Ilan Tsarfaty, PhD

2009-2010 BCRF Project:
Co-Investigator: George Vande Woude, PhD, Van Andel Research Institute, Grand Rapids, MI

Genome scale analysis of cancer helps researchers to expand their research focus from a few genes to a more complete view of the entire cancerous genetic network. The expression levels or DNA copy number of virtually all genes in a cell can be quantified simultaneously. This more complete analysis of human cancer cells will likely hold the key to solving the difficulties associated with the fact that breast cancer cells comprise complex, robust and evolving systems. Drs. Tsarfaty and Vande Woude are focusing on several aspects of genome scale analysis of human breast cancer.

First, they are developing bioinformatics methods that increase the accuracy of high throughput measurements. Second, from the data sets of increased accuracy they aim to extract quantitative measures of key biological processes in cancer. They are particularly interested in the various subtypes of genomic instability, their relative level in a given breast tumor and whether this could guide more effective therapeutic decisions. Third, the researchers are combining genome scale molecular profiling of chemotherapy-resistant breast cancer cell lines with bioinformatics analysis in order to determine whether clinical response to chemotherapy in breast cancer can be predicted by gene expression signatures derived from cell lines. The most immediate outcome of this research is to develop tools that would predict which breast cancer patient will respond to a given chemotherapeutic agent.

Met is a receptor tyrosine kinase that is aberrantly expressed in more than 30% of breast cancers. High Met expression correlates with poor prognosis independent of Her2/Neu. The goal of the studies led by Drs. Tsartay and Vande Woude is to understand the role of Met in breast cancer progression and to develop novel Met-targeted therapeutics and diagnostics. In the past year, they 1) measured the dynamic affects of Met activation on membrane blebbing and cell motility; 2) evaluated the therapeutic effects of Met-targeted therapy with multimodality molecular imaging; 3) investigated Met activation on cancer cell metabolism; 4) validated the prognostic value of a Met signature in breast cancer patients; and 5) examined the differences between Met and ErbB2 signaling in breast cancer progression. The knowledge gained from these studies will contribute to the design and preclinical assessment of Met-targeted therapies as well as early detection modalities for breast cancer.

Mid-Year Progress Report:
Drs. Tsarfaty and Vande Woude have generated novel cellular and laboratory models and imaging modalities for examining the role of Met in breast cancer progression and metastasis. In addition, they are utilizing these models to develop noveldiagnostics and Met-targeted therapeutics. The knowledge gained from these studies will contribute to the design and preclinical assessment of Met-targeted therapies, as well as early detection modalities for breast cancer. In the current grant period, they: 1) examined cellular trafficking of the Met receptor; 2) evaluated Met signaling with multi-modality molecular imaging; 3) investigated Met activation on cancer cell metabolism; 4) validated the prognostic value of a Met signature in breast cancer patients; and 5) examined the differences between Met and ErbB2 signaling in breast cancer progression.

Bio:
Dr. Ilan Tsarfaty received his BSc. (1983), MSc. (1986) and PhD (1990) from Tel Aviv University. From 1991-1994, he served as a postdoctoral research associate, in the ABL-Basic Research Program at the

National Cancer Institute's Frederick Cancer Research and Development Center. He was a visiting scientist at the Van Andel Research Institute Grand Rapids MI as a part of the Molecular Imaging Center University of Michigan (2001 - 2003). Since 1994 Dr. Tsarfaty is a member of the Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University. Dr. Tsarfaty is the recipient of the Bregamann Memorial Research and the CapCure Awards. He is the author of over 40 scientific research articles and over 10 books chapters.

During his Ph.D., Dr. Tsarfaty cloned the gene and was also involved in cloning the cDNA of the breast cancer antigen Muc1 and showed its potential use as a marker for breast cancer in a long term follow-up of several hundred breast cancer cases. During his postdoctoral training, he was the first to show that the Met tyrosine kinase growth factor receptor is involved in tubule formation in mammary tubule (Science, 1992) and in mesenchymal epithelial cell conversion (Science 1994).

Dr. Tsarfaty was the first to show that Met is a prognostic factor for breast cancer patients and that dominant negative form of the Met receptor could dramatically reduce tumorigenicity and metastasis of mammary cancer cells. Reduction of Met signaling to normal levels could also change the fate of malignant unorganized transformed cell to tubule forming cells. Dr. Tsarfaty studied the metabolic effects induced by Met signaling on breast cancer cells and showed that HGF/SF (hepatocyte growth factor/scatter factor) increase their metabolic activity. Met signaling induced a novel gene, designated Mimp that was cloned and characterize in Dr. Tsarfaty’s lab. This gene reduces the metabolic activity induced by Met and reduces Met induced tumorigenicity and metastasis.

In recent years Dr. Tsarfaty is leading an effort to develop a noninvasive breast tumor direct and functional molecular imaging modalities based on specific HGF/SF induced alteration of Hemodynamics. This novel functional molecular imaging modality is a powerful tool in understanding the metabolic activity induced by Met signal transduction. This technology that challenges the tumor and measures its activity enables better definition of tumor margins and may enable in the future earlier detection of smaller tumor and small metastatic lesions. Research conducted in the Laboratory of Dr. Tsarfaty uses a broad range of approaches to elucidate the molecular basis of breast cancer and to develop new agents for the diagnosis imaging and therapy of breast cancer. We are primarily interested in the expression and activities of the receptor tyrosine kinase known as Met, its interactions with the ligand HGF/SF, and the intracellular events influenced by Met activation. Aberrant expression of this receptor–ligand pair confers an invasive/metastatic phenotype in breast cancer model systems.