Preclinical assessment of a novel compound for treating radiation-induced oral mucositis

项目摘要 粘膜组织的炎症和溃疡，称为粘膜炎，是许多常见药物的严重副作用。 肿瘤治疗，包括化疗和放疗。粘膜炎的发展是昂贵的医疗保健 系统并可能导致患者的预后较差。口腔和食道的粘膜炎，称为口腔炎 粘膜炎在接受放射治疗的头颈癌患者中特别常见， 80%的患者会出现这种副作用。治疗口腔粘膜炎仍然是一个很大的临床未满足的需求， 用于实体瘤患者的获批治疗。使用Sinopia Biosciences的计算平台，我们 鉴定了用于预防和/或治疗粘膜炎的独特靶类别和相关的小分子。的 目标类别在实体瘤患者中具有确定的安全性特征。在两项急性辐射的研究中- 诱导的仓鼠口腔粘膜炎模型，我们观察到有希望的结果， 显著减少溃疡性粘膜炎的持续时间，并且在一些动物中完全防止了 溃疡的发展。所观察到的效应量与目前研究中的其他化合物一样大或更大。 在同一模型中进行临床试验。供试化合物是靶类中几种靶的泛抑制剂，每种靶均 具有多个结合域。在第一阶段的提案中，我们将测试另外三种不同的化合物， 选择性这些目标和域，以了解这类目标的药理学，以确定 最有助于粘膜炎改善的靶点。如果成功，在本提案的第二阶段，我们将 开发一种对最有效的靶点有选择性的新型化合物。然后我们将描述这种新化合物 在口腔粘膜炎和化疗诱导的胃肠道粘膜炎的分次放射模型中， 走向诊所。

Project Summary Inflammation and ulceration of mucosal tissue, called mucositis, is a severe side effect of many common treatments in oncology, including chemo- and radiotherapy. Mucositis development is costly to the health care system and can lead to poorer outcomes for patients. Mucositis of the mouth and esophagus, called oral mucositis, is particularly common in head and neck cancer patients receiving radiation therapy, where roughly 80% of patients develop this side effect. Treating oral mucositis remains a large clinical unmet need with no FDA approved treatments for patients with solid tumors. Using Sinopia Biosciences’ computational platform, we identified a unique target class and an associated small molecule for preventing and/or treating mucositis. The target class has an established safety profile in patients with solid tumors. In two studies with the acute radiation- induced hamster model of oral mucositis, we observed promising results that oral administration of the compound significantly decreased the duration of ulcerative mucositis and in some animals completely prevented the development of ulcers. The observed effect size was as large or larger than other compounds currently in the clinic tested in the same model. The test compound is a pan-inhibitor of several targets in the target class, each with multiple binding domains. In this Phase I proposal, we will test three additional compounds with different selectivity to these targets and domains in order to understand the pharmacology of this target class to determine the target that most contributes to mucositis amelioration. If successful, in Phase II of this proposal we will develop a novel compound selective for the most effective target. We will then characterize this new compound in the fractionated radiation model of oral mucositis and the chemotherapy-induced gastrointestinal mucositis to advance towards the clinic.