Rash from EGFR Inhibitors: Characterization & Palliation of a Symptom Cluster

EGFR 抑制剂引起的皮疹：特征

• 批准号: 7503895
• 负责人: Aminah Jatoi
• 金额: $ 20.4万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7503895
• 关键词: Adverse effects; Antidotes; Antineoplastic Agents; Apoptosis; Basic Science; Biopsy; Burn injury; Cancer Patient; Clinical; Clinical Research; Clinical Trials; Colon Carcinoma; Cutaneous; Data; Development; Distress; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exanthema; Face; Focus Groups; Frequencies; Functional disorder; Head and Neck Cancer; Inflammation; Inflammatory; Lead; Limb structure; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Nitric Oxide; Nitric Oxide Signaling Pathway; Non-Small-Cell Lung Carcinoma; Pain; Patients; Pharmaceutical Preparations; Placebos; Prevention; Pruritus; Public Health; Purpose; Randomized; Reaction; Reporting; Series; Signal Pathway; Signs and Symptoms; Skin; Symptoms; Testing; Tetracycline; Tetracyclines; Time; Topical application; Upper arm; Vitamin K 3; base; cancer therapy; human NOS3 protein; keratinocyte; pre-clinical; prevent; psychological distress; randomized placebo controlled trial

DESCRIPTION (provided by applicant): Rash is the most common side effect of epidermal growth factor receptor (EGFR) inhibitors, occurring in > 70% of cancer patients who take these drugs. This rash occurs on the face, trunk, and extremities and, when severe, can lead to discontinuation of cancer therapy. EGFR inhibitors are being prescribed with increasing frequency and have well established antineoplastic effects among patients with a variety of malignancies. Yet relatively little is known about the rash they cause. Our group has completed two clinical trials (n=177) in an effort to try to prevent and palliate this rash, and preliminary observations from our group and from others prompt a series of unanswered questions. Is the EGFR inhibitor-induced rash typically associated with other distressing symptoms such as cutaneous burning and itching? Is it associated with psychological distress, and, if so, to what extent? Can the promising preclinical data with topical menadione lead to the prevention and palliation of this rash in cancer patients? What is the pathophysiology underlying this rash, and might nitric oxide-mediated inflammation be a key component? In view of these unanswered questions, this proposal has the following aims: AIM #1: To utilize focus groups among cancer patients who had previously suffered from an EGFR inhibitor induced rash in an effort to characterize, for the first time, the entire cluster of signs and symptoms associated with this rash. AIM #2: To explore by means of a randomized, placebo-controlled trial, whether topical menadione prevents and palliates this rash and the other aspects of this rash-related symptom cluster. AIM#3: To explore, by means of serial skin biopsies, whether topically applied menadione, which in other settings has been shown to inhibit endothelial nitric oxide synthase, reverses cutaneous alterations of the nitricoxide signaling pathway, thereby leading to decreased keratinocyte apoptosis. PUBLIC HEALTH RELEVANCE: Epidermal growth factor receptor (EGFR) inhibitors are being used with increasing frequency in cancer therapy. These agents cause a rash which occurs on the face, trunk, and arms and is associated with a poorly characterized cluster of symptoms that appears to include itching, pain, and psychological distress. The purpose of this proposal is to better characterize this skin-related symptom cluster from a clinical and basic science standpoint and to test the agent menadione to prevent it all together.

描述（由申请人提供）：皮疹是表皮生长因子受体 (EGFR) 抑制剂最常见的副作用，在服用这些药物的癌症患者中发生率超过 70%。这种皮疹发生在面部、躯干和四肢，严重时可能导致癌症治疗的停止。 EGFR 抑制剂的使用频率越来越高，并且在多种恶性肿瘤患者中具有明确的抗肿瘤作用。然而，人们对它们引起的皮疹知之甚少。我们的小组已经完成了两项临床试验（n=177），试图预防和缓解这种皮疹，我们小组和其他人的初步观察结果提出了一系列尚未解答的问题。 EGFR 抑制剂引起的皮疹通常是否与其他令人痛苦的症状（如皮肤灼烧感和瘙痒）相关？它是否与心理困扰有关？如果有，程度如何？外用甲萘醌的有希望的临床前数据能否预防和缓解癌症患者的这种皮疹？这种皮疹的病理生理学是什么？一氧化氮介导的炎症可能是一个关键因素吗？鉴于这些未解答的问题，该提案有以下目标： 目标#1：利用先前患有 EGFR 抑制剂引起的皮疹的癌症患者的焦点小组，首次描述与皮疹相关的整个体征和症状。目标#2：通过一项随机、安慰剂对照试验探讨外用甲萘醌是否可以预防和缓解这种皮疹以及皮疹相关症状群的其他方面。 AIM#3：通过连续皮肤活检，探讨局部使用甲萘醌是否能逆转皮肤一氧化氮信号通路的改变，从而减少角质形成细胞凋亡。甲萘醌在其他情况下已被证明可以抑制内皮一氧化氮合酶。公共卫生相关性：表皮生长因子受体 (EGFR) 抑制剂在癌症治疗中的使用频率不断增加。这些物质会导致面部、躯干和手臂出现皮疹，并与身体状况不佳有关。 一系列症状的特征似乎包括瘙痒、疼痛和心理困扰。这 该提案的目的是从临床和基础科学的角度更好地描述这种与皮肤相关的症状群，并测试甲萘醌制剂以预防所有这些症状。