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Exploring the therapeutic potential of novel molecular targeted therapies in treating human ovarian cancer

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Description: Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy, and the fifth most common cause of cancer death among American women. Approximately 70% of all women diagnosed with EOC will die of the disease. There exists a significant need to define and exploit new drug targets, and to translate targeted agents towards new therapeutic trials. In my studies, I evaluated the efficacy of three molecular targeted agents, AMG 706 (VEGF inhibitor), Dasatinib (Src inhibitor) and GT13072 (XIAP inhibitor), in treating ovarian epithelial cancer. These drugs target important cell surface receptors and signaling molecules that are known to be important in cancer development and progression. Dasatinib was effective in inhibiting majority of ovarian cancer cell lines grown using two- and three-dimensional culturing conditions. In comparison, AMG 706 and GT13072 had little or no discernable activity in vitro. Next, I evaluated the efficacy of a combined treatment using GT13072 and SN-38 (a metabolite of irinotecan) on primary ovarian cancer cultures, but no significant synergistic effects were observed. Next, I investigated the effect of AMG 706 on inhibiting tumor growth using an orthotropic xenograft animal that I could assess tumor growth using bioluminescence imaging. Female SCID mice were implanted i.p. with human ovarian cancer cells, OVCAR5-Luc that constitutively express firefly luciferase. Animals were treated daily by oral administration of AMG 706 (10, 30, 75 mg/kg) and imaged weekly for 4 weeks. No change in tumor growth was observed between control and drug-treated groups. However, my studies have shown that monoagent-targeted therapies are unlikely to yield "silver bullets" for this complicated disease. Accordingly, I adapted siRNA screening as a tool to identify second site lethality effective in conjunction with a targeted agent. In these experiments a custom siRNA library composed of 638 EGFR (epidermal growth factor receptor)-related genes was screened using a dasatinib sensitive cell line, A1847, treated with a sublethal dose of dasatinib (IC 30 , 10 nM) and a dasatinib resistant cell line, UPN289, treated with 1 μM dasatinib. With a cutoff of fifteen percent viability reduction and a false discovery rate (FDR) of fifteen percent, I identified 29 and 0 "hits" respectively that could sensitize EOC cells to dasatinib. Database analysis suggested that AKT, PI-3kinase, CBL and NF-kB might play central roles among the interplay of these genes. Overall, my studies help showed the difficulties of single agent and that combined treatment is more likely to lead to successful effect.
Language: English
Format: Degree Work