Understanding and Overcoming Resistance to BRAF/MEK Kinase Inhibitors in Melanoma

了解并克服黑色素瘤对 BRAF/MEK 激酶抑制剂的耐药性

• 批准号: 10381269
• 负责人: Meenhard F Herlyn
• 金额: $ 4.62万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381269
• 关键词: Administrative Supplement; Automobile Driving; BRAF gene; Bar Codes; Biology; Cells; Computational Biology; Development; Disease; Dose; Drug resistance; Event; Experimental Designs; Goals; Grant; Immunotherapy; MAP3K1 gene; Malignant Neoplasms; Methods; Molecular; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Property; RNA; RNA Computations; Recurrent disease; Regimen; Relapse; Resistance; Statistical Data Interpretation; Techniques; Work; cellular imaging; kinase inhibitor; melanoma; new therapeutic target; response; targeted treatment; theories; therapy resistant; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Targeted immunotherapies against BRAFV600E/K-positive melanoma cancers have been efficacious at eradicating disease in >80% of patients. Nevertheless, the existence of populations of pre-resistant rare cells has posed a challenge to the efficacy of melanoma-targeted therapies, often leading to a disease relapse in the majority of patients. In the parent R01 grant, we proposed a multi-faceted approach combining new experimental techniques, statistical analysis, and theory to understand the origin of these rare, transient drug-resistant cell states and devise strategies to control them. In the current administrative supplement, our goal is to dissect the primordial cellular pathways governing cellular reprogramming that convert the transient state of resistance in the rare single cells into the permanent state of drug resistance that drive relapse. This work is related to the parent R01, but explores new concepts and experimental designs. By using a low dose exposure regimen, followed by high dose exposures, we seek to investigate whether a selective or an adaptive cellular response underlies the mechanism resulting in the conversion to permanent drug resistance. In a selection response, the permanently resistant cells share the same final resistant properties as the transient initial population. In an adaptive response, however, the final resistant properties of the permanently resistant cells could be different, most likely greater, than that of the initial transient cells. We will employ a multi-pronged approach consisting of single cell imaging, single cell barcoding, single cell RNA FISH, RNA sequencing and computational biology techniques to elucidate the primordial cellular/molecular regulators driving cellular reprogramming that results in permanently resistant cells. The mechanisms revealed by these studies will be important for the development of new targeted therapies that will be able to eradicate the relapse caused by therapy resistant cells.

项目总结/摘要 针对BRAFV 600 E/K阳性黑色素瘤癌症的靶向免疫疗法已经被广泛应用。 在>80%的患者中有效根除疾病。然而，人口的存在 对黑色素瘤靶向治疗的功效提出了挑战， 通常导致大多数患者的疾病复发。在母R 01补助金中，我们提议 一个多方面的方法结合新的实验技术，统计分析，和理论 了解这些罕见的，短暂的耐药细胞状态的起源，并制定策略， 控制他们。在目前的行政补充，我们的目标是解剖原始细胞 控制细胞重编程的途径，这些途径将细胞中的短暂抵抗状态转化为细胞中的细胞重编程。 罕见的单细胞进入永久的耐药性状态，从而导致复发。这项工作与 R 01，但探索新的概念和实验设计。通过使用低剂量 暴露方案，其次是高剂量暴露，我们试图调查是否有选择性 或者适应性细胞反应是导致转化为 永久耐药性。在选择反应中，永久抗性细胞共享 与瞬时初始种群相同的最终抗性特性。在适应性反应中， 然而，永久抗性细胞的最终抗性特性可能是不同的， 可能比最初的瞬时细胞更大。我们会多管齐下， 包括单细胞成像、单细胞条形码、单细胞RNA FISH、RNA测序 和计算生物学技术来阐明原始的细胞/分子调节因子 驱动细胞重新编程，导致永久抵抗细胞。的机制 这些研究所揭示的信息将对开发新的靶向治疗非常重要， 将能够根除由耐药细胞引起的复发。