Wistar PDX Development and Trial Center

Overall the outcomes of patients with metastatic melanoma have improved dramatically over the last decade due to an improved understanding of the molecular drivers of this disease. In particular, multiple targeted therapy regimens have been approved for patients with a BRAFV600E/K mutation, which are present in ~50% of cutaneous melanomas. These treatments achieve clinical responses in ~80% of patients with a BRAFV600E/K mutation, thus providing proof-of-concept of the therapeutic potential for personalized therapeutic strategies. However, most of the patients will progress within 2 years of starting those therapies. Further, currently there are no targeted therapies that have been shown to be effective in patients with a wild-type BRAF. Thus, there are unmet clinical needs to develop treatments that prevent or overcome resistance to existing therapies for patients with a BRAFV600E/K mutation, and that are effective in patients without a BRAF mutation. In order to facilitate the development of new therapeutic strategies, over the last 5 years we have led a major effort to develop a broad collection of PDX models to reflect the clinical, histological, and genetic heterogeneity of this disease. Our collection of PDX models represents one of the largest collections for any human malignancy, and our initial testing demonstrates that the collection accurately recapitulates the oncogenic drivers and molecular heterogeneity that is observed in patients. This collection also includes a subset of PDX established from patients with acquired resistance to targeted therapies that have been maintained on those agents in vivo to sustain their resistant phenotype. Together these efforts have generated a robust resource to develop, refine, and prioritize new personalized combinatorial therapies for patients. Thus, we propose to establish a multi-disciplinary and multi-institutional PDTC Program focused on the use and continued expansion of our robust melanoma PDX collection to identify new therapeutic approaches that fill important clinical gaps in this disease.]]>过去十年间，随着对转移性黑色素瘤分子驱动机制的认知不断深入，该疾病患者的临床结局得到了显著改善。针对BRAFV600E/K突变的多款靶向治疗方案已获批准，此类突变在约50%的皮肤黑色素瘤患者中存在。此类疗法可在约80%的BRAFV600E/K突变阳性患者中实现临床应答，从而验证了个性化治疗策略的治疗潜力。然而，多数患者在开始治疗后的2年内会出现疾病进展。此外，目前尚无获批的靶向疗法可用于BRAF野生型患者。因此，当前仍存在未被满足的临床需求：亟需开发可预防或克服BRAFV600E/K突变阳性患者对现有靶向疗法的耐药性，且对BRAF野生型患者同样有效的新型治疗方案。为推动新型治疗策略的研发，过去五年间我们牵头开展了一项大规模工作，构建了可覆盖该疾病临床、组织学及遗传异质性的广谱患者来源异种移植（Patient-Derived Xenograft, PDX）模型库。该PDX模型库是目前规模最大的人类恶性肿瘤模型库之一，且初步测试结果显示，其可精准重现患者体内所观察到的致癌驱动特征与分子异质性。此外，该模型库还包含一部分源自对靶向疗法获得性耐药患者的PDX模型，这些模型在体内持续暴露于对应药物以维持其耐药表型。上述工作共同构建了一套可靠的研究资源，可用于开发、优化并筛选新型个性化联合疗法，以惠及黑色素瘤患者。据此，我们提议建立一个多学科、多机构的PDTC项目，聚焦于对现有大规模黑色素瘤PDX模型库的应用与持续扩展，以发掘可填补该疾病临床治疗空白的新型治疗方案。