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Thomas Jefferson University - Giovanni M. Pitari, M.D., Ph.D.
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Giovanni M. Pitari, M.D., Ph.D.
Pharmacology and Experimental Therapeutics
Thomas Jefferson University
Department of Pharmacology and Experimental Therapeutics
Associate Professor
Thomas Jefferson University
Jefferson Medical College
Department of Medicine
Associate Professor
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Mailing Address
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1020 Locust Street, JAH 348
Philadelphia, Pennsylvania 19107
United States
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Qualifications
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M.D., University of Catania Medical School, Catania (Italy), 1991
Ph.D., University of Catania Medicals School, Catania (Italy), 1997
Specialty Certification, Italian and European Board of Medical Toxicology, 1999
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Expertise and Research Interests
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Expertise:
Dr. Pitari is an expert in basic and clinical pharmacology working in the field of translational medicine. His scientific activity investigates the translational potential of the cyclic guanosine 3`-5`-monophosphate (cGMP) signaling pathway.
Research Interests:
The research focus of Dr. Pitari`s laboratory is the identification of unique molecular mechanisms to prevent or treat cancer and its metastasis. Current research programs include:
1. The cGMP Signalome in cancer metastasis
Biological pathways regulated by cGMP mediate cell-environment interactions which influence cell shape, motility, proliferation and fate commitment. Signal transfer from cGMP is directly mediated by cyclic nucleotide-dependent protein kinases, phosphodiesterases, and cyclic nucleotide-gated channels and activate cellular processes that are spatially and temporally integrated virtually with all cell molecular pathways. Exploration of this cGMP signaling network in Dr. Pitari`s laboratory demonstrated its strategic role in controlling actin cytoskeletal remodeling underlying tumor cell migration, invasion and metastasis. These studies revealed that regulation of the cGMP signalome at dynamic membrane regions effectively inhibits the metastatic behavior of human cancer cells. Ongoing studies examine the role of cGMP and its downstream molecular effectors as novel diagnostic and therapeutic targets to prevent or treat metastasis and cancer disease progression.
2. MMP-9 and invadopodia regulation
Invadopodia are proteolytically active membrane protrusions formed by the actin cytoskeleton which mediate tumor invasion and metastasis. Instrumental to basement membrane degradation is the invadopodial component metalloproteinase 9 (MMP-9), a soluble protease released by cancer cells into the extracellular matrix during tissue invasion. Studies from this laboratory have demonstrated that MMP-9 signaling through its catalytic domain increases the metastatic potential of cancer cells by promoting actin cytoskeleton-driven locomotory organelle formation and matrix invasion. They also described a novel mechanism promoted by MMP-9 in cancer cells, the metastatic seeding of target organs in vivo, employing mouse models of cancer metastasis. Further, the laboratory has demonstrated that MMP-9 behaves as a prognostic and predictive factor for metastatic disease progression in patients with colorectal cancer. Ongoing studies examine the potential of approaches targeting MMP-9 and invadopodia as anti-metastatic therapies for cancer.
3. Bacterial enterotoxins as cancer therapeutics
Dysregulation of homeostatic mechanisms underlying cell proliferation and tissue renewal have a central role in neoplastic transformation. Studies from this laboratory have demonstrated that heat-stable enterotoxins (STs) produced by Escherichia Coli regulate intestinal epithelial cell turnover and colon cancer cell cycle progression. ST effects are principally mediated by the intestine-specific receptor guanylyl cyclase C and activation of cGMP-dependent signal transduction mechanisms, including calcium signaling through cyclic nucleotide-gated channels and calcium-sensing receptor. As a result of these studies, a novel paradigm for intestinal tumorigenesis has been formulated, that colon cancer is a disease of paracrine hormone insufficiency which could be treated by oral replacement therapy with bacterial enteorotoxins. Ongoing studies in the laboratory explore the utility of bacterial enterotoxins as therapeutics for the prevention and treatment of colorectal cancer.
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Industrial Relevance
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The work by Dr. Pitari has high translational potential for the diagnosis and cure of cancer and cancer metastasis.
