Dr. Pier-Paolo Claudio's Research Summary The focus of our by yaohongm

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									                        Dr. Pier-Paolo Claudio’s Research Summary


        The focus of our laboratory is to understand the molecular mechanisms governing
malignant transformation in order to tailor novel therapeutic strategies. To effectively
design novel biological drugs, a further understanding of the mechanism of cancer
pathogenesis is required. Toward this end, we have carried out in the past 15 years
studies to understand the crosstalk between those factors that contribute to cancer
progression versus those that protect from it.
        The ultimate destiny of a cell results from an intricate balance between multiple
regulators including oncogenes, tumor suppressor genes, cell cycle associated proteins,
and growth factors. Deregulation of the cell cycle machinery switches the phenotype
from a normal cell to a cancerous cell. Fundamental alteration of tumor suppressor genes
may result in an unregulated cell cycle with the accumulation of mutations and eventual
neoplastic transformation. As such, one may define cancer as a genetic disease of the cell
cycle.
        One of the most well-studied tumor suppressor genes is the retinoblastoma gene
and its product pRb/p105. The recently identified protein, p130 along with p107 and
pRb/p105 comprise the Retinoblastoma family of proteins. We have demonstrated the
growth suppressive properties of p130 in lung cancer cell lines as well as in vivo in
xenografts mouse model using viral delivery of the p130 gene, suggesting that p130
could be a novel biological drug. In a follow up of these in vivo studies we found that
overexpression of the wild-type p130 gene interferes with the angiogenic process by
specifically down-regulating VEGF.
        Gene therapy offers great potential for combating and curing a wide range of
pathologic lesions. One of the major limiting factors in gene therapy has been the
development of safe and effective delivery systems.
        The emphasis of our most recent research efforts is on imaging guided drug
delivery. The recent emergence of "molecular imaging" has set the stage for an
evolutionary jump in diagnostic imaging and therapy. The ability to incorporate drugs or
genes into detectable site-targeted nanosystems represents a new paradigm in therapeutics
that will usher in an era of image-based drug delivery.
        We have developed a novel gene therapy system based on the use of
commercially available ultrasound contrast agents and adenoviruses that enhance the
specificity of gene transfer in vitro as well in vivo. Ultrasound-mediated microbubble
destruction improves the efficacy and reduces the non-specific expression of gene
therapy vectors providing a useful tool for manipulating gene expression in the living
animal. We are currently working on further developing this useful targeting gene
therapy tool to help closing the gap that still exist between laboratory bench and bedside
application.
Most relevant publications

