Ilan Tsarfaty, PhD

2012-2013 BCRF Project:
Co-Investigator: George Vande Woude, PhD, Van Andel Research Institute, Grand Rapids, MI

The goal of Drs. Tsarfaty and Vande Woude's research is to understand the role of Met in breast cancer progression, metastasis, and therapeutic resistance. Met is over-expressed in 20%-30% of breast cancer tumors and is a strong, independent predictor of decreased survival. Met expression is highest in tumors that lack expression of estrogen and HER2 receptors, commonly called triple negative breast cancer. Recent studies have demonstrated that Met is involved in resistance to trastuzumab (Herceptin®), a targeted therapy developed for HER2+ breast cancer. These findings and many others underscore the strong relationship of Met with tumor progression and resistance to anti-HER2 therapy.

Drs. Tsarfaty and Vande Woude have created several unique models to evaluate how the Met oncogene influences breast cancer growth, metastasis, and therapeutic resistance. In the last funding period, they have examined how Met signaling affects cell migration, tumor blood flow, and cancer cell metabolism. They also discovered that Met may play an important role in resistance to targeted therapies in breast cancer. In 2012-2013, these researchers will continue to determine the cellular and molecular mechanisms of Met that contribute to breast cancer metastasis and therapy resistance.

Mid-year Progress: Dr. Tsarfaty's and Dr. Vande Woude's laboratories have combined several unique models to evaluate how the Met oncogene influences breast cancer growth, metastasis, and therapeutic resistance. In this grant period, they are examining how activation and inhibition of Met affects cell migration and cancer cell metabolism. They are also investigating a new imaging method as a diagnostic tool for imaging breast cancer presence and severity. Finally, they are interrogating how receptors, including Met, influence the intratumoral heterogeneity of breast cancer and the impact of this heterogeneity on therapeutic strategies for breast cancer.

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.