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Aaron T. Wild, MD
Johns Hopkins
RSNA Research Medical Student Grant
(2012 - 2013)
Radiosensitization of Hepatocellular Carcinoma Using Rationally Combined Molecular-targeted Agents
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Abstract:
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The multikinase inhibitor sorafenib has been validated as the first systemic therapy to show a survival benefit in patients with hepatocellular carcinoma (HCC). This survival benefit, however, is modest at less than three months. Furthermore, no delay in symptomatic progression is produced by sorafenib therapy. Consequently, novel methods of enhancing the efficacy of sorafenib are needed. We propose to investigate the efficacy of combining sorafenib with radiotherapy and rationally selected targeted agents for treatment of HCC in the laboratory setting. In particular, we will examine the effects of inhibiting the Ras/Raf/MAPK and PI3K/Akt/mTOR pathways separately as well as simultaneously on the radiosensitivity of HCC cells. Specific pathway inhibition will be achieved through treatment with the targeted agents sorafenib, BEZ235, and nelfinavir alone and in combination. We will first perform a series of in vitro experiments consisting of immunoblot, cell viability, and clonogenic assays. These studies are expected to identify novel agents/combinations for modulating the radiosensitivity of HCC cells and to elucidate molecular mechanisms underlying this modulation. Subsequently, we will confirm any radiosensitization or radioprotection effects observed in vitro through in vivo tumor growth delay experiments in a mouse xenograft model. Due to possible additional effects of the targeted agents on tumor stroma and vasculature in a living host that would go unobserved in vitro, these in vivo experiments will be important in assessing the potential of our findings to translate successfully into clinical practice. We believe our results will enhance mechanistic understanding of how radiation and targeted therapies can synergize to alter tumor cell biology. Ultimately, our goal is to generate high-quality and convincing preclinical data that will allow for thorough evaluation of the merits of initiating a phase I-II trial at our institution’s cancer center testing a novel treatment regimen which includes radiotherapy in patients with HCC.
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