Full voting member, University Reappointment, Promotion and Tenure (RPT) Appeals Committee
Full voting member, Integrated Biosciences PhD Graduate Studies and Curriculum Committees
Member, Deans Advisory Council (CAS)
Member NCGlaxoSmithKline STEM Program Internal Advisory Board
Member, Cancer Research Division, NCCU
Dr. Kevin P. Williams, Ph.D. is an Associate Professor in the Department of Pharmaceutical Sciences and a faculty member of BRITE at North Carolina Central University. Dr. Williams has over 25 years combined experience in both academic and biopharmaceutical-based research with a focus on cancer and drug discovery. Dr. Williams received his B.Sc. in Biochemistry from the University of Bath in the UK and received his Ph.D. in Biochemistry from the University of Cambridge (UK). He completed his postdoctoral work at Massachusetts General Hospital and the Joslin Diabetes Center in Boston. Prior to joining NCCU in 2007, he spent six years as a Senior Scientist at Biogen in the Department of Protein Engineering and four years at Amphora Corp as Director of Enzyme Drug Discovery. At NCCU he has obtained NIH and DOD research support and mentored 12 Masters level graduate students. His lab currently focuses on identifying novel modulators of the hedgehog pathway. Dr. Williams serves as course director and main instructor for the undergraduate bioprocessing and graduate-level biomanufacturing classes. He is co-author of over 45 publications and co-inventor on 9 patents.
- 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).
Complete List of Published Work in MyBibliography:
1. Ricci L. and Williams KP (2008) Development of Fluorescence Polarization Assays for the Molecular Chaperone Hsp70 Family Members: Hsp72 and DnaK. Current Chemical Genomics 2, 90-95.
2. Danshina PV, Temple B, Williams KP, Sexton JZ, Yeh, LA, and O'Brien DA (2009) New strategies for male fertility control: sperm glycolytic enzymes as targets. J Andrology 30, 23.
3. Daye L, Gibson W, and Williams KP (2010) Development of a high throughput screening assay for inhibitors of hedgehog-heparin interactions. International Journal of High Throughput Screening 1, 69-80.
4. Thomas ZI, Sexton JZ, Gibson W, Aird KM, Aldrich A, Devi G, and Williams KP (2010) Establishment of a high content assay to assess the effects of gene silencing on inflammatory breast cancer cell migration. Cancer Epidemiology, Biomarkers & Prevention, 19, 10-1.
5. Lamson DR, House AI, Danshina PV, Sexton JZ, Sanyang K, O?Brien DA, Yeh L-A, Williams KP (2011) Recombinant human sperm-specific gyceraldehyde-3-phosphate dehydrogenase (GAPDHS) is expressed at high yield as an active homotetrameric form in baculovirus-infected insect cells. Protein Expression and Purification 75, 104-113.
6. Sexton JZ, Lamson DR, Danshina PV, Hughes MH, House AJ, Yeh L-A, O?Brien DA, Williams KP (2011) Optimization, validation and high throughput screening of an assay for the human sperm-specific isoform of glyceraldehyde 3-phosphate dehydrogenase (GAPDHS). Current Chemical Genomics 5, 30-41.
7. Thomas ZI, Gibson W, Sexton JZ, Aird KM, Ingram SI, Aldrich A, Lyerly HK, Devi GR and Williams KP (2011) Targeting GLI1 expression in inflammatory breast cancer cells enhances apoptosis and attenuates cell migration. British Journal of Cancer 104 1575-1586.
8. Rangwala F, Williams KP, Smith GR, Allensworth J, Thomas ZI, Lyerly HK, Diehl AM, Morse MA and Devi GR (2012) Differential effects of arsenic trioxide on chemo-sensitization in human hepatic tumor and stellate cell lines, BMC Cancer 12 402-412.
9. Williams KP, Allensworth JL, Ingram SM, Smith GR, Aldrich AJ, Sexton JZ, Devi GR (2013) Quantitative high-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of acquired drug resistance and re-sensitization. Cancer Letters 337, 77-89.
10. Ghose S, Zhang J, Caple R, Williams KP, Conley L, Cecchini D (2014) Maximizing binding capacity for Protein A chromatography. Biotechnology Progress 30 1335-40 (doi: 10.1002/btpr.1980).
11. House AJ, Daye LR, Tarpley M, Addo K, Lamson DS, Parker MK, Bealer WE, Williams KP (2015) Design and characterization of a photo-activatable hedgehog probe that mimics the natural lipidated form. Arch Biochem Biophys 567 66-74 (doi: 10.1016/j.abb.2014.12.014).
1. Janzen W, Bernasconi P, Cheatham L, Mansky P, Popa-Burke I, Williams KP, Worley J, Hodge N (2004) Optimizing the chemical genomics process, in Chemical Genomics. (Eds.F Darvas, A Guttman, G Dorman), Marcel Dekker, New York, pp. 59-100.
2. Williams KP and Scott JE (2009) Enzymatic Assay Design for High Throughput Screening. In Methods in Molecular Biology: High Throughput Screening: Methods and Protocols 2nd ed). (Eds. Janzen WP and Bernasconi P), Humana Press Inc. Totowa, NJ, pp.107-126.
3. Scott JE and Williams KP (2012) Validating Identity, Mass Purity and Enzymatic Purity of Enzyme Preparations, in: Sittampalam GS, Weidner J, Auld D, et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004-.
4. Sexton JZ and Williams KP (2013) Evaluating the Peroxisomal Phenotype in High-Content Toxicity Profiling, in High-Throughput Screening Methods in Toxicity Testing, Pablo Steinberg Editor, Wiley Inc. Chapter 27, pp.501-517. DOI: 10.1002/9781118538203.ch27
5. Oldham CE, Williams KP, Love LG (2015) Undergraduate Research for Students Majoring in Pharmaceutical Sciences Leads to Student Success, in: Infusing Research into Historical Black Colleges and Universities Curricula, McClinton J, Melton MA, Engerman K, Adams JH. Editors, Emerald Publishing, Vol. 17, pp. 129-142.