Semaphorin 3F: Structure, Function, and Anti-Metastatic Activity

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DESCRIPTION (provided by applicant): The candidate, Dr. Diane Bielenberg, is an instructor in the Surgical Research Division at Children's Hospital and Harvard Medical School, chaired by Dr. Judah Folkman, the pioneer of the field of angiogenesis research. As part of the Vascular Biology Program, Dr. Bielenberg, a cancer biologist, has specialized in studies of metastasis, the spread of malignant tumor cells from one site in the body to another. The longterm career goals of the applicant are to remain in academic research and continue to study the biology of cancer metastasis and angiogenesis. Most cancer patients die from metastasis, and only by understanding the biology of this process can we hope to develop better tools to fight this disease. Dr. Bielenberg has previously studied the molecular mechanisms involved in anti-angiogenesis therapy by interferons, the role of endogenous interferon-beta in the involution of cutaneous infantile hemangiomas, and the identification and anti-tumor activity of a natural soluble receptor for vascular endothelial growth factor called soluble neuropilin. Since being promoted to an instructor, Dr. Bielenberg has focused on a novel suppressor of metastasis, called Semaphorin 3F. Semaphorin 3F is commonly deleted in lung cancer and is a putative tumor suppressor gene, but recently Dr. Bielenberg and her mentor, Dr. Michael Klagsbrun, have shown that Semaphorin 3F is inversely correlated with metastasis in many tumor cell lines. When Semaphorin 3F was expressed in metastatic cells, the tumors remarkably reverted to a benign, hypo-vascular and encapsulated tumor phenotype. This K01 research proposal will follow-up this exciting finding and focus on the molecular mechanisms responsible for the anti-metastatic effect of Semaphorin 3F. We hypothesize that Semaphorin 3F will regulate key steps in the metastatic cascade including angiogenesis and lymphangiogenesis and may offer a novel therapeutic strategy for patients with metastatic disease. A K01 award would facilitate the transition of this candidate from instructor to an independent investigator in the Department of Surgical Research at Harvard Medical School by providing additional training in areas of biochemistry including protein engineering and protein purification, as well as enabling additional collaborations and participation in regional and national meetings. Most of all, a Howard Temin Award would enable the continuation of this research project toward the ultimate goal of long-term stable disease.