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Dr. Fett received his Ph.D. in 1974 in biochemistry and immunochemistry from the Department of Physiological Chemistry, University of Wisconsin-Madison and then served as a postdoctoral fellow and junior faculty member from 1975 through 1978 in immunology at the Medical University of South Carolina in Charleston. He joined the laboratory and Harvard Medical School in 1978 as an Assistant Professor of Pathology and was later promoted to Associate Professor of Pathology in 1987. His research group discovered the blood vessel-inducing protein, named angiogenin, in 1985. Dr. Fett¡¯s current research focuses on developing and testing anti-angiogenin compounds for cancer therapy/prevention, evaluating the use of angiogenin as a cancer biomarker, and determining the relative importance of angiogenin expression and activity on the initiation and progression of cancer. Anti-angiogenin agents as cancer therapeutics and preventatives We have demonstrated that a wide variety of human tumor cell types secrete angiogenin, both in tissue culture and when implanted into immunocompromised athymic mice. Thus, inhibiting the functions of angiogenin may be a useful strategy for the treatment of several types of cancers. With this in mind, models using athymic mice for testing angiogenin antagonists have been developed (in major collaboration with Dr. Karen Olson of this Center). These include standard, ectopic models in which tumor cells are placed under the skin as well as more relevant orthotopic models in which tumor cells are injected into their tissues of origin. The latter models are also useful for the evaluation of metastasis. Inhibitors under development and analysis include antibodies, antisense DNA medicines, peptide mimetics, and small molecules (in collaboration of Dr. Shapiro and associates of the Center). To date, a number of these agents have shown dramatic potencies against the establishment of several different human tumor cell lines in mice and also impair the formation of metastatic lesions in models for prostate and breast cancer. The goal of these studies is to provide anti-angiogenin agents which can be tested either alone or in combination with more standard treatments (chemotherapy, radiation) for therapy and prevention of human cancers. Angiogenin as a cancer biomarker Since the studies noted above point to angiogenin as a key modulator of human tumor growth and metastasis, the question arises whether quantitation of this protein in patient biological fluids could signal outcome or be used as a monitor of treatment efficiency or recurrence. Initial investigations (again, in collaboration with Dr. Olson) to investigate these possibilities have focused on prostate cancer. An immunoassay is being used to determine angiogenin levels in urine and serum of patients and to correlate these findings with clinical status. Additionally, in collaboration with the Dana-Farber Cancer Center, sections of normal and cancerous prostate tissue are being stained using an angiogenin antibody. Initial data analysis shows that increased amounts of angiogenin protein may be associated with more aggressive disease. These studies are currently being validated and also expanded to other forms of human cancers. Transcriptional profiling Although several pro- and antiangiogenic mediators have been described, their various roles in determining cancer phenotypes have only begun to be elucidated. Therefore, we have begun to analyze angiogenin mRNA levels in cancer in relation to those of other members of the family of molecules involved in angiogenesis regulation. Custom microarrays are being used for this pupose and expression of RNA from cell lines and human tumor specimens are currently under analysis using this methodology. Selected publications Fett JW, Strydom DJ, Lobb RR, Alderman EM, Bethune JL, Riordan JF, Vallee BL. Isolation and Characterization of Angiogenin, an Angiogenic Protein from Human Carcinoma Cells. Biochemistry 1985; 24:5480-5486. Olson KA, French TC, Vallee BL, Fett JW. A Monoclonal Antibody to Human Angiogenin Suppresses Tumor Growth in Athymic Mice. Cancer Res 1994; 54: 4576-4579. Olson KA, Fett JW, French TC, Key ME, Vallee BL. Angiogenin Antagonists Prevent Tumor Growth in vivo. Proc Natl Acad Sci USA 1995; 92:442-446. Piccoli R, Olson KA, Vallee BL, Fett JW. Chimeric Anti-Angiogenin Antibody cAb 26-2F Inhibits the Formation of Human Breast Cancer Xenografts in Athymic Mice. Proc Natl Acad Sci USA 1998; 95: 4579-4583. Olson KA, Byers HR, Key ME, Fett JW. Prevention of Prostate Tumor Metastasis by Antisense Targeting of Human Angiogenin. Submitted. Olson KA, Byers HR, Key ME, Fett JW. Inhibition of Prostate Carcinoma Establishment and Metastatic Growth by an Anti-angiogenin Monoclonal Antibody. To be submitted. Olson KA, Fett JW. Inhibition of Breast Cancer Development and Metastasis in Mice by Angiogenin Antagonists. To be submitted. Crystal Structure of a Complex Between an Fab Antibody Fragment and Human Angiogenin: Unique Characteristics and Therapeutic Implications¡± In preparation. Patents (Inventorships) Issued 2/23/88 "Purified Protein Having Angiogenic Activity and Methods of Preparation." US #4,727,137. Issued 8/1/89 "Antibodies to Angiogenin: Immunotherapeutic Agents." US #4,853,219. Issued 11/7/89 "Method of Isolating Tumor-Secreted Products Using a Novel Protein-Free Medium." US #4,879,222. Issued 1/30/90 "Purified Protein Having Angiogenic Activity and Methods of Preparation." US #4,897,464. Filed 3/21/97 "Antisense Inhibition of Angiogenin Expression". Filed 4/5/99 "Chimeric and Humanized Antibodies to Angiogenin". Filed 9/20/00 ¡°Methods for Detecting Prostate Cancer¡± (Provisional) ¡¡ ¡¡ Last updated: February 1, 2002 |