J. Silvio Gutkind, Ph.D

Chief, Oral and Pharyngeal Cancer Branch
Chief, Cell Growth Regulation Section
Chief, Molecular Carcinogenesis Section


NATIONAL INSTITUTES OF HEALTH/NIDCR
BUILDING 30 ROOM 211
30 CONVENT DR MSC 4340
BETHESDA MD 20892-4340

Phone: (301) 496-6259
Fax: (301) 402-0823
E-mail: Dr. J. Silvio Gutkind

Biographical Sketch 

J. Silvio Gutkind received his Ph.D. in pharmacy and biochemistry from the University of Buenos Aires, Argentina. He was trained as a post-doctoral fellow at the National Institute of Mental Health (NIMH) and the National Cancer Institute (NCI) and then joined the NIDCR, where he is currently chief of the Oral and Pharyngeal Cancer Branch. His research team studies the molecular basis of cancer, with emphasis on basic mechanisms of signal transduction and cell growth control and their dysregulation in oral squamous cell carcinogenesis and AIDS-malignancies. He is recognized for his pioneering research aimed at unraveling the complexity of the intracellular signaling circuitries by which receptor tyrosine kinases and G protein-coupled receptors control the nuclear expression of growth promoting genes, thereby promoting normal and malignant cell proliferation. His recent studies have begun addressing how cancer cells gain the ability to co-opt the potent pro-migratory activity of chemokines and their G protein-linked receptors to metastasize to regional and distant organs, and how tumoral cells promote the formation of new vascular and lymphatic vessels. His laboratory is exploiting their recent advances for the identification of novel mechanism-based anti-cancer treatments.  

In particular, Dr. Gutkind is currently leading a multi-institutional effort aimed at exploring the biochemical consequences and clinical benefits of treating newly diagnosed head and neck cancer patients with mTOR inhibitors. He has published numerous original studies in prestigious journals, and has organized and co-organized multiple national and international meetings and symposia on signal transduction and oral cancer research. He has been a member of many editorial boards of scientific journals and national and international advisory committees, and has supervised and mentored numerous graduate students, research fellows, and tenure-track investigators, many of whom are now playing leadership roles in institutions in the U.S. and abroad.

Research Interests/Scientific Focus

Cell Growth Regulation Section

Certain alterations of proteins involved in mitogenic signaling are known to exert profound effects on cellular behavior, including malignant transformation. The overall aim of this section is to explore the molecular basis of cancer, approaching this problem through the study of normal and aberrant functioning of molecules that participate in the transduction of proliferative signals. A major emphasis in this program has been on the study of mitogenic signaling from G protein coupled receptors (GPCRs) as a simple model system to identify critical molecules regulating normal cell proliferation and tumorigenesis. GPCRs have been traditionally linked to tissue specific, fully differentiated cell functions such as exocytosis, chemotaxis, hemostasis, photoreception, neurotransmission, immune responses, and smell and taste. However, GPCRs are also expressed in proliferating cells, and they have also more recently been implicated in embryogenesis, tissue repair and remodeling, inflammation, and angiogenesis. Furthermore, GPCRs are expressed from the genome of cancer-associated viruses, and recent large cancer sequencing initiatives have revealed a surprisingly high incidence of mutations in G proteins and GPCRs in some of the most prevalent human malignancies. Ultimately, the work of this section is aimed at unraveling the complexity of the signaling networks by which GPCRs and other cell surface receptors regulate gene expression, thereby promoting normal and aberrant cell growth.

Current projects include:

• The use of synthetic biology approaches to build, and hence understand, GPCR-regulated signaling circuitries in cancer and metastasis
• Defining the molecular mechanisms by which GPCRs, tyrosine kinase growth factors, semaphorins and plexins control angiogenesis and lymphangiogenesis
• The study of signaling networks by which G proteins and their coupled receptors regulate adult stem cell function
• The development of therapeutic approaches targeting virally-encoded GPCRs and their regulated pathways for the management and prevention of AIDS-associated malignancies

Molecular Carcinogenesis Section

Squamous cell carcinoma of the head and neck (HNSCC) is the 6th most common cancer in the developed world, affecting nearly 44,000 patients each year in the US, which results in ~11,000 deaths. The vast majority of these malignancies involve neoplastic lesions in the oral cavity, lip, and pharynx. Like most cancers, HNSCC results from a series of discrete, irreversible and sequential alterations in genes that control cell growth and differentiation, together with genetic aberrations promoting invasion and metastasis. The goal of the program is scientific excellence in addressing the devastating problem of oral cancer. In particular, this section aims to elucidate the molecular changes that contribute to the evolution of oral neoplasia, and to use this knowledge to develop markers of disease progression and novel therapeutic approaches for oral malignancies.

