Development of Novel Cancer Therapeutics by Targeting Sphingolipid Signaling

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DESCRIPTION (provided by applicant): The overall goal of this highly integrated and clinically significant Program Project is to determine common signaling mechanisms regulated by sphingosine 1-phosphate (S1P) that induce cancer cell proliferation, resistance to therapy, and metastasis in solid tumors. The therapeutic goal is to utilize mechanistic information gained from these studies for the development of novel therapeutic strategies to treat patients with solid tumors, such as prostate, urinary and/or liver cancers by targeting pro-survival S1P signaling. This Program is designed to test a novel overall hypothesis that S1P signaling presents a unique target to attenuate resistance to radiation- and/or chemotherapy-mediated apoptosis (Project 1), prevent tumor metastasis (Project 2), and inhibit intracellular c-Myc signaling, leading to tumor suppression (Project 3) for improved therapeutic outcomes in the treatment of solid tumors. To test this hypothesis, three Specific Aims are proposed, which are within the common theme of three projects and four cores of the Program: Specific Aim 1. Dissect the mechanisms by which induction of SK1/S1P in response to acid ceramidase (AC) activation mediates resistance to radiation and/or chemotherapy via AKT/PTEN signaling. These studies are designed to test a novel hypothesis that cellular stress-mediated AC activation, invoked by radiation or chemotherapy, leads to resistance to apoptosis by induction of S1P-S1PR2-mediated AKT activation through nuclear PTEN export (Project 1). Thus, targeting the AC/S1P axis should attenuate resistance to apoptosis. Specific Aim 2. Define how cancer cells communicate with the host organism and induce tumor metastasis via S1P/S1PR and C5a/C5aR-complement signaling. These studies are designed to test a novel hypothesis that cancer cells communicate with the host organism via C5a/C5aR-induced systemic SK1/S1P, which then promotes tumor metastasis. Thus, inhibition of systemic S1P/C5aR signaling suppresses metastasis (Project 2). Specific Aim 3. Determine the mechanisms of nuclear SK2/S1P signaling to induce c-Myc stability and cancer cell proliferation. These studies are designed to test a novel hypothesis that SK2-generated nuclear S1P directly binds and stabilizes c-Myc, leading to increased cancer cell proliferation. Thus, targeting SK2/S1P signaling using ABC294640 results in c-Myc inhibition and tumor suppression. In this Aim, we will also establish and validate the therapeutic mechanisms and efficacy of ABC294640 in patients with advanced liver cancers in a Phase II clinical trial (Project 3). To achieve these Specific Aims, four essential cores are proposed: Lipidomics (with analytical, synthetic and imaging services), Animal Models and Pathology, Biostatistics and Administrative. These Projects and Cores are directed by independent and established researchers who have been highly collaborative during the past 14 years, generating 54 publications, with distinct but complementary scientific expertise and background. Thus, as one of the leading lipidomics group in the United States, we are in a unique position to dissect the mechanisms of lipid signaling in the regulation of apoptosis, tumor growth and metastasis, and translate these mechanistic studies to the clinic for the treatment of patients wit solid tumors.