Overcoming acute, adaptive BRAF inhibitor resistance in melanoma

克服黑色素瘤中急性、适应性 BRAF 抑制剂耐药性

基本信息

批准号：
8716705
负责人：
ROGER S LO
金额：
$ 31万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-07 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8716705
关键词：
AKT1 gene Acute Age Alternative Splicing Attenuated BRAF gene Back Cataloging Catalogs Cell Line Cells Chromatin Clinic Clinical Clinical Trials Collaborations Coupled Cutaneous Melanoma Data Diagnostic Disease Progression Drug resistance Epigenetic Process Event Evolution Gene Expression Gene Expression Profile Genetic Genotype Goals Growth Histone Deacetylase Human Incidence Knowledge Laboratories Lead Lesion Link MAP Kinase Gene MEKs Malignant Neoplasms Manuscripts Mediating Melanoma Cell Molecular Mutation Oncogenic Pathway interactions Patients Peer Review Pharmaceutical Preparations Phenotype Physicians Play Proliferating Proto-Oncogene Proteins c-akt Receptor Protein-Tyrosine Kinases Regressing Melanoma Relapse Resistance Role Scientist Series Signal Transduction Skin Cancer Staging Structural Models Surveys Testing Therapeutic Tissues Translating Treatment Protocols Up-Regulation base cancer therapy chromatin remodeling clinically relevant combinatorial design exome exome sequencing gain of function in vivo inhibitor/antagonist innovation insight meetings melanoma movie mutant non-genetic novel partial response pressure public health relevance research study resistance mechanism response senescence small molecule tool transcriptome sequencing transcriptomics translational approach treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): 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) for the treatment of advanced melanoma. Although BRAF inhibitors can induce unprecedented response rates in excess of 50%, most tumor responses achieved early are partial (i.e., acute, adaptive resistance), and most patients who initially respond later suffe from disease progression (i.e., acquired drug resistance). In fact, partially regressed melanomas induced by BRAF inhibitors frequently give way to tumor regrowth later due to acquired drug resistance. Thus, overcoming BRAF inhibitor resistance promises to significantly advance melanoma patient survivability. We propose achieving this important goal by understanding both early (adaptive, non-genetic) and late (genetic) mechanisms of drug resistance in order to effectively devise combinatorial targeted therapies based on common denominator core pathways. Based on data now under peer review, we hypothesize that early and late drug resistance are mechanistically linked and that epigenetic reprogramming plays a dominant role in early, adaptive drug resistance. The Lo Laboratory has a proven track record in integrating "omic" and functional analyses to uncover acquired resistance mechanisms operative in BRAF inhibitor-treated patients. These studies have already inspired combinatorial treatment strategies (e.g. BRAF + MEK inhibitors) with encouraging early results. We propose in Aim 1 to leverage whole-exome sequencing to comprehensively understand the mechanisms of acquired (late) BRAF inhibitor resistance in melanoma in order to inform the study of adaptive (early) drug resistance. Here, understanding how a genetic alteration confers acquired drug resistance in a specific cell context will trigger mechanistic studies into this cell context and the implicatd candidate pathway in acute, adaptive resistance. In Aim 2, we propose experiments to study specific, inter-related epigenetic pathways that contribute to a form of chromatin-mediated acute, adaptive drug resistance. This aim leverages transcriptomic sequencing and studies early, adaptive resistance as a series of tractable phenotypic states. Overall, our highly translational approaches are founded in innovative collaborations that have already proven productive in yielding novel clinical concepts. Translating knowledge of how melanomas resist BRAF inhibitors back to the clinic promises to make the 2010 melanoma turning point a story for the ages.

描述（由申请人提供）：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）用于治疗晚期黑色素瘤。尽管 BRAF 抑制剂可以诱导超过 50% 的前所未有的缓解率，但大多数早期实现的肿瘤缓解是部分的（即急性适应性耐药），并且大多数最初出现缓解的患者随后会遭受疾病进展（即获得性耐药）。事实上，由 BRAF 抑制剂诱导的部分消退的黑色素瘤经常会因获得性耐药性而导致肿瘤再生。因此，克服 BRAF 抑制剂耐药性有望显着提高黑色素瘤患者的生存率。我们建议通过了解耐药性的早期（适应性、非遗传性）和晚期（遗传性）机制来实现这一重要目标，以便有效地设计基于共同点核心途径的组合靶向治疗。根据目前正在接受同行评审的数据，我们假设早期和晚期耐药性在机制上是相关的，并且表观遗传重编程在早期适应性耐药性中起着主导作用。 Lo 实验室在整合“组学”和功能分析以揭示 BRAF 抑制剂治疗患者中有效的获得性耐药机制方面拥有良好的记录。这些研究已经激发了组合治疗策略（例如 BRAF + MEK 抑制剂）的灵感，并取得了令人鼓舞的早期结果。我们在目标 1 中建议利用全外显子组测序来全面了解黑色素瘤获得性（晚期）BRAF 抑制剂耐药性的机制，以便为适应性（早期）耐药性的研究提供信息。在这里，了解基因改变如何在特定细胞环境中赋予获得性耐药性将引发对该细胞环境以及急性适应性耐药中所涉及的候选途径的机制研究。在目标 2 中，我们提出实验来研究特定的、相互关联的表观遗传途径，这些途径有助于染色质介导的急性适应性耐药性。这一目标利用转录组测序并研究早期的适应性抗性作为一系列易于处理的表型状态。总体而言，我们的高度转化方法建立在创新合作的基础上，这些合作已被证明在产生新颖的临床概念方面富有成效。将黑色素瘤如何抵抗 BRAF 抑制剂的知识转化为临床有望使 2010 年黑色素瘤转折点成为千古佳话。