Project 3: Targeting SK2/S1P Signaling for the Regulation of c-Myc and Tumor Suppression

项目 3：针对 SK2/S1P 信号传导调节 c-Myc 和肿瘤抑制

• 批准号: 9072015
• 负责人: Carolyn D Britten
• 金额: $ 54.16万
• 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/9072015
• 关键词: Ablation; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; BAY 54-9085; Cause of Death; Cell Death; Cell Proliferation; Cells; Ceramides; Clinic; Clinical; Clinical Research; Critical Pathways; Data; Development; Drug Kinetics; Drug Targeting; Enrollment; Environment; FDA approved; Goals; Growth; Human; Incidence; Inflammatory; Laboratory Study; Link; Lipids; Liver; Liver neoplasms; Lymphocyte; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; Medical; Modeling; Molecular; Molecular Genetics; Monitor; Nexavar; Nuclear Envelope; Oncogenic; Patient Selection; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Phase II Clinical Trials; Phosphorylation; Plasma; Play; Primary carcinoma of the liver cells; Prostatic Neoplasms; Publishing; Refractory; Regulation; Research Infrastructure; Role; Safety; Signal Transduction; Solid Neoplasm; South Carolina; Sphingolipids; Stream; Testing; Therapeutic; Translating; Tumor Biology; Tumor Suppression; Universities; Work; Xenograft Model; anticancer activity; base; c-myc Genes; cancer cell; cancer type; cytokine; design; effective therapy; improved; in vivo; inhibitor/antagonist; innovation; mortality; mouse model; new therapeutic target; novel; novel therapeutics; outcome forecast; overexpression; pharmacodynamic biomarker; phase II trial; potential biomarker; profiles in patients; programs; research clinical testing; response; sphingosine 1-phosphate; sphingosine kinase; therapeutic target; tool; tumor; tumor growth

PROJECT SUMMARY Hepatocellular carcinoma (HCC) has an annual worldwide incidence of more than 600,000 cases and a mortality rate greater than 95%, and therefore new and more effective therapies are needed for HCC patients. Sphingolipids, particularly ceramides and sphingosine 1-phosphate (S1P), regulate critical aspects of tumor biology. The anti-apoptotic and pro-survival lipid S1P is generated by sphingosine kinases (SK1 and SK2), and there is strong evidence that SK2-generated S1P drives cancer cell proliferation. We have developed SK inhibitors, including ABC294640, that have in vivo anti-inflammatory and anticancer activities against a variety of cancer types, including HCC and prostate cancer. Mechanistically, our recently studies suggest that ABC294640 mediates tumor suppression at least in part by targeting c-Myc for proteasomal degradation. Because c-Myc is a critical driver of HCC, being overexpressed in most HCC tumors and correlating with enhanced tumor growth and poor prognosis, defining the molecular mechanism(s) for SK2-regulation of c-Myc activity is critical for optimizing the clinical activity of ABC294640 and other sphingolipid-targeted drugs. Importantly, we have successfully completed enrollment to the first-in-human Phase I clinical trial of ABC294640 at the Medical University of South Carolina in patients with advanced solid tumors, and the data demonstrate positive safety, pharmacokinetic and pharmacodynamic profiles in these patients. Of high importance, plasma levels of ABC294640 that decrease plasma S1P levels and that are predicted to have anticancer activity can be safely achieved in these patients. Based on our completed nonclinical and clinical studies, we hypothesize that inhibition of SK2/S1P by ABC294640 will mediate tumor suppression at least in part through inhibition of c-Myc expression. This novel hypothesis will be tested in the following Specific Aims: Specific Aim 1. Determine the mechanisms by which inhibition of SK2/S1P mediates tumor suppression via the regulation of c-Myc expression. In this Aim, we will test our mechanistic hypothesis that SK2-generated S1P protects c-Myc from proteasomal degradation, thereby allowing c-Myc activity, and increased tumor proliferation. As a corollary, we also hypothesize that inhibition of SK2/S1P signaling by ABC294640 results in proteasomal degradation of c-Myc, leading to tumor suppression. Specific Aim 2. To conduct a Phase II trial of ABC294640 in patients with advanced HCC. In this Aim, we will test our novel clinical hypothesis that ABC294640 will provide a treatment benefit to patients with advanced HCC, which will be associated with decreased c-Myc and S1P signaling in the tumor.

项目总结 肝细胞癌(HCC)每年在全球范围内发病率超过60万例，其中 死亡率高于95%，因此需要新的更有效的治疗方法来治疗肝癌患者。 鞘磷脂，特别是神经酰胺和鞘氨醇1-磷酸(S1P)，调节肿瘤的关键方面 生物学。抗凋亡和促进生存的脂质S1P是由鞘氨醇激酶(SK1和SK2)产生的，以及 有强有力的证据表明，SK2产生的S1P推动了癌细胞的增殖。我们开发了SK 包括ABC294640在内的对多种药物具有体内抗炎和抗癌活性的抑制剂 癌症类型，包括肝癌和前列腺癌。从机制上讲，我们最近的研究表明 ABC294640至少部分地通过靶向蛋白酶体降解c-Myc来调节肿瘤抑制。 因为c-Myc是肝细胞癌的关键驱动因素，在大多数肝细胞癌中过度表达，并与 促进肿瘤生长和预后不良，确定了SK2调节c-Myc的分子机制(S) 活性对于优化ABC294640和其他鞘磷脂靶向药物的临床活性至关重要。 重要的是，我们已经成功完成了人类第一阶段临床试验的登记工作。 ABC294640在南卡罗来纳医科大学的晚期实体肿瘤患者中的数据 在这些患者中表现出阳性的安全性、药代动力学和药效学特征。的高 重要的是，ABC294640的血浆水平降低了血浆S1P水平，预计 在这些患者中可以安全地实现抗癌活性。 基于我们已完成的非临床和临床研究，我们假设通过抑制SK2/S1P ABC294640将至少部分地通过抑制c-Myc的表达来调节肿瘤抑制。这部小说 假设将在以下具体目标中进行检验：具体目标1.确定 抑制SK2/S1P通过调节c-Myc的表达介导肿瘤抑制。为了实现这一目标，我们将 测试我们的机械假设，即SK2产生的S1P保护c-Myc免受蛋白酶体降解， 从而允许c-Myc的活性，并增加肿瘤的增殖。作为推论，我们还假设 ABC294640抑制SK2/S1P信号转导导致c-Myc蛋白酶体降解，导致肿瘤 压制。具体目的2.对晚期肝细胞癌患者进行ABC294640的II期试验。在这 目的，我们将检验我们的新的临床假说，即ABC294640将为以下疾病患者提供治疗益处 晚期肝细胞癌，这将与肿瘤中c-Myc和S1P信号的降低有关。