Protection Against Chemotherapy-Induced Gastrointestinal Mucositis by a Sphingosi

鞘氨醇可预防化疗引起的胃肠粘膜炎

• 批准号: 8643861
• 负责人: Charles D Smith
• 金额: $ 22.41万
• 依托单位: APOGEE BIOTECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643861
• 关键词: Adverse effects; Animal Model; Animals; Antineoplastic Agents; Attenuated; Biochemical; Biotechnology; C57BL/6 Mouse; Cancer Patient; Cells; Cisplatin; Clinic; Clinical; Clinical Trials; Colon; Complement; Cyclophosphamide; Disease; Dose; Drug Targeting; Fluorouracil; Gastrointestinal tract structure; Goals; Health; High Dose Chemotherapy; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Interleukin-4; Malignant Neoplasms; Methotrexate; Modeling; Mucositis; Mus; Neutrophil Activation; Pancreas; Patients; Pharmaceutical Preparations; Phase; Prevention; Prevention approach; Process; Production; Radiation; Rodent Model; Role; Signal Transduction; Small Business Innovation Research Grant; Solid Neoplasm; Sphingolipids; Testing; Toxic effect; Translating; Tumor Necrosis Factor-alpha; Work; Xenograft procedure; cancer therapy; chemotherapy; cytokine; experience; gastrointestinal; inhibitor/antagonist; innovation; kinase inhibitor; melanoma; neoplastic cell; pre-clinical; prevent; research clinical testing; response; sphingosine 1-phosphate; sphingosine kinase; tumor; tumor growth

DESCRIPTION (provided by applicant): Mucositis caused by excessive inflammation within the gastrointestinal tract is a costly and debilitating toxicity commonly experienced by patients receiving radiation and/or drugs as cancer therapy. Sphingolipids are being increasingly recognized as key mediators of inflammation, and are known to be essential for signaling by pro-inflammatory cytokines such as tumor necrosis factor-α(TNFα) and IL-4 that are of central importance in mucositis. In particular, sphingosine 1-phosphate (S1P) within gastrointestinal cells generated in response to many common anticancer drugs is critical for the recruitment and activation of neutrophils that escalate inflammatory processes in mucositis. Therefore, disruption of chemotherapy-induced S1P production is a new targeted approach to the prevention and/or treatment of mucositis. Because of the pivotal roles of sphingosine kinases (SKs) in regulating inflammation and tumor growth, Apogee Biotechnology Corporation is developing SK inhibitors to treat cancer and inflammatory diseases. We have previously shown that the SK2 inhibitor ABC294640 effectively attenuates GI damage in rodent models of inflammatory bowel diseases, as well as in radiation-induced GI toxicity. In preclinical cell and tumor models, SK inhibitors enhance the antitumor activity of several drugs, and ABC294640 is currently in single-agent phase 1/2a clinical testing in patients with advanced solid tumors. In addition to its direct antiproliferative effects on tumor cells, we hypothesize that ABC294640 will reduce GI mucositis following treatment with chemotherapy drugs, thereby providing substantial clinical benefit to patients undergoing cancer treatment. The goal of this phase 1 SBIR project is to determine the ability of a clinical drug targeting SK2 (ABC294640) to prevent chemotherapy-induced mucositis, and will consist of the following Specific Aims: 1. To determine the ability of ABC294640 to protect against GI mucositis in mice treated with anticancer drugs; and 2. To determine the effects of ABC294640 on the antitumor activity of anticancer drugs. This work will provide the first proof-of-principle efficacy studies of an SK inhibitor in models of chemotherapy-induced mucositis. We have extensive experience with animal models of GI toxicity, and believe that the use of ABC294640 for the prevention of mucositis is an innovative approach that can be rapidly translated to the clinic.

描述（由申请人提供）：胃肠道内过度炎症引起的粘膜炎是接受放射和/或药物作为癌症治疗的患者通常经历的昂贵且使人衰弱的毒性。鞘脂越来越被认为是炎症的关键介质，并且已知对于促炎细胞因子如肿瘤坏死因子-α（TNFα）和IL-4的信号传导至关重要，这些细胞因子在粘膜炎中具有核心重要性。特别是，响应于许多常见抗癌药物而产生的胃肠道细胞内的1-磷酸鞘氨醇（S1 P）对于中性粒细胞的募集和激活是至关重要的，所述中性粒细胞使粘膜炎中的炎症过程升级。因此，破坏化疗诱导的S1 P产生是预防和/或治疗粘膜炎的新的靶向方法。由于鞘氨醇激酶（SK）在调节炎症和肿瘤生长中的关键作用，Apogee生物技术公司正在开发SK抑制剂来治疗癌症和炎性疾病。我们之前已经证明，SK2抑制剂ABC 294640有效地减弱炎症性肠病啮齿动物模型中的GI损伤，以及辐射诱导的GI毒性。在临床前细胞和肿瘤模型中，SK抑制剂增强了几种药物的抗肿瘤活性，ABC 294640目前正在晚期实体瘤患者中进行单药1/2a期临床试验。除了对肿瘤细胞的直接抗增殖作用外，我们假设ABC 294640将 减少化疗药物治疗后的胃肠道粘膜炎，从而为接受癌症治疗的患者提供实质性的临床益处。该1期SBIR项目的目标是确定靶向SK2（ABC 294640）的临床药物预防化疗诱导的粘膜炎的能力，并将包括以下具体目的：1.确定ABC 294640在用抗癌药物治疗的小鼠中保护免受GI粘膜炎的能力;和2.探讨ABC 294640对抗癌药物抗肿瘤活性的影响。这项工作将提供SK抑制剂在化疗诱导的粘膜炎模型中的第一个原理验证有效性研究。我们在胃肠道毒性动物模型方面拥有丰富的经验，并相信使用ABC 294640预防粘膜炎是一种创新方法，可以迅速转化为临床。