Establishing the Preclinical Model for Metastatic Melanoma

项目背景：转移性黑色素瘤对几乎所有的常规治疗方法都有耐药性，预后很差。大约60%的黑色素瘤病例表现为BrafV600E突变，而靶向药物vemurafenib于2011年通过快速通道被FDA批准用于治疗BrafV600E突变的黑色素瘤。在临床研究中，该药使70%的患者肿瘤缩小。然而，几乎所有接受治疗的患者在12-15个月内疾病复发，总生存期仅延长了几个月。另一方面，目前对于非brafv600e转移性黑色素瘤尚无有效的治疗方法。研究表明，两种类型的黑色素瘤都可能利用组成型激活的受体酪氨酸激酶（如c-Met）及其下游途径（如MEK途径）来生长和抵抗初级治疗。因此，迫切需要开发更有效和持久的治疗方法，以a)防止brafv600e突变黑色素瘤的复发，b)为非brafv600e黑色素瘤提供治疗方法。关键目标：转移性黑色素瘤GEM模型开发项目的合作者将共同努力，利用他们的最佳实践、知识和专业知识，建立临床相关的转移性黑色素瘤临床前模型，以确定耐药性和复发机制，并开发/测试有效的治疗和诊断策略。理由：我们为临床前模型设定了以下质量标准：(1)为了代表人类黑色素瘤亚型，应该选择与人类同类基因或信号相关的braf突变和非braf突变小鼠黑色素瘤；(2)肿瘤应仅在同源免疫能力强的小鼠上扩增、传代和试验，使其维持在适当的微环境中，防止其因体外细胞培养条件或缺乏免疫反应而改变；(3)肿瘤应该被标记，以便在体内跟踪疾病进展和对治疗的反应；(4)为了测试治疗方法，模型应该能够概括黑色素瘤的进展和患者的治疗过程。

Project Background: Metastatic melanoma is resistant to almost all of the conventional therapies and results in dismal prognosis. About 60% of melanoma cases exhibit BrafV600E mutation, and the targeted drug, vemurafenib, was approved for treatment of Braf-mutated melanoma by FDA via fast track in 2011. In clinical studies, the drug induced tumor shrinkage in 70% of patients. However, the disease recurred in almost all the treated patient within 12-15 months, and the overall survival was prolonged for only a few months. On the other hand, there is no efficacious treatment for non-BrafV600E metastatic melanoma so far. Studies have shown both types of melanoma may take advantage of constitutively activated receptor tyrosin kinases (e.g. c-Met) and their downstream pathways (e.g. MEK pathways) for their growth and resistance to primary treatment. Therefore, development of more efficacious and durable treatment to a). prevent recurrence of Braf-mutated melanoma, and b). provide therapies for non-BrafV600E melanoma, is urgently needed. Key Goal: The metastatic melanoma GEM model development project collaborators will work together to employ their best practices, knowledge and expertise to build clinically relevant preclinical models of metastatic melanoma for identification of resistance and recurrence mechanisms and development/testing of effective treatments and diagnostic strategies. Rationale: We set quality criteria for the preclinical model as following: (1) to represent human melanoma subtypes, a Braf-mutated and a non-Braf-mutated mouse melanoma with genetics or signaling relevant to human counterparts should be chosen; (2) the tumors should be expanded, passed, and tested only on syngeneic immunocompetent mice to maintain them in an appropriate microenvironment and prevent their alteration by in vitro cell culture condition or lack of immune response; (3) the tumors should be labeled/tagged to allow in vivo tracking of disease progression and response to therapies; (4) to test therapies, the model should be able to recapitulate the melanoma progression and treatment procedures in patients.