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：
8595186
负责人：
ROGER S LO
金额：
$ 31.96万
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/8595186
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，我们目睹了BRAF抑制剂（Vemurafenib/Zelboraf）的FDA批准，用于治疗晚期黑色素瘤。尽管BRAF抑制剂可以诱导前所未有的反应率超过50％，但早期达到的大多数肿瘤反应是部分的（即急性，适应性抗性），并且大多数最初从疾病进展（即获得耐药性耐药性）反应后反应的患者。实际上，由于获得的耐药性，由BRAF抑制剂诱导的部分回归的黑色素瘤经常让位于肿瘤再生。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能力。我们建议通过理解耐药性的早期（自适应，非遗传）和晚期（遗传）机制来实现这一重要目标，以便基于共同的分母核心途径有效地设计组合靶向疗法。基于现在的数据，我们假设早期和晚期耐药性是机械上的，并且表观遗传重编程在早期的适应性耐药性中起主要作用。 LO实验室在整合“ OMIC”和功能分析以发现BRAF抑制剂治疗的患者中可获得的耐药机制方面具有良好的记录。这些研究已经激发了组合治疗策略（例如BRAF + MEK抑制剂），并令人鼓舞。我们建议在AIM 1中利用全外活体测序，以全面了解黑色素瘤中获得的（晚）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，了解遗传改变如何在特定细胞环境中赋予获得的耐药性，这将触发机械研究到这种细胞环境中，以及急性，适应性抗性中的含义候选途径。在AIM 2中，我们提出了实验，以研究特定相关的表观遗传途径，这些途径有助于染色质介导的急性急性，适应性耐药性。这个目标利用了转录组测序和早期研究，适应性抗性，作为一系列可进行的表型状态。总体而言，我们高度转化的方法建立在创新的合作中，这些合作已经证明了在产生新颖的临床概念方面有效的生产力。将黑色素瘤如何抵抗BRAF抑制剂的知识回到诊所有望使2010年黑色素瘤转折点成为这个时代的故事。