Ilan Tsarfaty, Ph.D.

Chair, Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine

Tel Aviv University

Speech Title:

Novel Molecular Imaging Modalities as a Tool to Understand Breast Cancer and Personalize Treatment

Abstract:

Breast cancer is the most common malignant disease presently ailing western women. Complications from metastases rather than the primary tumor is the cause of death in the majority of cancer patients. Developing novel molecular imaging modalities for early detection, diagnosis and personalizing therapy is essential for better treatment of the cancer patients. The molecular, cellular and biophysical mechanisms controlling tumor cell motility and bio energetics are poorly understood HGF/SF-Met have been shown to be involved in tumor cell metabolism, proliferation, motility and blood flow. Tumor cell motility was carefully studied and analyzed in vitro and in vivo using novel imaging and algorithms. Our results demonstrate that Met activation by HGF/SF increases cell velocity, acceleration, kinetic energy and induces collective cell motility. We have shown that Met downstream inhibition constrains tumor growth. Using animal models we have demonstrated that tumors develop micrometastases as detected by whole animal spectral imaging; macro to micro and two photon confocal imaging demonstrated HGF/SF induced changes in blood flow at single vessel resolution, localization of metalloprotease and cathapsine activity at the tumor edge and increase in single cell motility. Using contrast-medium ultrasonography we have demonstrated that the inhibition of downstream Met signaling molecules, on their own, do not lead to decreased tumor blood volume demonstrating the mismatch between altered metabolism and blood flow regulation in the tumor, yet its inhibition abrogates HGF/SF-Met induced increase in blood volume. We have recently developed a novel molecular imaging method for the detection of tumors and metastases based on 2-deoxy-glucose chemical exchange saturation transfer (CEST) MRI. Using Met functional molecular imaging will facilitate the understanding of the molecular mechanisms of Met induced metastatic breast cancer motility and hemodynamic changes. Better understanding of these mechanisms may facilitate anti-Met targeted therapy, by indicating novel targets for personalized therapy.

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. Tsarfatyï¿½s 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.