TARGETED COMBINATORIAL TREATMENT OF BRAF MELANOMAS

2010年被癌症科学家和医生称为“黑素瘤年”。在2011年，我们见证了FDA批准BRAF抑制剂（vemurafenib/Zelboraf）和免疫调节剂（ipilimumab/Yeradine）用于治疗晚期黑色素瘤。尽管BRAF抑制剂可以诱导超过50%的前所未有的应答率，但大多数肿瘤应答是部分的（即，急性抵抗）并且大多数最初应答的患者后来遭受疾病进展（即，获得性抵抗）。因此，克服BRAF抑制剂耐药性有望显著提高黑色素瘤患者的存活率。我们建议通过了解每一种耐药机制来实现这一重要目标，以便有效地设计基于共同分母核心途径的组合靶向治疗。 Lo实验室在整合基因组和功能分析以揭示BRAF治疗患者的获得性耐药机制方面有着良好的记录（3-8）。这些研究已经提出了目前正在临床试验中测试的组合治疗策略（例如BRAF抑制剂+ MEK抑制剂）。我们在目标1中提出利用下一代测序来全面了解黑色素瘤中BRAF抑制剂耐药的机制。在目标2中，我们提出了实验来研究特定的表观遗传途径，这些途径有助于形成染色质介导的和潜在可逆的耐药性。在目标3中，我们提出了一种利用RNAi的大规模功能基因组方法来了解V600 E BRAF共依赖和合成致死基因。这一认识将为BRAF抑制剂治疗患者的原发性耐药机制提供关键见解。与P01计划项目资助的其他领导人一起，我们正在建立一个全面的黑色素瘤计划，以克服黑色素瘤中BRAF抑制剂的耐药性。我们的正向和反向翻译方法建立在已经证明富有成效的现有团队工作基础上。医学和外科专业知识（Ribas和Lo博士）和基础科学方法（Graeber和Tseng博士）的结合解决了这一重要的生物学和临床问题，有望使2010年黑色素瘤的转折点成为一个时代的故事。

2010 has been called the "Year of Melanoma" by cancer scientists and physicians. In 2011, we witnessed the FDA approval of a BRAF inhibitor (vemurafenib/Zelboraf) and an immunomodulatory agent (ipilimumab/Yervoy) for the treatment of advanced melanoma. Although BRAF inhibitors can induce unprecedented response rates in excess of 50%, most tumor responses are partial (i.e., acute resistance) and most patients who initially respond later suffer disease progression (i.e., acquired resistance). Thus, overcoming BRAF inhibitor resistance promises to significantly advance melanoma patient survivability. We propose achieving this important goal by understanding each and every mechanism of resistance in order to effectively devise combinatorial targeted therapies based on common denominator core pathways. The Lo Laboratory has a proven track record in integrating genomic and functional analyses to uncover acquired resistance mechanisms operative in BRAF inhibitor-treated patients (3-8). These studies have already suggested combinatorial treatment strategies being tested currently in clinical trials (e.g. BRAF inhibitor + MEK inhibitor). We propose in Aim 1 to leverage next-generation sequencing to comprehensively understand the mechanisms of BRAF inhibitor resistance in melanoma. In Aim 2, we propose experiments to study specific epigenetic pathways that contribute to a form of chromatin-mediated and potentially reversible type of drug resistance. In Aim 3, we propose a large-scale functional genomic approach utilizing RNAi to understand V600E BRAF co-dependent and synthetic lethal genes. This understanding should shed key insights into mechanisms of primary resistance in patients treated with BRAF inhibitors. With the other leaders of this P01 Program Project Grant, we are building a comprehensive melanoma program to overcome BRAF inhibitor resistance in melanoma. Our forward and reverse translational approaches are founded in existing team work that has already proven productive. The combination of medical and surgical expertise (Drs. Ribas and Lo) and basic science approaches (Drs. Graeber and Tseng) to solve this important biologic and clinical problem promises to make the 2010 melanoma turning point a story for the ages.