Protection Against Chemotherapy-Induced Gastrointestinal Mucositis by a Sphingosi

描述(由申请人提供)：胃肠道过度炎症引起的粘膜炎是一种昂贵且使人虚弱的毒性，接受放射和/或药物作为癌症治疗的患者通常会经历这种毒性。鞘磷脂被越来越多地认为是炎症的关键介质，并被认为是通过促炎细胞因子如肿瘤坏死因子-α(肿瘤坏死因子-α)和IL-4在粘膜炎中起关键作用的信号转导所必需的。特别是，胃肠道细胞对许多常见抗癌药物的反应产生的鞘氨醇1-磷酸(S1P)对于中性粒细胞的招募和激活至关重要，中性粒细胞在粘膜炎中加剧炎症过程。因此，阻断化疗诱导的S1P的产生是预防和/或治疗粘膜炎的一种新的靶向方法。由于鞘氨醇激酶(SKS)在调节炎症和肿瘤生长中的关键作用，Apogee Biotech Corporation正在开发SK抑制剂来治疗癌症和炎症性疾病。我们之前已经证明，SK2抑制剂ABC294640有效地减轻了炎症性肠病啮齿动物模型的GI损害，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，ABC294640目前正处于单剂1/2a期临床测试中，用于晚期实体瘤患者。除了它对肿瘤细胞的直接抗增殖作用外，我们假设ABC294640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好处。这一阶段SBIR项目的目标是确定针对SK2的临床药物(ABC294640)预防化疗引起的粘膜炎的能力，并将包括以下具体目标：1.确定ABC294640对抗癌药物治疗的小鼠胃肠道粘膜炎的保护能力；2.确定ABC294640对抗癌药物抗肿瘤活性的影响。这项工作将首次提供SK抑制剂在化疗诱导的粘膜炎模型中的原理有效性验证研究。我们在胃肠道毒性的动物模型方面有丰富的经验，并相信使用ABC294640预防粘膜炎是一种创新的方法，可以迅速推广到临床。

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.