The overall goal of this R01 application is to develop high-affinity and high-specificity targeting agents for ovarian cancer. We hypothesize that (i) a3|31integrin is an excellent therapeutic target for ovarian cancer, (ii)the D-amino acid containing cyclic peptide leads that have already been identified in our laboratory, after further optimization, will become effective therapeutic agent for human ovarian cancer, (iii) some of these peptides, in oligomeric form (either homopolymer or heteropolymer) may be able to cross-link cell surface molecules resulting in higher avidity and possibly causing cell signaling and cellular responses. We believe these targeting agents, when radiolabeled (e.g. with Y) or conjugated to liposomes containing chemotherapeutic agents such as doxorubicin (e.g. Doxil?), can be used as highly specific therapeutic agents for ovarian cancer. Through screening one-bead one-compound combinatorial peptide libraries, we have already identified peptide ligands that can target ovarian cancer in the xenograft model. In this application, we propose to use combinatorial chemistry, molecular modeling methods, and other biophysical techniques to further optimize our lead compounds, and to characterize the compounds with respect to binding specificity and affinity of, as well as their biochemical effects on normal and malignant ovarian cancer cells. We believe these peptides, when conjugated onto the surface of Doxil?, will be able to facilitate the delivery of doxorubicin to the tumor, and therefore will preferentially kill the tumor cells. Research performance locations: UC-Davis Cancer Center, Research III, 4645 2nd Ave, suite #1300 Sacramento, CA95817 KEY PERSONNEL. See instructions on Page 11. Use continuation pages as needed to provide the required information in the format shown below. Name KitS. Lam,M.D., Ph.D. Ruiwu Liu,Ph. D. Pappanaicken R. Kumaresan, Park, See-Hyoung, B.S. Bob O-Donnell, M.D., Ph.D. Organization UC-Davis Cancer Center, Dept of Int Med UC-Davis Cancer Center, Dept of Int Med UC-Davis Cancer Center, Dept of Int Med UC-Davis Cancer Center, Dept of Int Med Role on Program , Program Leader Investigaor Investigator Graduate student UC-Davis Cancer Center, Dept of Int Med Consultant PHS 398 {Rev. 05/01) Page 2 Number pages consecutively at the bottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b. Principal Investigator/Program Director (Last, First, Middle): Lam, Kit S. M.D., Ph.D. The name of the principal investigator/programdirector must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,
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