Clinical and Molecular Evaluation of Cancer Therapy Induced Mucositis

描述（由申请人提供）：口腔粘膜炎是癌症治疗的剂量限制性后果，通常导致疼痛、治疗改变和生活质量下降。口腔粘膜炎的发病机制尚未完全阐明，因此，最佳的治疗策略尚未建立。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作为细胞毒性剂的旁观者效应而被破坏的快速增殖的上皮细胞的再生。我们对其发病机制的兴趣在于由促炎细胞因子（特别是TNF-α）介导的炎症反应，其启动粘膜信号传导，产生的炎症级联反应，以及导致组织损伤和疼痛的蛋白水解和凋亡的上调。由于TNF-α是炎症的关键早期介质，因此它是粘膜炎的理想治疗靶点。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，沙利度胺是生物利用度在组织水平时，局部应用，并存在于唾液中的粘膜炎患者。现有证据表明，局部给予沙利度胺将抑制粘膜炎症级联反应，而不会出现与肠内沙利度胺相关的高循环药物水平和不良反应。然而，在进一步开发这种干预之前，有必要确定人类受试者的安全性、耐受性、剂量和给药间隔。我们将在健康志愿者和口腔粘膜炎患者中利用药理学和分子方法在三个特定目标中测试我们的假设。前两个目的将检验以下假设：局部沙利度胺显示耐受性和安全性，通过在健康志愿者（目的1）和粘膜炎患者（目的2）中增加剂量时不良事件的发生率和血浆药物浓度进行测量。目标3将通过将促炎细胞因子TNF-α与粘膜炎的临床体征和疼痛症状相关联来建立原理证据，并将改进门诊设置中的数据收集技术。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在未来的局部沙利度胺含漱液治疗粘膜炎的II/III期研究中评估的分子和临床终点。安全性和耐受性的证明将为进一步测试该给药途径提供基础。因此，该建议有望在相对较短的时间内用于临床应用。

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.