Development of Novel Cancer Therapeutics by Targeting Sphingolipid Signaling

通过靶向鞘脂信号传导开发新型癌症疗法

• 批准号: 9072008
• 负责人: Besim Ogretmen
• 金额: $ 181.11万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9072008
• 关键词: Animal Model; Animals; Apoptosis; Attenuated; Binding; Binding Proteins; Biometry; Cell Death; Cell Proliferation; Cell membrane; Cells; Cellular Stress; Ceramides; Clinic; Communication; Complement; Complement 5a; Data; Data Analyses; Development; Distant; Figs - dietary; G-Protein-Coupled Receptors; Goals; Health; Human Pathology; Image; Induction of Apoptosis; Knockout Mice; Lipids; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metabolism; Modeling; Neoplasm Metastasis; Nuclear; Organ; Organism; PTEN gene; Pathology; Patients; Phase II Clinical Trials; Positioning Attribute; Prostate; Proto-Oncogene Proteins c-akt; Publications; Publishing; Radiation; Regulation; Research Design; Research Personnel; Resistance; Services; Signal Transduction; Site; Solid Neoplasm; Sphingolipids; Stress; Testing; Therapeutic; Translating; Tumor Suppression; United States; Wit; c-myc Genes; cancer cell; cell growth; chemotherapy; clinically significant; data sharing; design; galactosylgalactosylglucosylceramidase; improved; improved outcome; innovation; novel; novel therapeutics; prevent; programs; receptor; response; sphingosine 1-phosphate; sphingosine kinase; therapeutic development; therapeutic target; therapy outcome; therapy resistant; tumor; tumor growth; urinary

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.

描述（由申请人提供）：该高度整合且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）调节的常见信号传导机制，这些机制诱导实体瘤中的癌细胞增殖、治疗抗性和转移。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，以通过靶向促生存S1P信号传导来治疗实体瘤患者，例如前列腺癌、泌尿系统癌和/或肝癌。该项目旨在检验一个新的总体假设，即S1P信号转导是一个独特的靶点，可减弱对放疗和/或化疗介导的细胞凋亡的抵抗（项目1），预防肿瘤转移（项目2），并抑制细胞内c-Myc信号转导，从而抑制肿瘤（项目3），改善实体瘤治疗的疗效。为了验证这一假设，提出了三个具体目标，它们属于三个项目的共同主题和该计划的四个核心：具体目标1。分析酸性神经酰胺酶（AC）激活诱导SK1/S1P通过AKT/PTEN信号传导介导对放疗和/或化疗的抗性的机制。这些研究旨在检验一种新的假设，即放射或化疗引起的细胞应激介导的AC激活通过诱导S1P-S1PR2介导的AKT激活（通过核PTEN输出）导致对细胞凋亡的抵抗（项目1）。因此，靶向AC/S1P轴应减弱对细胞凋亡的抗性。具体目标2。定义癌细胞如何通过S1P/S1PR和C5a/C5aR补体信号传导与宿主生物体沟通并诱导肿瘤转移。这些研究旨在验证一种新的假设，即癌细胞通过C5a/C5aR诱导的系统性SK1/S1P与宿主生物体进行通信，然后促进肿瘤转移。因此，抑制系统性S1P/C5aR信号传导抑制转移（项目2）。具体目标3。确定核SK2/S1P信号传导诱导c-Myc稳定性和癌细胞增殖的机制。这些研究旨在测试一种新的假设，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信号传导导致c-Myc抑制和肿瘤抑制。为此，我们还将在II期临床试验中建立并验证ABC 294640在晚期肝癌患者中的治疗机制和疗效（项目 3）。为了实现这些特定目标，提出了四个基本核心：脂质组学（分析，合成和成像服务），动物模型和病理学，生物统计学和管理。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年中一直高度合作，产生了54篇出版物，具有独特但互补的科学专业知识和背景。因此，作为美国领先的脂质组学团队之一，我们处于独特的地位，可以剖析脂质信号在细胞凋亡、肿瘤生长和转移调节中的机制，并将这些机制研究转化为临床治疗实体瘤患者。