   1. Claudio P.P., et al. (1994): p130/PRb2 has similar yet distinctive growth suppressive
       properties as retinoblastoma family members, pRb and p107. Cancer Research 54: 5556-
       5560.
   2. Claudio P.P., et al. (1996): Functional analysis of pRb2/p130 interaction with cyclins.
       Cancer Research 56: 2003-2008.
   3. Howard C.M., Claudio P.P., et al. (1998): Retinoblastoma-related protein pRb2/p130
       and suppression of tumor growth in vivo. J.Nat. Cancer Inst. 19: 1451-1460.
   4. Claudio P.P., et al. (1999): Adenoviral RB2/p130 gene transfer inhibits smooth muscle
       cell proliferation and prevents restenosis following angioplasty. Circulation Research,
       85: 1032-39.
   5. Claudio P.P., et al (2000): Mutations in the Retinoblastoma-related gene RB2/p130 in
       lung tumors and suppression of tumor growth in vivo by retroviral-mediated gene
       transfer. Cancer Research, 60: 372-382.
   6. Claudio P.P., et al. (2001): RB2/p130 gene enhanced expression down-regulates
       Vascular Epithelial Growth Factor expression and inhibits Angiogenesis in vivo. Cancer
       Research, (62):462-68.
   7. Giuseppe Russo, Alessandra Zamparelli, Candace M. Howard, Corrado Minimo,
       Cristiana Bellan, Giovanna Carrillo, Luigi Califano, Lorenzo Leoncini, Antonio
       Giordano, and Pier Paolo Claudio. Expression of Cell-Cycle Regulated Proteins
       pRB2/p130, p107, E2F4, p27, and of pCNA in Salivary Gland Tumors. Prognostic and
       diagnostic implications. Clinical Cancer Research, 2005 May 1;11(9):3265-73.
   8. Francesca Sanseverino, Rosa Santopietro, Michela Torricelli, Giuseppina D’Andrilli,
       Gabriele Cevenini, Alessandro Bovicelli, Lorenzo Leoncini, Giovanni Scambia, Felice
       Petraglia, Antonio Giordano and Pier Paolo Claudio. pRb2/p130 and VEGF
       expressions in endometrial carcinoma in relation to angiogenesis and tumor
       histopathologic grade. Cancer Biol Ther. 2006 Jan 22;5(1).
   9. Elettra Merola, Eliseo Mattioli, Corrado Minimo, Weineng Zuo, Carla Rabitti, Michele
       Cicala, Renato Caviglia, Lucio Pollice, Antonio Giordano and Pier Paolo Claudio.
       Immunohistochemical evaluation of pRb2/p130, VEGF, EZH2, p53, p16, p21waf-1, p27,
       and PCNA in Barrett’s Esophagus. Journal Cell Physiology, 207(2): 512-9, 2006.
   10. Claudio, P.P. et al. Phosphorylation of p53 by cdk9 prevents HIV-1 gene transcription
       and viral replication. Journal Cell Physiology 208(3): 602-612, 2006.
   11. Howard, C.M., Forsberg F., Liu, J.B., Merton D.A., Minimo C., and Claudio P.P.
       Ultrasound guided site specific gene delivery system using adenoviral vectors and
       commercial ultrasound contrast agents. Journal Cell Physiology 2006 Nov; 209 (2):413-
       21.
   12. Eliseo Mattioli, Paraskevi Vogiatzi, Ang Sun, Giovanni Abbadessa, Giulia Angeloni,
       Domenico D’Ugo, Daniela Trani, John P. Gaughan, Fabio Maria Vecchio, Gabriele
       Cevenini, Roberto Persiani, Antonio Giordano, and Pier Paolo Claudio
       Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, p16 INK4A, p27KIP1,
       p21WAF1, Ki-67 expression patterns in gastric cancer. J Cell Physiol. 2007 Jan;
       210(1):183-91.
   13. De Falco G, Leucci E, Lenze D, Piccaluga PP, Claudio P.P., Onnis A, Cerino G, Nyagol
       J, Mwanda W, Bellan C, Hummel M, Pileri S, Tosi P, Stein H, Giordano A, Leoncini L.
       Gene expression analysis identifies novel RBL2/p130 target genes in endemic Burkitt's
       lymphoma cell lines and primary tumors. Blood. 2007 May 7, in press.
Fluorescence imaging of mice tissues and DB-1melanoma xenografts obtained from mice
injected in their tail vein with complement treated Ad-GFP/microbbubbles demonstrating
site-specific delivery of the transgene. A: Nude mice with melanoma xenografts (DB-1
cells) implanted on its flank; (B) dissected tumor showing the vascular axis; (C) US
enhancement of tumor vasculature by US-targeted microbubble destruction (see red
arrowhead). D–F: H&E staining of tumor, hearth, and lung, respectively; (G–I)
lightmicroscopy of tumor, hearth, and lung, respectively; (J–L) fluorescence microscopy
of tumor, hearth, and lung, respectively.
Tumor growth inhibition of human lung carcinoma cells in nude mice and the average
tumor volume over time of two separate studies. At day 15, tumors were transduced with
an intratumoral injection (20 l) of a solution containing 5 x 106 retroviruses carrying the
puromycin resistance gene alone (a and b), the lacZ gene (c and d), or the p130 gene (e
and f).
                                  Laboratory personnel:
                         Pierpaolo Aimola (Graduate student, Ph.D.)
                          Miranda Carper (Graduate student, Ph.D.)
                            Sarah Kelly (Graduate student, Ph.D.)
                           Weineng Zuo (Laboratory Technician)

								
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