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Kevin P Williams

Kevin P Williams, Associate Professor
Kevin P Williams, Associate Professor
  • Earned B.S and Ph.D. in Biochemistry in the United Kingdom at University of Bath and University of Cambridge, respectively
  • Postdoctoral Fellow at Massachusetts General Hospital and Joslin Diabetes Center at Harvard Medical School in immunology and diabetes
  • 12 years in industry at Perseptive Biosystems, Biogen Idec and Amphora Discovery Corp – major focus was drug discovery and protein therapeutics development
  • Registered as the inventor on nine patents
  • Contact: kpwilliams@nccu.edu or (919) 530-7726 

Research Focus

  • Hedgehog Pathway Dysregulation in Cancer,
  • Pharmacologic Profiling of Cancer Cells;
  • Identification and Development of Novel Hedgehog Pathway Inhibitors;
  • Role of Hedgehog Pathway in Alcohol-Induced Birth Defects.

The hedgehog (Hh) family of morphogens is critical for embryonic development and in the development of a number of adult tissues. A plethora of steps and components are involved in Hh signaling, from its expression, processing and secretion to pathway engagement on the responding cell. After expression, Hh protein is initially processed into a 20 kDa dual-lipidated form which is the active form of the protein. Our team was the first to identify that Hh is modified at the N-terminus by a palmitoyl group (Pepinsky et al. 1998). Hh signaling is initiated by binding to the Patched (Ptc) receptor on the responding cell which relieves the Ptc mediated inhibition of Smoothened (Smo) and leads to activation of GLI transcription factors. Dysregulation of Hh signaling has been implicated in disease with the pathway driving growth in a number of cancers through multiple mechanisms including but not limited to Hh overexpression, mutational inactivation of Ptc, mutational activation of Smo and overexpression of GLI transcription factors. Thus, significant effort has been expended to target this pathway with the most success being small molecule inhibitors of Smo including two FDA-approved drugs Vismodegib and Sonidegib. The identification of SMO resistance, however has led to efforts to target elsewhere in the pathway.

Key Research Initiatives

  • Identifying mechanisms of GLI activation in breast cancer and role in drug resistance.
  • High throughput screening to identify novel inhibitors of Hh signaling.
  • Large scale profiling of approved oncology drugs in cancer cell lines to identify patterns of drug sensitivity.

Recent Research Highlights

Molecular mechanisms of fetal alcohol pathology: As part of a recent U54 award from NIAAA to NCCU and the Bowles Alcohol Center at UNC-CH, our lab is studying genes that confer susceptibility to alcohol-induced birth defects with a focus on the Hedgehog pathway.

Photoactivatable Hedgehog Probe: Our lab has generated a photoactivatable form of sonic hedgehog protein that has potency comparable to that of the endogenous dual-lipidated form of ShhN (House et al. 2015). We suggest this modified form of ShhN can serve as a relatively facile and preferred source of ShhNp for in vitro assays and as a probe to identify novel Hh protein interactions. This work was funded by a NIH R15 award.

High-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of drug resistance: In collaboration with Dr. Gayathri Devi at Duke, we have characterized the sensitivity of an acquired therapeutic resistance IBC model to FDA approved oncology drugs (Williams et al. 2013). We observed that lapatinib-induced acquired resistance in SUM149 cells led to the occurrence of cross-resistance to other targeted- and chemotherapeutic drugs occurring. These lapatinib-resistant cells had increased anti-apoptotic proteins implicating a role for redox adaptation on anti-cancer drug efficacy.

Targeting Hh/GLI in Inflammatory Breast Cancer:  In collaboration with Dr. Gayathri Devi at Duke, we have observed elevated expression of GLI1, typically a marker for Hh pathway activation in the IBC cell line SUM149 (Thomas et al. 2011). Reducing GLI1 expression in SUM149 by siRNA or a small molecule GLI inhibitor resulted in decreased proliferation, and increased apoptosis. We are currently extending these studies to assess combination therapies for IBC (funded through a DOD BCRP IDEA award).

