Hepatocellular carcinoma (HCC) accounts for an estimated 600,000 deaths annually, and in North America mortality due to HCC has nearly doubled in the last 20 years. Recently it has been shown that the signaling pathway controlled by the mammalian Target Of Rapamycin (mTOR) protein kinase is upregulated a large number of human HCCs. Rapamycin and its derivatives, RAD001 and CCI-779, which are in Phase 2 and 3 clinical trials for the treatment of solid tumors, inhibit mTOR phosphorylation of its substrates. mTOR is a nutrient effector, involved in the regulation of cell growth and exists in a complex with two proteins, raptor and G?L (Complex 1). However, the molecular events associated with rapamycin inhibition of mTOR, have recently become less clear. First, because mTOR was found to exist in a second signaling complex with G?L and a protein termed rictor (Complex 2), which is rapamycin resistant and proposed to control Protein Kinase B (PKB) activation, a pro-growth, pro-survival kinase. Second because our recent studies have shown that the Complex 1, triggered by either an insulin-induced negative feedback loop or nutrient mediated activation, inhibits PKB activation. Thus, as rapamycin blocks Complex 1 signaling, this increases PKB activity, potentially promoting tumor survival. However, if Complex 2 mediates PKB activation, then inhibiting Complex 2 should abolish PKB activation and all associated tumor survival functions. Given these observations, """"""""Our hypothesis is that loss of mTOR function in liver would abolish both Complex 1 and 2 signaling and thus would have a more profound inhibitory effect on HCC progression than rapamycin treatment"""""""".
Our specific aims are to (1) use mTOR floxed mice to determine the effect of deleting mTOR in the liver on development of HCC, (2) measure the individual contribution of Complex 1 and 2 to this response and (3) the determine which of these effects are mimicked by the rapamycin derivative RAD001. Worldwide HCC is cited as the fifth most common cause of cancer and due to poor prognosis is ranked third in cancer deaths. Moreover, in Western societies the incidence of HCC is strongly rising, whereas efficient therapeutic strategies for the treatment of HCC are clearly lacking. We have written a proposal to test the role of mTOR, the target of the anticancer agent rapamycin, in HCC.
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