EGFR controls skin barrier integrity and microbiota

EGFR 控制皮肤屏障完整性和微生物群

• 批准号: 422781646
• 负责人: Professor Dr. Bernhard Homey
• 金额: --
• 依托单位: Zentrum für Krebsforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422781646?language=en
• 关键词: EGFR; controls; skin; barrier; integrity

Tyrosine kinase inhibitors are, together with immunotherapy, among the most promising approaches for modern efficient cancer therapy. In particular inhibitors for the epidermal growth factor receptor (EGFR-I), which are widely used to treat solid tumors such as colorectal and lung cancer, are associated with a high frequency of stigmatizing cutaneous side effects, including a papular pustulous rash, dry skin, pruritus, paronychia, alopecia or aberrant hair growth. Importantly, there is a direct correlation between cancer therapy response and rash severity, indicating that the rash severity correlates with EGFR blockade efficiency. It has been established that cutaneous side effects are caused by the direct inhibition of EGFR signaling in the skin. The majority of human epithelial cancers show an overexpression and/or functional activation of the EGFR, thereby promoting proliferation, anti-apoptosis, angiogenesis, and metastasis. EGFR was selected as one of the first candidates for the development of targeted cancer drugs and up to date various EGFR-inhibitors (EGFR-I) have successfully been established for the treatment of cancer, including non-small cell lung, colorectal, and head-and-neck cancer. Whereas EGFR-I therapy is effective, its feasibility is limited by characteristic side effects that affect patients` quality of life (QoL) and bear a severe threat for therapy adherence. Of note, the pre¬dominance of cutaneous side effects reflects the central function of the EGFR for the skin. Characteristic papulopustular rashes are the most frequent adverse effect of EGFR-I and develop in 60-90% of the patients.A team of dermatologists from Germany and a team of immunologists from Austria could recently clarify the events induced by EGFR-I in the skin. The hallmarks of the epidermal inflammation could be identified as a barrier disruption at the hair follicle followed by a bacterial invasion. The present project aims to clarify the mechanisms behind the breakdown of the skin barrier and the anti-microbial defense, identify the responsible microorganisms and characterize in detail the compositional shifts in the skin microbiota.Understanding the mechanistic details of the events following EGFR inhibition in the skin of cancer patients, will not only significantly advance our knowledge of the central function of EGFR for the skin but may furthermore identify new therapeutic targets for prevention and management of EGFR-I induced adverse effects. This may not only lead to an improved QoL for cancer patients but may eventually enable intensified anti-cancer therapy.

酪氨酸激酶抑制剂与免疫疗法一起是现代有效癌症治疗的最有前途的方法之一。特别地，广泛用于治疗实体瘤如结肠直肠癌和肺癌的表皮生长因子受体（EGFR-I）的抑制剂与高频率的污名化皮肤副作用相关，包括丘疹性脓疱性皮疹、皮肤干燥、瘙痒、甲沟炎、脱发或异常毛发生长。重要的是，癌症治疗反应与皮疹严重程度之间存在直接相关性，表明皮疹严重程度与EGFR阻断效率相关。已经确定皮肤副作用是由皮肤中EGFR信号传导的直接抑制引起的。大多数人上皮癌显示EGFR的过表达和/或功能性活化，从而促进增殖、抗凋亡、血管生成和转移。EGFR被选为开发靶向癌症药物的首批候选药物之一，迄今为止，已成功建立了各种EGFR抑制剂（EGFR-I）用于治疗癌症，包括非小细胞肺癌、结直肠癌和头颈癌。虽然EGFR-I治疗是有效的，但其可行性受到影响患者生活质量（QoL）的特征性副作用的限制，并严重威胁治疗依从性。值得注意的是，皮肤副作用的优势反映了EGFR对皮肤的中心功能。特征性丘疹脓疱性皮疹是EGFR-I最常见的不良反应，在60-90%的患者中发生。来自德国的皮肤科医生团队和来自奥地利的免疫学家团队最近可以澄清EGFR-I在皮肤中诱导的事件。表皮炎症的标志可以被确定为毛囊屏障破坏，随后是细菌入侵。本项目旨在阐明皮肤屏障破坏和抗微生物防御背后的机制，确定负责的微生物，并详细描述皮肤微生物群的组成变化。了解癌症患者皮肤中EGFR抑制后事件的机制细节，不仅将显著地提高我们对EGFR对皮肤的中心功能的认识，而且还可以进一步鉴定用于预防和处理EGFR-I诱导的不良反应的新的治疗靶点。这不仅可以改善癌症患者的生活质量，而且最终可以加强抗癌治疗。