gmp101

Giovanni M. Pitari, MD, PhD

Contact Dr. Pitari

1020 Locust Street
JAH 348
Philadelphia, PA 19107

(215) 955-5647
(215) 955-7006 fax

Medical School

MD, University of Catania Medical School, Catania (Italy) - 1991

Expertise and Research Interests

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.

Industrial Relevance

The work by Dr. Pitari has high translational potential for the diagnosis and cure of cancer and cancer metastasis.