Glycosaminoglycans to Treat and Prevent Radiation-Induced Oral Mucositis

描述（由申请人提供）：GlycoMira Therapeutics开发了安全有效的抗炎糖胺聚糖衍生物，并提议测试使用其先导化合物治疗或预防口腔粘膜炎的可行性。粘膜炎是癌症治疗中一种常见且使人衰弱的并发症。接受放射或化疗的癌症患者通常在开始放射化疗的一周内患上这种痛苦的炎症性疾病。临床表现为口腔和胃肠道溃疡，并可因口腔和病原微生物的机会性感染而加重。许多患者还因唾液流量减少而出现口干，伴有疼痛和吞咽困难，通常需要安装喂食管。黏膜炎的严重程度经常导致癌症治疗中断，剂量减少，甚至计划外的急诊室就诊和住院。在头颈癌治疗中，超过80%的患者会患上这种疾病，黏膜炎使每位患者的平均费用增加了17,000美元，大大增加了医疗保健支付者的经济负担。目前的治疗方法仅用于控制粘膜炎相关症状和疼痛；Palifermin”是FDA批准的唯一一种治疗药物，在降低辐射性粘膜炎发生率方面显示出边际疗效。专家列举了许多常见抗炎药物的临床试验失败，强调需要一种针对粘膜炎初始阶段的新治疗方法。在分子水平上，粘膜炎是由放射或化疗损伤的细胞释放促炎信号分子引起的。这些信号分子反过来将炎症细胞吸引到该区域，并放大附近健康细胞的凋亡细胞死亡。虽然参与早期炎症过程的许多关键分子因素尚不清楚，但这些早期分子因素是开发有效治疗粘膜炎的潜在靶点。GlycoMira的主要候选药物GM-0111可防止炎症诱导的细胞死亡，并阻断炎症途径，包括P-和l -选择素、中性粒细胞的髓过氧化物酶和RAGE的体外激活。我们假设GM-0111通过抑制早期炎症信号传导来预防辐射诱导的粘膜炎。在本课题中，(1)我们将在体内模型中研究GM-0111减少辐射诱导的口腔黏膜炎的可行性；(2)我们将阐明GM-0111在x射线诱导的细胞死亡中的细胞保护机制。这项研究的结果将为了解粘膜炎早期重要的分子机制以及GM-0111在减轻辐射性粘膜炎方面的潜力提供见解。

DESCRIPTION (provided by applicant): GlycoMira Therapeutics has developed safe and effective anti-inflammatory glycosaminoglycan derivatives and proposes to test the feasibility of using its lead compound to treat or prevent oral mucositis. Mucositis is a common and debilitating complication of cancer treatment. Cancer patients undergoing radiation or chemotherapy often develop this painful inflammatory disease within a week of starting radio-chemotherapy. The clinical manifestations include ulcers in the mouth and gastrointestinal tract, and are exacerbated by opportunistic infections by oral and pathogenic microorganisms. Many patients also suffer from dry mouth due to decreased salivary flow, with pain and difficulty in swallowing, often necessitating installation of a feeding tube. The severity of mucositis frequently results in interruptions to the cancer treatment, dose reductions and even unplanned emergency room visits and hospitalizations. In head and neck cancer treatments, where more than 80% of the patients will develop this disorder, mucositis adds an average cost of $17,000 per patient, significantly increasing the financial burden on health care payers. Current treatments only serve to manage mucositis-related symptoms and pain; Palifermin", the only FDA approved therapeutic, shows marginal efficacy in reducing the incidence of radiation-induced mucositis. Experts cite failed clinical trials of many common anti-inflammatory drugs, highlighting the need for a new therapeutic that targets the initial stages of mucositis. On a molecular level, mucositis is initiated by the release of pro-inflammatory signaling molecules from cells damaged by radiation or chemotherapy treatment. These signaling molecules in turn attract inflammatory cells to the area and amplify apoptotic cell death in nearby healthy cells. While many key molecular factors involved in the early inflammatory process remain unclear, these early molecular factors are potential targets for developing an effective therapeutic for mucositis. GlycoMira's lead candidate GM-0111 prevents inflammation-induced cell death and blocks inflammatory pathways that include P- and L-selectins, myeloperoxidase from neutrophils, and RAGE activation in vitro. We hypothesize that GM-0111 prevents radiation-induced mucositis by inhibiting early inflammatory signaling. In this proposal, (1) we will study the feasibility of using GM-0111 to reduce radiation-induced oral mucositis in an in vivo model of the disease, and (2) we will elucidate the cytoprotective mechanism of GM-0111 in x-ray induced cell death. The results of this research will provide insight into the molecular mechanism important in the early stages of mucositis and the potential of GM-0111 in mitigating radiation-induced mucositis.