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, Bethesda, MD; 2006

Curriculum Vitae

Current Positions:

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

Contact Information:

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

Email: howard.donninger@louisville.edu

Research Description

Our lab is interested in studying the molecular mechanisms that are deregulated during tumor progression. To this end, our laboratory research can be broken down into 3 main areas of interest.

1.The Function of RASSF Family Members

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.

2. Development of novel small molecule inhibitors of IL-6 signaling

IL-6 is 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. 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.  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.

3. Identifying potential new therapeutic targets in the tumor microenvironment of pediatric cancers

Very few patients with certain pediatric cancer types are completely cured, and particularly, brain cancer is a leading cause of cancer-related deaths in young adults. Tumors secrete various factors that promote an immunosuppressive tumor microenvironment, resulting in resistance to immunotherapy. In collaboration with Dr. Kavitha Yaddanapudi’s lab, we have identified the chemokine CCL2 as a factor that is secreted by brain tumor cells that facilitates the recruitment immunosuppressive cells to the tumor microenvironment, and using preclinical brain cancer models, are currently exploring the option of targeting CCL2 as a novel therapeutic option for pediatric brain cancer.

Representative Publications:

1. Donninger H, Harrell-Stewart D, Clark GJ.  Detection of endogenous RASSF1A interacting proteins.  Methods in Molecular Biology 2021;2262:303-310.  doi: 10.1007/978-1-0716-1190-6_18.  PMID: 33977485.
2. Schmidt ML, Hobbing KR, Donninger H, Clark GJ.  RASSF1A deficiency enhances RAS-driven lung tumorigenesis.  Cancer Research 2018 May 15;78(10):2614-2623.  doi: 10.1158/0008-5472.CAN-17-2466.  Epub 2018 May 7.  PMID: 29735543.  PMCID:  PMC5955812.
3. Donninger H, Schmidt ML, Mezzanotte J, Barnoud T, Clark GJ.  Ras signaling through RASSF proteins.  Seminars in Cell & Devopmental Biology 2016 Oct;58:86-95.  doi: 10.1016/j.semcdb.2016.06.007.  Epub 2016 Jun 8.  PMID: 27288568.  PMCID: PMC5034565.
4. Barnoud T, Wilkey DW, Merchant ML, Clark JA, Donninger H.  Proteomics analysis reveals novel RASSF2 interaction partners.  Cancers (Basel) 2016 Mar 16;8(3):37.  doi: 10.3390/cancers8030037.  PMID: 26999212.  PMCID: PMC4810121.
5. 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 of Cell Biology 2015 Mar 16;208(6):777-89.  PMID: 25778922.  PMCID: PMC4362463.
6. 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 & Cellular Biology 2015 Jan;35(1):277-87.  PMID: 25368379.  PMCID: PMC4295385 .
7. Clark J, Freeman J, Donninger H.  Loss of RASSF2 enhances tumorigenicity of lung cancer cells and confers resistance to chemotherapy.  Molecular Biology International 2012;2012:705948.  doi: 10.1155/2012/705048.  PMID: 22693671.  PMCID: PMC3368207.
8. 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.  doi: 10.1016/j.ccr/2009.10.1018.  PMID: 19962670.  PMCID: PMC3008560 .
9. 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 2006 Sep 1;66(17):8404-12.  doi: 10.1158/0008-5472.CAN-06-0683 .  PMID: 16951150.  
10. 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.  doi: 10.1038/sj.onc.1207959.  PMID: 15361855.

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