Project 3

项目3

• 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
• 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

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.

项目摘要 基因型定向治疗是治疗相当大比例的晚期非霍奇金淋巴瘤的标准。 小细胞肺癌患者，其肿瘤在EGFR内具有靶向基因突变， ALK、ROS1、BRAF、RET、MET、NTRK或HER2。虽然这种治疗方法是有效的， 获得性耐药性不可避免地发生。目前的管理战略， 耐药是通过活检评估耐药机制，以帮助指导后续的 治疗然而，耐药机制可能是异质性的，并不是所有患者的肿瘤 具有可操作的抵抗机制。此外，即使有一个有针对性的机制， 一旦发现耐药性，随后的治疗可用，就会产生获得性耐药性 再另一种策略是在临床发展之前进行治疗干预， 通过特异性靶向残留的耐药持续（DTP）细胞获得耐药性， 在有效的基因型定向治疗后仍然存在的一小群细胞， 引起后天的抵抗。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械学理解。 在本项目中，我们将通过以下方式为针对DTP细胞的临床治疗策略奠定基础： 发现导致DTP状态形成的因素，并确定可以杀死DTP的目标 细胞我们将建立在我们小组围绕EGFR中DTP状态的先前研究的基础上， 突变型肺癌显示：1）雅普/TEAD激活导致转录抑制， 促凋亡蛋白BMF，从而限制EGFR抑制剂介导的凋亡; 2）DTP状态 显示出细胞衰老的某些特征，抗凋亡剂可能是一种有效的 3）肿瘤微环境中的癌症相关成纤维细胞可以促进DTP 出现和调节衰老表型的建立DTP。在此基础上 在此基础上，本项目中详细介绍的实验利用了创新技术的组合 以及一个独特的和大量的患者来源的癌症和成纤维细胞模型的集合， 基因组驱动的癌症，以了解DTP状态的脆弱性，并设计最佳的 临床方法来对抗这些患者耐药性的先兆。