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Keywords
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Cyclic GMP; matrix metalloproteinase 9 (MMP-9); guanylyl cyclases; bacterial enterotoxins; cell turnover; cytoskeletal remodeling; invadopodia; cancer prevention; cancer metastasis; targeted therapy
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Publications
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- Selected Publications:
- Lucas K., Pitari G.M., Kazerounian S., Ruiz-Stewart I., Park J., Schulz S., Chepenik K.P., Waldman S.A. Guanylyl cyclases and signaling by cyclic GMP. Pharm. Rev. 52:375-414, 2000
- Pitari G.M., Di Guglielmo M., Park J., Schulz S., Waldman S. Guanylyl cyclase C agonists regulate progression through the cell cycle of human colon carcinoma cells. Proc. Natl. Acad. Sci. U S A. 98:7846-7851, 2001
- Kazerounian S., Pitari G.M., Ruiz-Stewart I., Schulz S., Waldman S. Nitric oxide activation of soluble guanylyl cyclase reveals high and low affinity sites that mediate allosteric inhibition by calcium. Biochemistry 41:3396-3404, 2002
- Ruiz-Stewart I., Kazerounian S., Pitari G.M., Schulz S., Waldman S. Soluble guanylyl cyclase is allosterically inhibited by direct interaction with 2-substituted adenine nucleotides. Eur. J. Biochem. 269:2186-2193, 2002
- Pitari G.M., Zingman L.V., Hodgson D.M., Alekseev A.E., Kazerounian S., Bienengraeber M., Hajnóczky G., Terzic A., Waldman S. Bacterial enterotoxins are associated with resistance to colon cancer. Proc. Natl. Acad. Sci. U S A. 100:2695-2699, 2003
- Ruiz-Stewart I., Tiyyagura S.R., Lin J.E., Kazerounian S., Pitari G.M., Schulz S., Martin E. Murad F., Waldman S.A. Guanylyl cyclase is an ATP sensor coupling nitric oxide signaling to cell metabolism. Proc. Natl. Acad. Sci. U S A. 101:37-42, 2004
- Kazerounian S., Pitari G.M., Shah F.J., Frick G.S., Madesh M., Ruiz-Stewart I., Schulz S., Hajnóczky G., Waldman S.A. Proliferative signaling by store-operated calcium channels opposes colon cancer cell cytostasis induced by bacterial enterotoxins. J. Pharmacol. Exp. Ther. 314:1013-1022, 2005
- Pitari G.M., Baksh R.I, Harris D.M., Li P., Kazerounian S., Waldman S.A. Interruption of homologous desensitization in cyclic guanosine 3'',5''-monophosphate signaling restores colon cancer cytostasis by bacterial enterotoxins. Cancer Res., 65:11129-11135, 2005
- Lubbe W.J., Zhou Z.Y., Fu W., Zuzga D., Schulz S., Fridman R., Muschel R.J., Waldman S.A., Pitari G.M. Tumor epithelial cell matrix metalloproteinase-9 is a target for antimetastatic therapy in colorectal cancer. Clin. Cancer Res., 12:1876-1882, 2006
- Debruyne P., Witek M., Gong L., Birbe R., Chervoneva I., Jin T., Domon-Cell C., Palazzo J.P., Freund J.N., Li P., Pitari G.M., Schulz S., and Waldman S.A. Bile acids induce ectopic expression of the intestinal marker guanylyl cyclase C through NF-kB and Cdx2 in gastroesophageal cells. Gastroenterology, 130:1191-1206, 2006
- Pitari G.M., Li T., Baksh R.I., Waldman S.A. Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells. Mol. Cancer Ther., 5:1190-1196, 2006
- Li P., Schulz S., Bombonati A., Palazzo J.P., Hyslop T.M., Barab A.A., Siracusa L.D., Pitari G.M.*, Waldman S.A.* Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity. Gastroenterology, 133:599-607, 2007. *Contributed equally; correspondent Authors
- Pitari G.M., Li P., Lin J.E., Zuzga D., Gibbons A.V., Snook A.E., Schulz S., Waldman S.A. The paracrine hormone hypothesis of colorectal cancer. Clin. Pharmacol. Ther., 82:441-447, 2007
- Li P., Chervoneva I., Schulz S., Waldman S.A., Pitari G.M. Homeostatic control of the crypt-to-villus axis by the bacterial enterotoxin receptor guanylyl cyclase C restricts the proliferating compartment in intestine. Am. J. Pathol., 171:1847-1858, 2007
- Li P., Schulz S., Pitari G.M., Waldman S.A. Sex modulates intestinal transformation by the tumor suppressor GCC. Clin. Transl. Sci., 1:146-150, 2008
- Zuzga D., Gibbons A.V., Li P., Lubbe W.J., Chervoneva I., Pitari G.M. Overexpression of matrix metalloproteinase 9 in tumor epithelial cells correlates with colorectal cancer metastasis. Clin. Transl. Sci., 1:136-141, 2008
- Pitari G.M., Lin J.E., Shah F.J., Lubbe W.J., Zuzga D.S., Li P., Schulz S., Waldman S.A. Enterotoxin preconditioning restores calcium-sensing receptor-mediated cytostasis in colon cancer cells. Carcinogenesis, 29:1601-1607, 2008
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Individual Expertise profile of
Giovanni M. Pitari, M.D., Ph.D., Copyright © Giovanni M. Pitari, M.D., Ph.D..
Last Updated
by Admin
: Wednesday, January 21, 2009 11:19:52 AM
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