Targeting both intrinsic and extrinsic apoptosis by FLLL-12 in lung cancer

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DESCRIPTION (provided by applicant): Lung cancer is the deadliest of all malignancies with an estimated 221,130 new cases and 156,940 deaths in the year 2011 in the United States. Despite advances in conventional surgical procedures, radiotherapy, and chemotherapy, the 5 year survival rate for lung cancer remains almost unchanged, at less than 15%. Mortality from lung cancer could be reduced through the implementation of chemopreventive strategies that can reverse or impede the progression of pre-malignant disease. Activation of apoptotic pathways to eliminate pre- malignant cells is an important approach for chemoprevention. Moreover, reactivation of the tumor suppressor pathways which are inactivated throughout disease progression is important to develop effective chemopreventive strategies. Activation of AKT is a critical component downstream of several driver oncogenic mutations frequently found in lung cancers such as EGFR, KRAS, PTEN, PI3KCA, etc. We hypothesize that the tumor suppressor FOXO pathway is inactivated through phosphorylation by activated AKT rather than deletion or mutation. Therefore, agents that could reactivate the FOXO pathway by inactivating AKT and simultaneously activate other apoptotic pathways, such as death receptor-mediated apoptosis, might be effective chemopreventive agents. Extensive preclinical research over the last several decades has demonstrated that curcumin has strong potential for chemoprevention, which brought this agent into clinical trials. However, low potency and poor bioavailability are critical challenges. To circumvent these problems, several approaches are being undertaken, such as synthesis of more potent analogs, modification of the delivery system or identification of agents that show synergy with natural curcumin. We found that the synthetic curcumin analog FLLL-12 shows 5-10-fold more potency against lung cancer cell lines and activates Bim, a downstream pro-apoptotic effector of AKT-FOXO signaling along with inactivation of AKT. At the same time, FLLL-12 activates the DR5-caspase 8 apoptotic pathway. Since FLLL-12 activates biomarkers of both intrinsic and extrinsic pathways, we hypothesize that FLLL-12 is a novel non-toxic agent that targets the AKT-FOXO- Bim and DR5-caspase 8 pathways in its chemopreventive efficacy against lung tumorigenesis. To test our hypothesis, we have designed three specific aims: (1) to study the mechanism of intrinsic apoptosis induced by FLLL-12; (2) to investigate the DR5 pathway to understand extrinsic (caspase 8-mediated) apoptosis; and (3) to study the in vivo efficacy and bioavailability of FLLL-12 in mice. We anticipate that this proposed study will identify FLLL-12 as a mechanism-based agent for the prevention and control of lung cancer growth. This will establish its in vivo efficacy in a pre-clinical mouse model. Accordingly, completion of this pilot study would help us to further develop this compound for clinical application for lung cancer prevention.