Geoffrey J. Clark, Ph.D.

Education:

B.Sc.  University of Manchester 1985
Ph.D., Molecular Oncology, 1989

Curriculum Vitae

Current Positions:

Associate Professor, Dept. Pharmacology and Toxicology University of Louisville.  KY.

Contact Information:

Dept. Pharm/Tox,
Clinical Translational Research Building, Room 417
University of Louisville
505 Hancock St.
Louisville, KY 40202, USA
Phone 502-852-4485

Email: gjclar01@louisville.edu

http://louisville.edu/medicine/departments/pharmacology/faculty/primary/clark

Research Description:

K-Ras is the most frequently activated oncogene in human cancer.  RASSF1A is the most frequently inactivated tumor suppressor.  K-Ras binds RASSF1A to stimulate its tumor suppressing effects. The Clark lab is interested in how the interplay between Ras and RASSF1A (and its related family members) modulates the development of cancer.  We also have a strong interest in novel and more realistic animal models for cancer.  Laboratory projects fall into three categories:

  1. Ras/RASSF tumor suppressors
  2. Porcine models for human cancer
  3. Development of novel anti-Ras therapeutics
    1. Based on observations that in addition to driving growth and transformation, activated K-Ras was also powerfully pro-apoptotic, we used an in silico approach to identify potential novel Ras binding proteins that might mediate the growth inhibitory properties of Ras.  We identified the RASSF1 gene and showed that its protein served as a K-Ras apoptotic effector that was frequently down-regulated in primary tumors.  This was the first evidence of a K-Ras death effector pathway.  We subsequently identified several more RASSF family members and were the first to show they also have Ras death effector/tumor suppressor properties.  In further studies we have defined novel Ras signaling pathways modulated via RASSF proteins that include the microtubule skeleton, Bax, Salvador, PAR-4, SCF-B-TRCP, XPA and HIPK2.   These pathways link RASSF proteins into the control of motility, genetic stability, apoptosis, the cell cycle, regulation of protein stability, senescence and DNA repair.  We are currently studying additional novel signaling pathways modulated by Ras/RASSF interactions and examining mouse models to determine the role of RASSF proteins in ras mediated transformation in vivo.
    2. Mouse models of human disease suffer from the limitations imposed by the large genetic and physiological differences between mouse and man.  We believe that it is this discrepancy that forms the rate limiting factor for the effective translation of new anti-cancer drugs from the laboratory to the clinic.  In contrast to mice, pigs are extremely similar to humans at both a genetic and biochemical level.  Therefore, we have hypothesized that a porcine model for cancer could serve as a highly effective test bed for the testing of the utility and toxicity of novel therapeutics.  In collaboration with colleagues at the University of Illinois, We are currently developing a transgenic swine model for breast cancer.
    3. Although targeted inhibitors for Ras have been under development for more than 2 decades, none has yet proved successful in the clinic.  Indeed, until recently, Ras was described as undruggable.  We have used an in silico approach to identify potential small molecule Ras inhibitors.  We have identified compounds effective at low uM levels.  We are proceeding to validate and optimize the compounds as progenitors for a low toxicity high specificity inhibitor for Ras driven cancers.

    Literature:

