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都有耐药性，预后差。约60%的黑色素瘤病例存在BrafV 600 E突变，靶向药物vemurafenib于2011年通过快速通道被FDA批准用于治疗Braf突变的黑色素瘤。在临床研究中，该药物在70%的患者中诱导肿瘤缩小。然而，几乎所有接受治疗的患者在12-15个月内复发，总生存期仅延长了几个月。另一方面，迄今为止，对于非BrafV 600 E转移性黑色素瘤没有有效的治疗。研究表明，这两种类型的黑色素瘤都可以利用组成型激活的受体酪氨酸激酶（例如c-Met）及其下游途径（例如MEK途径）来促进其生长和对初级治疗的抗性。因此，开发更有效和持久的治疗方法是a）。预防Braf突变的黑素瘤的复发，和B）.为非BrafV 600 E黑色素瘤提供治疗是迫切需要的。 关键目标：转移性黑色素瘤GEM模型开发项目合作者将共同努力，利用他们的最佳实践，知识和专业知识，建立转移性黑色素瘤的临床前相关模型，以识别耐药性和复发机制，并开发/测试有效的治疗和诊断策略。基本原理：我们为临床前模型设定了以下质量标准：（1）为了代表人类黑素瘤亚型，应选择具有与人类对应物相关的遗传学或信号传导的Braf突变和非Braf突变的小鼠黑素瘤;（2）肿瘤应扩大，通过，并且仅在同基因免疫活性小鼠上进行测试，以将它们维持在适当的微环境中，并通过体外细胞培养来防止它们的改变（3）肿瘤应该被标记/加标签以允许体内跟踪疾病进展和对治疗的反应;（4）为了测试治疗，模型应该能够概括患者中的黑色素瘤进展和治疗程序。

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.