Overcoming Drug Resistance in Multiple Myeloma

克服多发性骨髓瘤的耐药性

基本信息

批准号：
10006064
负责人：
Peter Leif Bergsagel
金额：
$ 118.03万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006064
关键词：
Accounting Address Age Antibodies Area Biological Models Biology Bone Marrow Cell Line Clinical Clonal Expansion Combined Modality Therapy Complex DNA Sequence Alteration Development Disease Drug resistance Engineering Future Gene Expression Genetic Hematologic Neoplasms Hematopoietic Neoplasms Heterogeneity Human Immunomodulators In Vitro Incidence Malignant - descriptor Malignant Neoplasms Modeling Molecular Morbidity - disease rate Multiple Myeloma Mus Mutation Outcome Patients Pharmaceutical Preparations Plasma Cell Neoplasm Plasma Cells Play Proteasome Inhibitor Refractory Disease Relapse Research Research Personnel Resistance Role Sampling Structure of germinal center of lymph node Therapeutic Effect Therapeutic Uses Toxic effect Tumor Biology United States Variant base cancer statistics effective therapy high-throughput drug screening improved outcome in vivo individual patient inter-individual variation mortality neoplastic cell novel novel therapeutics programs protein expression response targeted treatment therapeutic development tool treatment response treatment strategy tumor tumor DNA tumor heterogeneity

项目摘要

OVERALL 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.

总体抽象 MM是骨髓内的浆细胞肿瘤，具有显着的复杂性，分子水平的异质性。尽管临床结果有所改善通过较新的疗法实现，响应治疗的个体间差异很大是实现一致的治疗作用或治愈的主要局限性。并非所有患者应对初始疗法（先天抵抗），以及经常复发的疗法难治性疾病（获得的抗药性）。我们要解决的中心假设是 MM中合理的治疗发展应基于对肿瘤的潜在遗传学和生物学，鉴定出对当前和未来的药物。在此骨髓瘤-DRSC中，我们提出了3个项目，这些项目将： 1）为代表的骨髓瘤细胞系开发高吞吐药筛查平台 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的最有效反应，包括组合疗法； 2）发展将与药物相关的综合突变和种系变化面板体外和体内的反应以及毒性； 3）确定机制 MM中使用的两种最常见的治疗剂的反应和抗性治疗：iMID和蛋白酶体抑制剂； 4）发展遗传和免疫表型有效预测肿瘤反应，耐药性和患者毒性的特征； 5）确定可能导致新兴耐药性的肿瘤亚群；和6）确定预测耐药性和克服抗药性方法的策略。