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Our Science – Giubellino Website

Alessio Giubellino, M.D.

Laboratory of Pathology
Clinical Fellow
Center for Cancer Research
National Cancer Institute
Building 10 - Hatfield Clinical Research Center, Room 1W-5848
10 Center Drive
Bethesda, MD 20892
Phone:  
301-594-7953
Fax:  
301-402-0922
E-Mail:  
giubella@mail.nih.gov

Education

Degree:   M.D.
Field of Degree:   Medicine
Degree Institution:   University of Torino, Italy
Date Degree Granted:   1999

Biography

Dr. Alessio Giubellino received his M.D. from the University of Torino Medical School in 1999 and trained in the Division of Molecular Oncology of the same University studying cell signal transduction with emphasis on HGF/c-Met signaling. He joined the NCI's Urologic Oncology Branch in 2004 under the mentorship of Dr. Donald Bottaro.
Dr. Giubellino research has focused on cancer biomarkers and on pre-clinical drug development, specifically targeting aberrant protein signaling networks associated with cancer as a new therapeutic strategy.

Research

Summary of research interests and accomplishment at NCI

c-Met Ectodomain Shedding Rate Correlates with Malignant Potential
Upon my arrival at NCI I started experiments to evaluate soluble c-Met as a biomarker for urologic cancers, a project with important translational implication and clinical endpoints.
Many proteins are proteolytically released from the cell surface by a process known as shedding, which occurs under physiologic conditions and is increased in certain pathologies. The overexpression of c-Met in several human malignancies, coupled with the increased proteolytic activity of tumor cells, led us to hypothesize that increased c-Met shedding might correlate with cancer progression. Together with other colleagues in the lab, I characterized several cultured cell models of malignant progression, demonstrating a direct correlation between c-Met ectodomain shedding and increased metastatic potential. I then further showed that blood and urine samples from mice harboring human tumor xenografts contained soluble human c-Met levels that were measurable before tumors became palpable, and correlated directly with tumor volume.
My work was recognized in 2005 with a NIH Fellows Award for Research Excellence; the work was presented at the AACR-NCI-EORTC International Conference Molecular Target and Cancer Therapeutics in 2005 and published in Clinical Cancer Research in 2006. There are now ongoing studies analyzing samples obtained from patients with urologic and other malignancies seen in the NCI/UOB and in other clinics. Preliminary results show that patient values fall above the range observed for normal controls, suggesting a positive correlation between c-Met shedding and malignancy, and proving the validity of this approach.

Mechanism of tumor metastasis Grb2-mediated
This project consist in the development of antagonists of signaling by c-Met, as well as other receptor tyrosine kinases, as anti-cancer drugs. Upon ligand binding, c-Met kinase activation results in autophosphorylation and the recruitment of downstream effectors containing Src Homology type-2 (SH2) domains, such as Grb2. In collaboration with Dr. Terry Burke (NCI), selective Grb2 SH2 domain antagonists have been developed that potently block HGF-driven cell motility and matrix invasion, and I have characterized these antagonists in cultured cell-based models as well as in mouse tumor xenograft models of metastasis. To minimize drug and animal requirements, I have characterized luciferase transfected human tumor xenografts, which allow non-invasive quantitation of tumor burden by measuring visible light emission. I explored animal models of metastasis, adapting them to our goal, designing and executing the mouse studies, as well as interpreting the results and planning future studies. Using non-invasive bioluminescent technology to quantitate metastatic tumor burden, I was able to demonstrate for the first time in vivo the efficacy of this class of compounds in reducing the metastatic spread of highly invasive primary solid tumors. These findings offer substantial promise for validating Grb2 as a drug target, and are important steps toward obtaining proof of principle for the development of anti-cancer drugs that act specifically on the metastatic process. The work with these novel agents will also improve our understanding of Grb2 function and efficiently guide us in the use of these compounds as anti-cancer drugs. My work on these inhibitors was also recognized in 2006 with a second NIH Fellows Award for Research Excellence.
A manuscript describing these data has been recently published in Cancer Research, and the article has been chosen to be featured in the Highlights section.

Screening of c-Met Tyrosine Kinase Inhibitors
Inhibitors of oncogenic function such as Gleevec, that are directed at the kinase itself, have recently shown promise in the treatment of certain cancers. In a collaboration between the laboratories of Dr. Bottaro and Dr. Marc Nicklaus (Laboratory of Medicinal Chemistry) an in silico screen of commercially-available compounds was conducted to identify potential c-Met kinase inhibitors. This screen employed the published crystal structure of the c-Met inhibitor K-252a bound to the enzyme catalytic site as a model for inhibitor selection; Dr. Nicklaus's Group performed an in silico screen of the 13.5 million compounds in the ChemNavigator data base. After several rounds of refinement a subset of 175 molecules was selected for evaluation and I conducted studies for their ability to inhibit c-Met autophosphorylation in whole cells. For compounds that showed promising inhibitor potencies, I conducted a range of further studies to identify whether the inhibition was due to factors other than blockade of the kinase function, such as induction of protein degradation. These studies are currently ongoing.

This page was last updated on 1/21/2014.