Clinical and Molecular Evaluation of Cancer Therapy Induced Mucositis

描述（由申请人提供）：口腔黏膜炎是癌症治疗的剂量限制后果，通常导致疼痛、治疗改变和生活质量下降。口腔黏膜炎的发病机制尚未完全阐明；因此，尚未建立最佳治疗策略。大多数研究都集中在癌症治疗的毒性上，使用生长因子来促进快速增殖的上皮细胞的再生，作为细胞毒性药物的旁观者效应。我们对其发病机制的兴趣在于由促炎细胞因子介导的炎症反应，特别是tnf - α，它启动粘膜信号传导，导致炎症级联，上调蛋白水解和细胞凋亡，导致组织损伤和疼痛。由于tnf - α是炎症的关键早期介质，因此它是治疗粘膜炎的理想靶点。在可用的tnf - α抑制剂中，我们选择沙利度胺。我们的初步数据表明，局部应用时，沙利度胺在组织水平上具有生物利用度，并且存在于粘膜炎患者的唾液中。现有证据表明，局部给药沙利度胺可以抑制粘膜炎症级联，而没有高循环药物水平和与肠内沙利度胺相关的不良反应。然而，在进一步发展这种干预措施之前，有必要确定人类受试者的安全性、耐受性、剂量和给药间隔。我们将利用药理学和分子方法在健康志愿者和口腔黏膜炎患者中验证我们的假设。前两个目的将检验一个假设，即通过不良事件发生率和随剂量增加的血浆药物浓度在健康志愿者（目的1）和粘膜炎患者（目的2）中测量，局部使用沙利度胺具有耐受性和安全性。目的3将通过将促炎细胞因子tnf - α与粘膜炎的临床症状和疼痛症状相关联来建立原理证明，并将完善门诊环境中的数据收集技术。这些数据的分析将有助于剂量选择，干预和观察的时机，以及分子和临床终点，以在未来的局部沙利度胺漱口水治疗粘膜炎的i / ii期研究中进行评估。安全性和耐受性的论证将为进一步试验这种给药途径提供基础。因此，该方案有望在较短时间内进行临床应用。

DESCRIPTION (provided by applicant): Oral mucositis is a dose-limiting consequence of cancer therapy, often leading to pain, treatment alterations, and decreased quality of life. The mechanisms underlying the pathogenesis of oral mucositis remain incompletely elucidated; as a consequence, optimal treatment strategies have not been established. Most research has focused on the toxicity of cancer therapy, using growth factors to boost regeneration of quickly proliferating epithelial cells destroyed as a bystander effect of cytotoxic agents. Our interest in its pathogenesis lies in the inflammatory response mediated by pro-inflammatory cytokines, particularly TNF-alpha, which initiates mucosal signaling, the resultant inflammatory cascade, and the upregulation of proteolysis and apoptosis resulting in tissue injury and pain. Because TNF-alpha is a key early mediator of inflammation, it is an ideal therapeutic target for mucositis. Among the available TNF-alpha inhibitors, we select thalidomide. Our preliminary data suggest that thalidomide is bioavailable at the tissue level when topically applied and is present in the saliva of patients with mucositis. Available evidence suggests that administration of thalidomide topically will suppress the mucosal inflammatory cascade without the high circulating drug levels and adverse effects associated with enteral thalidomide. However, prior to further development of this intervention it is necessary to establish safety, tolerability, dose, and dosing interval in human subjects. We will test our hypotheses in three specific aims utilizing pharmacologic and molecular approaches in healthy volunteers and patients with oral mucositis. The first two Aims will test the hypothesis that topical thalidomide demonstrates tolerability and safety as measured by incidence of adverse events and plasma drug concentrations with increasing dose in healthy volunteers (Aim 1) and in patients with mucositis (Aim 2). Aim 3 will establish proof of principle by correlating the pro-inflammatory cytokine TNF-alpha with the clinical sign of mucositis and the symptom of pain, and will refine data collection techniques in the outpatient setting. Analysis of these data will contribute to dose selection, timing of intervention and observations, and molecular and clinical endpoints to be evaluated in a future Phase ll/lll study of topical thalidomide mouth rinse for mucositis. Demonstration of safety and tolerability will provide a basis to test further this route of administration. Hence, this proposal holds promise for clinical application in a relatively short period.