    1. Vos, M., Ellis, C.A., Bell, A., Birrer, M.J. and Clark G.J. Ras utilizes the tumor suppressor RASSF1 as an effector to mediate apoptosis. (2000) J.Biol.Chem. 17;275(46):35669-35672 (PMID: 10998413).  PMC Journal - In Process.
    2. Ellis, C.A. Vos, M.D., Howell, H.,Vellacorsa T., Fults D.W., and Clark, G.J. Rig is a novel Ras-related protein and potential neural tumor suppressor. (2002) Proc. Nat. Acad. Sci. vol 99, no.15, pp 9876-9881 (PMID: 12107278)(PMCID PMC125049).   PMC Journal - In Process.
    3. Vos, M., Martinez, A., Ellis, C.A., Vallecorsa, T. and Clark G.J. The pro-apoptotic Ras effector Nore1 may serve as a Ras regulated tumor suppressor in the lung. (2003)
J. Biol. Chem. 278, 21938-21943 (PMID: 12676952).  PMC Journal - In Process.
    4. Jindong Chen, Weng-Onn Lui, Michele D. Vos, Geoffrey J. Clark, Masayuki Takahashi,Jacqueline Schoumans, Sok Kean Khoo, David Petillo, Todd Lavery, Jun Sugimura, DewiAstuti, Chun Zhang, Susumu Kagawa, Eamonn Maher, Catharina Larsson, Arthur S. Alberts, Hiro-omi Kanayama, and Bin Tean The.  The t(1;3) breakpoint-spanning genes LSAMP and NORE1 are involved in clear cell renal cell carcinomas. (2003) Cancer Cell. 4 (5) 405-413 (PMID: 14667507).  PMC Journal - In Process.
    5. Vos, M.D., Dallol, A., Martinez, A., Elam, C., Taylor, B.J., Latif, F. and. Clark G.J.A role for the RASSF1A tumor suppressor in the regulation of tubulin polymerization and genomic stability (2004) Cancer Research. 64 (12) 4244-50 (PMID: 15205337).  PMC Journal - In Process.
    6. Vos, M.D., Aganathalou, A., Eckfeld, K, Hesson, L. Latif, F and Clark G.J. The RASSF1A tumor suppressor activates Bax via MOAP-1 J. Biol. Chem (2006) 281(8):4557-63 (PMID: 16344548).  PMC Journal - In Process.
    7. Calvisi, D.F., Donninger, H., Vos, M,.D., Birrer, M., Gordon, L., Leaner, V. and Clark, GJ. The NORE1A tumor suppressor candidate modulates p21 CIP1 via p53. Cancer Research. (2009) Jun 1;69(11):4629-37 (PMID: 19435914) PMC Journal - In Process.
    8. Donninger H, Hesson L, Vos M, Beebe K, Gordon, K, Sidransky, D, Wei Liu J, Schlegel T, Paynne S, Hartmann A, Latif F and Clark G.J. The Ras effector RASSF2 controls the PAR-4 tumor suppressor.- (2010) Jun;30(11):2608-20) Mol. Cell Biol.(PMID: 20368356) (PMC2876522)
    9. Donninger H, Allen N.P., Henson A, Pogue, J., Williams A., Gordon L, Kassler, S. Dunwell, T., Latif F and Clark, GJ.: Salvador is a tumor suppressor effector of RASSF1A effector with Hippo pathway independent functions. J.Biol.Chem. (2011) May 27;286(21):18483-91(PMID:21489991)( PMC3099665).
    10. Yan, J., Kloecker, G., Fleming, C., Hansen, R., Hu, X., Ding, C., Cai, Y., Dong, X., Donninger, H., Eaton, J.W. and Clark G.J. Human Polymorphonuclear Neutrophils Specifically Recognize Tumor Cells for Killing.   Oncoimmunology-  Nov (2014), Issue 7 volume  3.PMC Journal - In Process.
    11. Mezzanotte J,  Hill, V.,  Schmidt, M.L., Krex, D., Schackert, G.,Pfeifer, G.P., Latif, F Clark, G.J. RASSF6 exhibits promoter hypermethylation in metastatic melanoma and inhibits invasion in melanoma cells. Epigenetics (2014), 9:11, 1-8  PMC Journal – In Process.
    12. Schmidt, M.L., Donninger, H and Clark, G.J.Ras regulates SCF-β-TrCP activity and specificity via its effector NORE1A.  J. Biol. Chem. (2014)  Nov 7;289(45):31102-10. PMC Journal - In Process
    13. 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.J. Biol. Chem. (2014)  Nov 7;289(45):31287-95.PMC Journal - In Process.
    14. Donninger, H., Clark, J. Rinaldo, F., Hobbing, K., Nelson, N., Barnoud, T., Schmidt, M.L., Vos, M.D., Sils, B and Clark G.J. The RASSF1A tumor suppressor regulates XPA mediated DNA repair.    Mol. Cell Biol.  (2015) Jan 1;35(1):277-87. PMC Journal - In Process.
    15. Donninger H, Calvisi, DF, Barnoud, T, Clark, J,  Schmidt, M. L., Vos, M  and Clark, GJNORE1A is a Ras senescence effector that controls the apoptotic/senescent balance of p53 via HIPK2.  J. Cell Biology: (2015), in press PMC Journal – In Process

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