2 controls the PAR-4 tumor suppressor.  Molecular & Cellular Biology 2010 Jun;30(11):2608-20. PMID: 20368356. PMCID: PMC2876522.
  5. Donninger H, Allen N, Henson A, Pogue J, Williams A, Gordon L, Kassler S, Dunwell T, Latif F, and Clark GJ.  Salvador protein is a tumor suppressor effector of RASSF1A with hippo pathway-independent functions.  Journal ofBiologicalChemistry 2011 May 27;286(21):18483-91. PMID: 21489991. PMCID: PMC3099665.
  6. Donninger H, Barnoud T, Nelson N, Kassler S, Clark J, Cummins TD, Powell DW, Nyante S, Millikan RC, Clark GJ.  RASSF1A and the rs2073498 cancer associated SNP.  Frontiers in Oncology 2011 Dec 28;1:54. PMID: 22649770. PMCID: PMC3355887.
  7. Clark J, Freeman J, Donninger H.  Loss of RASSF2 enhances tumorigenicity of lung cancer cells and confers resistance to chemotherapy.  MolecularBiologyInternational 2012;2012:705948. PMID: 22693671. PMCID: PMC3368207.
  8. Donninger H, Clark JA, Monaghan MK, Schmidt ML, Vos M, Clark GJ.  Cell cycle restriction is more important than apoptosis induction for RASSF1A tumor suppression.  Journal ofBiologicalChemistry 2014 Nov 7;289(45):31287-95. PMID: 25225292. PMCID: PMD4223329.
  9. Donninger H, Clark J, Rinaldo F, Nelson N, Barnoud T, Schmidt ML, Hobbing KR, Clark GJ.  The RASSF1A tumor suppressor regulates XPA mediated DNA repair.  Molecular &CellularBiology 2015 Jan;35(1):277-87. PMID: 25368379. PMCID: PMC4285395.
  10. Donninger H, Calvisi DF, Barnoud T, Clark J, Schmidt ML, Vos MD, Clark GJ.  NORE1A is a Ras senescence effector that controls the apoptotic/senescent balance of p53 via HIPK2.  Journal ofCellBiology 2015 Mar 16;208(6):777-89. PMID: 25778922. PMCID: PMD4362463.
  11. Barnoud T, Wilkey DW, Merchant ML, Clark JA, Donninger H.  Proteomics analysis reveals novel RASSF2 interaction partners.  Cancers (Basel) 2016 Mar 16;8(3). pii: E37. PMID: 26999212. PMCID: PMC4810121.
  12. Schmidt ML, Hobbing KR, Donninger H, Clark GJ.  RASSF1A deficiency enhances RAS-driven lung tumorigenesis.  Cancer Research 2018 May 15;78(10):2614-23. PMID: 29735543.

Identification of Pathways Critical for the Development of Ovarian Cancer

  1. Donninger H, Bonome T, Radonovich M, Pise-Masison CA, Brady J, Shih JH, Barrett JC, Birrer MJ.  Whole genome expression profiling of advance stage papillary serous ovarian cancer reveals activated pathways.  Oncogene 2004 Oct 21;23(49):8065-77. PMID: 15361855.
  2. Sunde JS*, Donninger H*, Wu K, Johnson ME, Pestell RG, Rose GS, Mok SC, Brady J, Bonome T, Birrer MJ.  Expression profiling identifies altered expression of genes that contribute to the inhibition of transforming growth factor-b signaling in ovarian cancer.  (* authors contributed equally).  Cancer Research 2006Sep 1;66(17):8404-12. PMID: 16951150. [ www.cancerres.aacrjournals.org/content/66/17/8404.long ]
  3. Mok SC, Bonome T, Vathipadiekal V, Bell A, Johnson ME, Wong KK, Park DC, Hao K, Yip DKP, Donninger H, Ozbun L, Samimi G, Brady J, Radonovich M, Pise-Masison CA, Barrett JC, Wong WH, Welch WR, Berkowitz RS, Birrer MJ.  A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: Microfibril-associated glycoprotein 2.  Cancer Cell 2009 Dec 8;16(6):521-32. PMID: 19962670. PMCID: PMC3008560.

The Role of the AP-1 Transcription Complex in Human Cancer

  1. Hommura F, Katabami M, Leaner VD, Donninger H, Sumter TF, Resar LMS, Birrer MJ.  HMG-I/Y is a c-Jun/activator protein-1 target gene and is necessary for c-Jun-induced anchorage-independent growth in Rat1a cells.  Molecular Cancer Research 2004 May;2(5):305-14. PMID: 15192124. [ www.mcr.aacrjournals.org/content/2/5/305.long ]
  2. Katabami M*, Donninger H*, Hommura F, Leaner VD, Kinoshita I, Chick JFB, Birrer MJ.  Cyclin A is a c-Jun target gene and is necessary for c-Jun-induced anchorage independent growth in Rat1a cells. (* authors contributed equally).  Journal ofBiologicalChemistry 2005 Apr 29;280(17):16728-38. PMID: 15737994. [ www.jbc.org/content/280/17/16728.long ]
  3. Leaner VD, Donninger H, Ellis CA, Clark GJ, Birrer MJ.  p75-Ras-GRF1 is a c-Jun/AP-1 target protein: its upregulation results in increased Ras activity and is necessary for c-Jun-induced nonadherent growth of Rat1a cells.  Molecular & Cellular Biology 2005 Apr 8;25:3324-37. PMID: 15798216. PMCID: PMC1069594.
  4. Leaner VD, Chick JF, Donninger H, Linniola I, Mendoza A, Khanna C, Birrer MJ.  Inhibition of AP-1 transcriptional activity blocks the migration, invasion, and experimental metastasis of murine osteosarcoma.  AmericanJournal ofPathology 2009 Jan;174(1):265-75. PMID: 19074613. PMCID: PMC2631339.

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