We propose to evaluate the therapeutic feasibility of a humanized antibody drug DAPI- 01 (anti-FGFR2-IIIc) in prostate cancer model systems. The molecular target of the antibody is fibroblast growth factor receptor-2 (FGFR2) isoform IIIc, which is involved in androgen-independent tumor growth and metastasis. Our specialized antibody drug is designed with the intention of targeting the "bad isoform" of FGFR2 receptor on tumor, but spare the "good isoform" FGFR2-IIIb on normal prostate epithelia that functions to suppress tumor growth. Objectives of this Phase-I SBIR proposal include both in vitro and in vivo evaluations using hormone-independent tumor lines, DU145 and DU9479. The following experiments will be conducted: 1) Testing DAPI-01 in vitro activity and cellular mechanism a. Inhibition of receptor activation and signaling b. Blocking ligand binding or receptor dimerization c. Effects on cell proliferation and apoptosis 2) Testing DAPI-01 in vivo efficacy in human prostate cancer xenografts d. Effect on inhibiting tumor growth, tumor angiogenesis The results of these studies will form the basis for SBIR phase-II study, which will focus on pre-clinical development of this drug candidate. Our long-range goal is to develop a tumor-selective therapeutic agent with high potency for hormone-refractory prostate cancer. Several large clinical trials are underway in the US to evaluate the efficacy and safety of immunotherapeutic drugs for prostate cancer. The side effects of these drug candidates had been a major concern. The proposed drug candidate, anti-FGFR-2IIIc may have attractive safety features because it does not cross-react with other similar proteins, which include the "good protein isoforms" that suppress tumor growth and maintain normal physiological functions. This therapeutic strategy may achieve the result of maintaining a more normal state of slow growth in the prostate epithelial tissue, and kill the invasive cancer cell and prevent metastatic diseases.
Public Health Relevance: We propose a feasibility study for a therapeutic candidate, a humanized antibody against a growth factor receptor variant specifically expressed on hormone-refractory prostate cancer (HRPC). We will obtain data on antibody's tumor-killing activity from in vitro studies using HRPC tumor cell lines, and in vivo studies using human xenografts in nude mice.
Public Health Relevance Statement: Principal Investigator (Last, first, middle): Chang, Jia X. Narrative: We propose a feasibility study for a therapeutic candidate, a humanized antibody against a growth factor receptor variant specifically expressed on hormone-refractory prostate cancer (HRPC). We will obtain data on antibody's tumor-killing activity from in vitro studies using HRPC tumor cell lines, and in vivo studies using human xenografts in nude mice. Terms:
