TARGETED COMBINATORIAL TREATMENT OF BRAF MELANOMAS

2010年被癌症科学家和医生称为“黑色素瘤年”。2011年，我们见证了FDA批准BRAF抑制剂(Vemurafenib/Zelboraf)和免疫调节剂(ipilimumab/Yerway)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，但大多数肿瘤反应是部分的(即急性耐药)，而大多数最初有效的患者后来经历了疾病的进展(即获得性耐药)。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通路的联合靶向治疗。 LO实验室在整合基因组和功能分析以揭示在接受BRAF抑制剂治疗的患者中起作用的获得性耐药性机制方面有良好的记录(3-8例)。这些研究已经表明，目前正在进行临床试验的联合治疗策略(如BRAF抑制剂+MEK抑制剂)。在目标1中，我们建议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，我们建议进行实验来研究特定的表观遗传途径，这些途径有助于一种染色质介导的潜在可逆型耐药性。在目标3中，我们提出了一种大规模的功能基因组方法，利用RNAi来理解V600E BRAF相互依赖的和合成的致死基因。这一理解将对使用BRAF抑制剂治疗的患者的原发耐药机制提供关键的见解。与P01计划项目赠款的其他领导人一起，我们正在建立一个全面的黑色素瘤计划，以克服黑色素瘤对BRAF抑制剂的耐药性。我们的正向和反向转换方法建立在已被证明富有成效的现有团队工作中。结合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)来解决这一重要的生物和临床问题，有望使2010年的黑色素瘤转折点成为一个永恒的故事。

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.