Development of Novel Cancer Therapeutics by Targeting Sphingolipid Signaling

DESCRIPTION（由申请人提供）：这个高度整合和具有临床意义的项目项目的总体目标是确定由鞘氨醇1-磷酸（S1P）调节的、诱导实体肿瘤细胞增殖、耐药和转移的常见信号机制。治疗目标是利用从这些研究中获得的机制信息来开发新的治疗策略，通过靶向促生存的S1P信号来治疗实体肿瘤患者，如前列腺癌、肾癌和/或肝癌。该项目旨在验证一个新的整体假设，即S1P信号提供了一个独特的靶点，可以减弱对放射和/或化疗介导的细胞凋亡的耐药性（项目1），防止肿瘤转移（项目2），抑制细胞内c-Myc信号，从而抑制肿瘤（项目3），从而改善实体瘤的治疗效果。为了验证这一假设，提出了三个具体目标，这是三个项目的共同主题和计划的四个核心：分析SK1/S1P响应酸性神经酰胺酶（AC）激活通过AKT/PTEN信号通路介导放射和/或化疗耐药的机制。这些研究旨在验证一个新的假设，即辐射或化疗引起的细胞应激介导的AC激活，通过核PTEN输出诱导s1p - s1pr2介导的AKT激活，从而导致细胞凋亡抵抗（项目1）。因此，以AC/S1P轴为靶点可减弱细胞对凋亡的抗性。具体目标2。明确癌细胞如何通过S1P/S1PR和C5a/ c5ar补体信号与宿主生物进行交流并诱导肿瘤转移。这些研究旨在验证一个新的假设，即癌细胞通过C5a/ c5ar诱导的系统性SK1/S1P与宿主生物交流，从而促进肿瘤转移。因此，抑制系统性S1P/C5aR信号可以抑制转移（Project 2）。具体目标3。确定细胞核SK2/S1P信号诱导c-Myc稳定性和癌细胞增殖的机制。这些研究旨在验证一个新的假设，即sk2产生的核S1P直接结合并稳定c-Myc，导致癌细胞增殖增加。因此，利用ABC294640靶向SK2/S1P信号通路可以抑制c-Myc并抑制肿瘤。在本目标中，我们还将在II期临床试验（项目）中建立和验证ABC294640对晚期肝癌患者的治疗机制和疗效

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.