Project 3 - Modeling Proteasome Inhibitor Response and Resistance in Cell Lines and Patient Samples with Single Cell Analysis of Subpopulations

项目 3 - 通过亚群的单细胞分析来模拟细胞系和患者样本中的蛋白酶体抑制剂反应和耐药性

• 批准号: 9444854
• 负责人: ALEXANDER KEITH STEWART
• 金额: $ 70.96万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9444854
• 关键词: Address; Affect; Biology; Bone Marrow; CRISPR interference; Cell Line; Characteristics; Clinical; Clonal Evolution; Combined Modality Therapy; Cytometry; DNA Mutational Analysis; Drug Kinetics; Drug resistance; Future; Gene Expression; Gene Mutation; Genes; Genetic; Heterogeneity; Human; Immunophenotyping; In Vitro; Kinetics; Lead; Modeling; Molecular; Multiple Myeloma; Mutation; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phenotype; Plasma Cell Neoplasm; Preclinical Drug Evaluation; Proteasome Inhibitor; Proteome; Refractory Disease; Relapse; Resistance; Sampling; Testing; Therapeutic; Therapeutic Effect; Therapeutic Uses; Time; Toxic effect; Tumor Biology; Variant; Vertebral column; base; chemotherapy; in vivo; individual patient; inter-individual variation; neoplastic cell; novel therapeutics; predictive signature; resistance factors; response; single cell analysis; therapeutic development; therapeutic target; transcriptome; treatment response; tumor; tumor heterogeneity; vector

PROJECT 3 ABSTRACT MM is a plasma cell neoplasm within the bone marrow with significant complexity and heterogeneity at the molecular level. Despite improvements in the clinical outcomes achieved with newer therapies, wide inter- individual variation in response to treatment is a major limitation in achieving consistent therapeutic effects, or cures. Not all patients respond to initial therapies (innate resistance), and those that do frequently relapse with refractory disease (acquired resistance). The central hypothesis we are addressing is that rational therapeutic development in MM should be based on an understanding of the underlying genetics and biology of the tumor that identify sensitivity and resistance to current and future drugs. In this Myeloma-DRSC we are proposing 3 Projects that will: 1) develop a high throughput drug screening platform for myeloma cell lines representing the wide diversity of MM biology; and use this platform to screen primary patient tumor cells for most effective responses, including combination therapies; 2) develop a comprehensive mutational and germline variation panel that will be correlated to drug responses in vitro and in vivo, as well as toxicities; 3) identify the mechanism of response and resistance for two of the most common therapeutics used in MM treatment: IMiDS and proteasome inhibitors; 4) develop genetic and immunophenotypic signatures that effectively predict tumor response, resistance, and patient toxicities; 5) identify tumor sub-populations that may contribute to emerging resistance; and 6) identify strategies to predict drug resistance and approaches to overcome resistance.

项目3摘要 MM是骨髓内的浆细胞肿瘤，在骨髓中具有显着的复杂性和异质性 分子水平。尽管通过较新的疗法改善了临床结果，但很广泛 响应治疗的个体变异是实现一致的治疗作用或 治疗。并非所有患者都对初始疗法（先天抵抗）做出反应，而那些经常复发的患者 难治性疾病（获得的抗药性）。我们要解决的中心假设是理性的治疗 MM的发展应基于对肿瘤的潜在遗传学和生物学的理解 确定对当前和未来药物的敏感性和抵抗力。在这个骨髓瘤-DRSC中，我们提出了3 将：1）为骨髓瘤细胞系开发高吞吐药物筛查平台，代表骨髓瘤 MM生物学的广泛多样性；并使用此平台筛选初级患者肿瘤细胞，以获得最有效的 反应，包括组合疗法； 2）发展全面的突变和种系变化 面板将与体外和体内的药物反应以及毒性相关； 3）确定 MM治疗中使用的两种最常见的治疗剂的反应和耐药机制： imID和蛋白酶体抑制剂； 4）开发遗传和免疫表型特征，以有效地预测 肿瘤反应，抗性和患者毒性； 5）确定可能有助于 新兴的抵抗力； 6）确定预测耐药性和克服方法的策略 反抗。