Publications

Complete List of Published Work in My Bibliography:

http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/40734586/?sort=date&direction=ascending

Journal Articles (since joining NCCU in 2007):

  1. A.J. House, L.R. Daye, M. Tarpley, K. Addo, D.S. Lamson, M.K. Parker, W.E. Bealer, K.P. Williams, Design and characterization of a photo-activatable hedgehog probe that mimics the natural lipidated form. Archives of Biochemistry and Biophysics 567 (2015) 66-74.
  2. S. Ghose, J. Zhang, L. Conley, R. Caple, K.P. Williams, D. Cecchini, Maximizing binding capacity for protein A chromatography. Biotechnology progress 30 (2014) 1335-1340.
  3. K.P. Williams, J.L. Allensworth, S.M. Ingram, G.R. Smith, A.J. Aldrich, J. Z Sexton, G. R Devi, Quantitative high-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of acquired drug resistance and re-sensitization. Cancer Letters 337 (2013) 77-89.
  4. F. Rangwala, K.P. Williams, G.R. Smith, J. Allensworth, Z. Thomas, H.K. Lyerly, A.M. Diehl, M.A. Morse, G.R. Devi, Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines. BMC Cancer 12 (2012) 402.
  5. Z. Thomas, W. Gibson, J. Sexton, K. Aird, S. Ingram, A. Aldrich, H. Lyerly, G. Devi, K. Williams, Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration. British Journal of Cancer 104 (2011) 1575-1586.
  6. J.Z. Sexton, P.V. Danshina, D.R. Lamson, M. Hughes, A.J. House, L.A. Yeh, D.A. O’Brien, K.P. Williams, Development and Implementation of a High Throughput Screen for the Human Sperm-Specific Isoform of Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDHS). Current Chemical Genomics 5 (2011) 30-41.
  7. D.R. Lamson, A.J. House, P.V. Danshina, J.Z. Sexton, K. Sanyang, D.A. O'Brien, L.A. Yeh, K.P. Williams, Recombinant human sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDHS) is expressed at high yield as an active homotetramer in baculovirus-infected insect cells. Protein expression and purification 75 (2011) 104-113.
  8. L. Daye, W. Gibson, K. Williams, Development of a high throughput screening assay for inhibitors of hedgehog-heparin interactions. International Journal of High Throughput Screening 1 (2010) 69-80.
  9. L. Ricci, K. Williams, Development of Fluorescence Polarization Assays for the Molecular Chaperone Hsp70 Family Members: Hsp72 and DnaK. Current Chemical Genomics 2 (2008) 90-95.

Book Chapters

  1. C.E. Oldham, K.P. Williams, L.G. Love, Undergraduate Research for Students Majoring in Pharmaceutical Sciences Leads to Student Success, in: J. McClinton, (Ed.), Diversity of Higher Education Emerald, Bingley, 2015, pp. 129-142.
  2. J. Sexton, K. Williams, Evaluating the Peroxisomal Phenotype in High-Content Toxicity Profiling, in: P. Steinberg, (Ed.), High-Throughput Screening Methods in Toxicity Testing, Wiley, New Jersey, 2013, pp. 501-518.
  3. J. Scott, K. Williams, Validating Identity, Mass Purity and Enzymatic Purity of Enzyme Preparations, in: G.S. Sittampalam, N. Gal-Edd, M. Arkin, D. Auld, C. Austin, B. Bejcek, M. Glicksman, J. Inglese, V. Lemmon, Z. Li, (Eds.), Assay Guidance Manual [Internet] Eli Lilly & Company and the National Center for Advancing Translational Sciences, Bethesda (MD), 2012.
  4. K. Williams, J. Scott, Enzyme assay design for high-throughput screening., in, Methods in Molecular Biology (Clifton, NJ), Springer, 2009, pp. 107.
  5. W. Janzen, P. Bernasconi, L. Cheatham, P. Mansky, I. Popa-Burke, K. Williams, J. Worley, N. Hodge, Optimizing the chemical genomics process, in, Chemical Genomics, Marcel Dekker Inc, 2004, pp. 59.
 
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