Current projects include:

• Genomic and proteomic approaches to understand oral cancer
• The pre-clinical and clinical evaluation of novel mechanism-based approaches for HSNCC prevention and treatment, with emphasis on the PI3K-Akt-mTOR pathway
• The development of genetically-defined and chemically induced oral-specific animal models to study HNSCC
• The study of the molecular mechanisms involved in the malignant reprogramming of oral epithelial stem cells into cancer initiating cells

Selected Publications

1. Yagi H., Tan W., Dillenburg-Pilla P., Armando S., Amornphimoltham P., Simaan M., Weigert R., Molinolo A.A., Bouvier M., and Gutkind J.S. A synthetic biology approach reveals a CXCR4-G13-Rho signaling axis driving transendothelial migration of metastatic breast cancer cells. Science Signaling, 4:ra60, 2011.
2. Martin D., Galisteo R., Molinolo A.A., Wetzker R., Hirsch E., and Gutkind J.S.  PI3Kγ mediates Kaposi's sarcoma-associated herpesvirus vGPCR-induced sarcomagenesis. Cancer Cell, 19: 805-813, 2011.
3. Patel V., Marsh C.A., Dorsam R.T., Masedunskas A., Amornphimoltham P., Nathan C.O., Singh B., Weigert R., Molinolo A.A., and Gutkind J.S. Decreased lymphangiogenesis and lymph node metastasis by mTOR inhibition in head and neck cancer.  Cancer Research, 71:7103-7112, 2011.
4. Knox S.M., Lombaert M. A., Reed X., Vitale-Cross L., Gutkind J.S. and Hoffman M.P. Parasympathetic innervation maintains epithelial progenitor cells during salivary organogenesis. Science, 329:1645-1647, 2010.
5. Sakurai A., Gavard J., Annas-Linhares Y., Basile J.R., Amornphimoltham P., Palmby T.R., Yagi H., Zhang F., Randazzo P.A., Li X., Weigert R., and Gutkind J.S. Semaphorin 3E initiates anti-angiogenic signaling through Plexin-D1 by regulating Arf6 and R-Ras. Mol Cell Biol. 2010
6. Castilho R.M, Squarize C.H., Chodosh L.A., Williams B.O., and Gutkind J.S. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell, 5:279-289, 2009.
7. Czerninski R., Amornphimoltham P., Patel V., Molinolo A.A., and Gutkind J.S. Targeting mTOR by rapamycin prevents tumor progression in an oral-specific chemical carcinogenesis model. Cancer Prevention Research, 2:27-36, 2009.
8. Amornphimoltham P., Patel V., Leelahavanichkul K., Abraham R.T, and Gutkind J.S. A retro-inhibition approach reveals a tumor cell-autonomous therapeutic response to rapamycin in head and neck squamous cell carcinomas. Cancer Research, 68:1144-1153, 2008.
9. Basile J.R., Castilho R.M., Williams V.P., and Gutkind JS. Semaphorin4D provides a link between anon guidance processes and tumor-induced angiogenesis, Proc. Natl. Acad. Sci. U.S.A. 103:9017-9022, 2006.
10. Gavard J. and Gutkind J.S. VEGF controls endothelial cell permeability by promoting the β-arrestin-dependent endocytosis of VE-cadherin. Nature Cell Biol., 11:1223-1234, 2006.
11. Amornphimoltham P., Patel V., Sodhi A., Nikitakis N.G., Sauk J.J., Sausville E.A., Molinolo A.A., and Gutkind J.S. mTOR, a molecular target in squamous cell carcinomas of the head and neck. Cancer Research, 65:9953-9961, 2005.
12. Castellone M.D., Teramoto H., Williams B.O., Druey K.M., and Gutkind J.S. Prostaglandin E2 promotes colon cancer cell growth through a novel Gs-axin-β-catenin signaling axis. Science, 310:1504-1510, 2005.
13. Montaner S., Sodhi A., Molinolo A., Bugge T.H., Sawai E.T., He Y., Li Y., Ray P.E., and Gutkind J.S. Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell, 3:23-36, 2003.
14. Coso O., Chiariello M., Yu J.-C., Crespo P., Teramoto, H., Xu N., Miki T., and Gutkind J.S. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK (SAPK) signaling pathway. Cell, 81:1137-1148, 1995.
15. Crespo P., Xu N., Simonds W.F., and Gutkind J.S. Ras-dependent activation of MAP kinase pathway mediated by G-protein βγ subunits.  Nature, 369:418-420, 1994.
    

Current Clinical Trials

• NCT01195922, A Pilot Trial Targeting mTOR as a Novel Mechanism-Based Neoadjuvant Therapy for Head and Neck Cancer. NIDCR/NCI/NIDCD/MUSC.
  PI: Gutkind J.S. 2010.
  
  
• T-D-0024, The Molecular Anatomy of Oral Wound Healing. NIDCR.
  PI: Gutkind J.S. 2010.

Patents

• 5,384,243, issued January 24, 1995. J. Silvio Gutkind and Keith C. Robbins: Method for screening an agent for its ability to prevent cell transformation.
• Use of mTOR inhibitors for oral cancer chemoprevention. Filed, 2008.
• DSG3 as a Biomarker for the Detection of Metastasis. Filed, 2009.

Complete CV and Publications (PDF File, 202KB)