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

• 批准号: 9283342
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-07 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9283342
• 关键词: AKT1 gene; Acute; Age; Alpha Cell; Alternative Splicing; Attenuated; BRAF gene; Back; Cataloging; Catalogs; Cell Line; Cells; Chromatin; Clinic; Clinical; Clinical Trials; Collaborations; Common Neoplasm; Coupled; Cutaneous Melanoma; Data; Diagnostic; Disease Progression; Drug resistance; Epigenetic Process; Event; Evolution; Gene Expression; Genetic; Genotype; Goals; Growth; Histone Deacetylase; Human; Incidence; Knowledge; Laboratories; Lead; Lesion; Link; MAP Kinase Gene; 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; Structural Models; Surveys; Testing; Therapeutic; Tissues; Translating; Treatment Protocols; Up-Regulation; acquired drug resistance; base; chromatin remodeling; clinically relevant; combinatorial; design; exome; exome sequencing; experimental study; gain of function; genetic resistance; in vivo; inhibitor/antagonist; innovation; insight; melanoma; movie; mutant; non-genetic; novel; partial response; pressure; public health relevance; receptor upregulation; resistance mechanism; response; senescence; small molecule; small molecule inhibitor; targeted treatment; tool; transcriptome; transcriptome sequencing; transcriptomics; translational approach; treatment strategy; tumor

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(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%的前所未有的应答率，但大多数早期获得的肿瘤反应是部分的(即急性适应性耐药)，而最初起效较晚的大多数患者都患有疾病进展(即获得性耐药)。事实上，由于获得性耐药，由BRAF抑制剂引起的部分消退的黑色素瘤通常会让位于稍后的肿瘤再生长。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。我们建议通过了解耐药的早期(适应性、非遗传)和晚期(遗传)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。基于目前接受同行评审的数据，我们假设早期和晚期耐药是机械联系的，表观遗传重新编程在早期适应性耐药中起主导作用。LO实验室在整合“OMIC”和功能分析以揭示在接受BRAF抑制剂治疗的患者中操作的获得性耐药机制方面有着良好的记录。这些研究已经启发了组合治疗策略(如BRAF+MEK抑制剂)，取得了令人鼓舞的早期结果。在目标1中，我们建议利用整个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，了解基因改变是如何在特定的细胞环境中赋予获得性耐药的，将引发对该细胞环境和在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，我们建议进行实验来研究特定的、相互关联的表观遗传途径，这些途径有助于一种染色质介导的急性适应性耐药。这一目标利用转录片段测序，并将早期适应性抗性作为一系列易处理的表型状态进行研究。总体而言，我们高度翻译的方法建立在创新合作的基础上，这些合作已经被证明在产生新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知识，有望使2010年的黑色素瘤转折点成为一个经久不衰的故事。