Development of Novel Cancer Therapeutics by Targeting Sphingolipid Signaling

描述(由申请人提供)：这个高度集成和具有临床意义的计划项目的总体目标是确定由1-磷酸鞘氨醇(S1P)调控的共同信号机制，这些机制可诱导实体肿瘤中的癌细胞增殖、耐药和转移。治疗的目标是利用从这些研究中获得的机制信息，开发新的治疗策略，通过靶向有利于生存的S1P信号来治疗实体肿瘤患者，如前列腺癌、尿路癌和/或肝癌。本计划旨在测试一个新的总体假设，即S1P信号呈现一个独特的靶点，以减弱对放射和/或化疗介导的细胞凋亡的抵抗(项目1)，防止肿瘤转移(项目2)，并抑制细胞内c-Myc信号，导致肿瘤抑制(项目3)，以改善实体瘤治疗的治疗结果。为了验证这一假说，提出了三个特定的目标，它们是该计划的三个项目和四个核心的共同主题：特定的目标1.剖析酸性神经酰胺酶(AC)激活诱导SK1/S1P通过AKT/PTEN信号转导对放射和/或化疗的抗性的机制。这些研究旨在验证一种新的假说，即放射或化疗引发的细胞应激介导的AC激活，通过核PTEN输出诱导S1P-S1PR2介导的AKT激活而导致对凋亡的抵抗(项目1)。因此，以AC/S1P轴为靶点应该会减弱对细胞凋亡的抵抗。明确肿瘤细胞如何通过S1P/S1PR和C5a/C5aR-补体信号与宿主沟通并诱导肿瘤转移。这些研究旨在检验一种新的假设，即癌细胞通过C5a/C5aR诱导的系统性SK1/S1P与宿主机体通信，从而促进肿瘤转移。因此，抑制全身性S1P/C5aR信号可抑制肿瘤转移(项目2)。具体目的3.确定核SK2/S1P信号诱导c-Myc稳定和癌细胞增殖的机制。这些研究旨在检验一个新的假设，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，使用ABC294640靶向SK2/S1P信号导致c-Myc抑制和肿瘤抑制。为此，我们还将在第二阶段临床试验(Project)中建立和验证ABC294640对晚期肝癌患者的治疗机制和疗效 3)。为了实现这些具体目标，提出了四个基本核心：脂质组学(包括分析、合成和成像服务)、动物模型和病理学、生物统计学和行政管理。这些项目和核心由独立和成熟的研究人员指导，他们在过去14年中高度合作，出版了54份出版物，具有独特但互补的科学专门知识和背景。因此，作为美国领先的脂质组学研究小组之一，我们正处于一个独特的位置来剖析脂质信号在调节细胞凋亡、肿瘤生长和转移中的机制，并将这些机制研究转化为临床治疗实体瘤患者。

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.