Topic 386: Proof of Concept for a Topical MEK Inhibitor as a Chemopreventive Agent for Squamous Cell Carcinoma in High Risk Organ Transplant Patients

主题 386：局部 MEK 抑制剂作为高危器官移植患者鳞状细胞癌化学预防剂的概念验证

• 批准号: 10020607
• 负责人: Chris Powala
• 金额: $ 29.97万
• 依托单位: NFLECTION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2020-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020607
• 关键词: Actinic keratosis; Biological Assay; Biological Markers; Blood; Blood Circulation; Cell Survival; Chemoprevention; Chemopreventive Agent; Clinical Trials; Data; Dose; Drug vehicle; Funding; Gel; Hour; Human; Immunohistochemistry; Immunosuppression; Incidence; Lead; Life; MAP Kinase Gene; MEKs; Malignant Squamous Cell Neoplasm; Measures; Metabolic; Miniature Swine; Modeling; Mus; Operative Surgical Procedures; Oral; Organ Transplantation; Papilloma; Pathway interactions; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Play; Quality of life; Rodent; Savings; Signal Pathway; Signal Transduction; Skin; Solid; Squamous cell carcinoma; Time; Toxic effect; Transplant Recipients; Western Blotting; high risk; inhibitor/antagonist; keratinocyte; mouse model; novel; prevent; response; skin squamous cell carcinoma; systemic toxicity; tumorigenesis; ultraviolet irradiation

Solid organ transplantation can be life‐saving. However, immunosuppression necessary to prevent rejection increases the incidence of cutaneous squamous cell carcinoma (cSCC) 65–250 fold. Current treatments for solid organ transplant recipients (SOTRs) are largely surgical, which can be disfiguring and impact quality of life. There is a huge need for a safe and effective chemoprevention agent for cSCC in SOTRs. The RAF‐MEK‐ERK signaling pathway plays a key role in cSCC tumorigenesis. Therefore, we identified a novel soft (metabolically labile) MEK inhibitor, NFX‐179, which we have formulated into a stable, topical gel. We have demonstrated in minipigs and rodents that topical NFX‐179 inhibits p‐ERK (a downstream biomarker of RAS/MAPK signaling) in the skin but is efficiently cleared from circulation, thereby minimizing systemic toxicities observed with oral MEK inhibitors. We have demonstrated that topical NFX‐179 is an effective chemoprevention agent in a well‐established UV‐driven mouse model of cSCC. We are seeking funding to (a) determine if topical NFX‐179 gel penetrates human cSCC explants and (b) evaluate the durability of the chemoprevention response in the cSCC mouse model. Data from these studies will support advancement into a clinical trial to evaluate topical NFX‐179 as chemopreventive agent in SOTRs.

实体器官移植可以挽救生命。但免疫抑制有必要预防