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

项目摘要 肝细胞癌（HCC）在全世界每年的发病率超过60万例， 死亡率大于95%，因此HCC患者需要新的和更有效的疗法。 鞘脂，特别是神经酰胺和1-磷酸鞘氨醇（S1 P），调节肿瘤的关键方面 生物学抗凋亡和促存活脂质S1 P由鞘氨醇激酶（SK 1和SK 2）产生， 有强有力的证据表明SK2产生的S1 P驱动癌细胞增殖。我们开发了SK 抑制剂，包括ABC 294640，其对多种肿瘤具有体内抗炎和抗癌活性， 包括肝癌和前列腺癌。从机制上讲，我们最近的研究表明， ABC 294640至少部分通过靶向c-Myc进行蛋白酶体降解来介导肿瘤抑制。 因为c-Myc是HCC的关键驱动因素，在大多数HCC肿瘤中过表达，并与HCC相关， 肿瘤生长增强和预后不良，定义了SK2调节c-Myc的分子机制 活性对于优化ABC 294640和其他鞘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首次人体I期临床试验的招募， ABC 294640在南卡罗来纳州医科大学的晚期实体瘤患者中的应用， 在这些患者中显示出积极的安全性、药代动力学和药效学特征。高 重要的是，血浆中ABC 294640的水平降低血浆S1 P水平，并预测其具有 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， ABC 294640将至少部分地通过抑制c-Myc表达来介导肿瘤抑制。这本小说 将在以下具体目标中检验假设：具体目标1。确定机制， SK2/S1 P的抑制通过调节c-Myc表达介导肿瘤抑制。在这个目标中，我们将 测试我们的机制假设，即SK2产生的S1 P保护c-Myc免受蛋白酶体降解， 从而允许c-Myc活性和增加的肿瘤增殖。作为推论，我们还假设， ABC 294640抑制SK2/S1 P信号传导导致c-Myc蛋白酶体降解，导致肿瘤 镇压具体目标2。在晚期HCC患者中进行ABC 294640的II期试验。在这 目的是，我们将测试我们的新的临床假设，即ABC 294640将为患有以下疾病的患者提供治疗益处： 晚期HCC，这将与肿瘤中c-Myc和S1 P信号转导的减少相关。

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.