Project 3

项目3

基本信息

批准号：
10673938
负责人：
Pasi A Janne
金额：
$ 37.88万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673938
关键词：
Aftercare Apoptosis Apoptotic Attenuated BRAF gene Biological Biological Models Biopsy Cancer Center Cancer Patient Cell Aging Cell Line Cells Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collection Coupled DNA Sequence Alteration Data Drug Targeting Drug Tolerance Drug resistance EGFR inhibition ERBB2 gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Fibroblasts Foundations Future Genomics Genotype Goals Growth In Vitro In complete remission Infrastructure Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Mutation Non-Small-Cell Lung Carcinoma Oncogenes Patient-Focused Outcomes Patients Phase Phenotype Population Pre-Clinical Model Quality of life ROS1 gene Research Residual state Resistance Stromal Neoplasm Symptoms Techniques Testing Therapeutic Tissues Work acquired drug resistance analytical tool clinical application clinical development clinical efficacy combat design drug development experimental study gene repression improved improved outcome in vivo inhibitor innovation kinase inhibitor mortality mutant neoplastic cell novel novel therapeutic intervention partial response patient derived xenograft model prevent pro-apoptotic protein resistance mechanism response senescence standard of care targeted treatment treatment response treatment strategy tumor tumor microenvironment

项目摘要

PROJECT SUMMARY Genotype directed therapy is the standard of care for the significant proportion of advanced non- small cell lung cancer patients whose tumors harbor a targetable genetic mutation within EGFR, ALK, ROS1, BRAF, RET, MET, NTRK or HER2. Although this therapeutic approach is effective, acquired drug resistance inevitably occurs. The current management strategy for acquired resistance is to evaluate the mechanism of resistance with a biopsy to help guide subsequent treatment. However, mechanisms of resistance can be heterogenous and not all patients’ tumors harbor an actionable resistance mechanism. Moreover, even when a targetable mechanism of resistance is identified and a subsequent therapy available, acquired resistance will develop again. An alternative strategy is to intervene therapeutically prior to the clinical development of acquired drug resistance by specifically targeting the residual drug tolerant persister (DTP) cells, a small population of cells that remain after effective genotype directed therapies and ultimately give rise to acquired resistance. There have been no clinical strategies developed against DTPs, in part due to the lack of the biological and mechanistic understanding of this state. In this project we will lay the foundation for clinical therapeutic strategies aimed at DTP cells by uncovering factors that lead to formation of the DTP state and identifying targets that can kill DTP cells. We will build on prior research from our group centered around the DTP state in EGFR- mutant lung cancer showing: 1) YAP/TEAD activation results in transcriptional repression of the pro-apoptotic protein BMF and thus limits EGFR inhibitor mediated apoptosis; 2) the DTP state displays some features of cellular senescence and anti-apoptosis agents may be an effective strategy; and 3) cancer-associated fibroblasts in the tumor microenvironment can facilitate DTP emergence and modulate the senescence phenotype of established DTPs. Building upon this foundation, the experiments detailed in this project utilize a combination of innovative techniques and a unique and large collection of patient-derived cancer and fibroblast models from genomically-driven cancers to understand the vulnerabilities of the DTP state and design optimal clinical approaches to combat these harbingers of drug resistance in patients.

项目概要基因型定向治疗是相当比例的晚期非晚期患者的标准治疗小细胞肺癌患者的肿瘤含有 EGFR 内的靶向基因突变， ALK、ROS1、BRAF、RET、MET、NTRK 或 HER2 虽然这种治疗方法有效，但目前的获得性耐药策略不可避免地会发生。耐药是通过活检评估耐药机制，以帮助指导后续治疗然而，耐药机制可能是异质的，并非所有患者的肿瘤都存在耐药性。拥有可操作的抵抗机制。确定耐药性并可进行后续治疗，获得性耐药性将会发展另一种替代策略是在临床发展之前进行治疗干预。通过专门针对残留的耐药持久性（DTP）细胞获得耐药性，在有效的基因型定向治疗后留下的一小群细胞，最终引起获得性耐药性，目前还没有针对 DTP 的临床策略。部分原因是缺乏对这种状态的生物学和机制理解。在这个项目中，我们将通过以下方式为针对 DTP 细胞的治疗临床策略奠定基础：揭示导致 DTP 状态形成的因素并确定可以杀死 DTP 的目标我们将以我们小组之前围绕 EGFR 的 DTP 状态进行的研究为基础。突变型肺癌显示：1) YAP/TEAD 激活导致转录抑制促凋亡蛋白 BMF 从而限制 EGFR 抑制剂介导的细胞凋亡 2) DTP 状态；显示细胞衰老的一些特征，抗凋亡剂可能是一种有效的方法策略；3) 肿瘤微环境中的癌症相关成纤维细胞可以促进 DTP 在此基础上出现并调节已建立的 DTP 的衰老表型。基础上，该项目中详细的实验利用了创新技术的组合以及来自患者的独特且大量的癌症和成纤维细胞模型基因组驱动的癌症了解 DTP 状态的脆弱性并设计最佳方案对抗患者耐药性先兆的临床方法。