Pier Paolo Claudio, M.D., Ph.D., Associate Professor
Department: Biochemistry and Microbiology
Research Cluster: Cancer Biology
Phone: (304) 696-3516 Fax: (304) 696-3713
E-mail: claudiop@marshall.edu
Office: BBSC 336-Q
Laboratory: BBSC 312
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
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.
Claudio P.P., et al. (1996): Functional analysis of pRb2/p130 interaction with cyclins. Cancer Research 56: 2003-2008.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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 Aug 15;110(4):1301-7.
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 ml) 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 (Post Doctoral Fellow) Altomare Di Benedetto (PhD Graduate Student) Weineng Zuo (Laboratory Technician) 
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.
Sarah Kelly (PhD Graduate Student)
