Regulation of Bcl-2 dependence in multiple myeloma

多发性骨髓瘤中 Bcl-2 依赖性的调节

基本信息

批准号：
10525761
负责人：
Vikas Anand Gupta
金额：
$ 24.29万
依托单位：
EMORY UNIVERSITY
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：
2022-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10525761
关键词：
ATAC-seq Acute Address Affect Apoptosis Apoptotic B lymphoid malignancy B-Lymphocytes BCL2 gene BCL2L1 gene Binding Binding Sites Bioinformatics Biological Markers Biology Bortezomib CRISPR screen Cell Line Cell Survival Cell surface Cells Cellular biology Cessation of life Characteristics Chromatin Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Cytometry Dependence Development Disease Drug resistance Family Flow Cytometry Foundations Funding Future Gene Expression Profile Genes Genetic Transcription Genetic study Genomics Goals Grant Heterogeneity Immunomodulators In Vitro K-Series Research Career Programs Laboratories Leadership MCL1 gene Machine Learning Malignant Neoplasms Manuscripts Measures Mediating Mentors Molecular Multiple Myeloma New Agents Pathogenesis Patient Selection Patient-Focused Outcomes Patients Pattern Pharmaceutical Preparations Phenotype Physicians Plasma Cells Precision medicine trial Proteasome Inhibitor Protein Family Proteins Regulation Research Technics Resistance Role Sampling Scientist Signal Transduction Source Testing Therapeutic Training Transcription Factor AP-1 Translating United States National Institutes of Health Work Writing base biomarker-driven career differential expression epigenomics improved inhibitor knock-down multidisciplinary novel novel drug class novel marker overexpression patient subsets precision medicine predicting response predictive signature pro-apoptotic protein programs resistance mechanism response skills standard of care therapy resistant transcription factor transcriptome sequencing treatment response tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Multiple myeloma is an incurable malignancy of plasma cells for which new treatments and precision guided approaches are acutely needed. Current treatments target the plasma cell biology thought to be common to all myeloma. However, response to these treatments is highly variable pointing to an underlying heterogeneity in biology. One recently identified source of heterogeneity with important therapeutic implications involves dependence on the Bcl-2 family of proteins, which includes Bcl-2, Bcl-xL, and Mcl-1. These proteins regulate cell survival and are the targets of a new class of drugs being studied for use in myeloma. Although both normal plasma cells and myeloma are typically dependent on Mcl-1 for survival, a subset of myeloma with a B cell-like phenotype is Bcl-2 dependent and sensitive to venetoclax, a Bcl-2 specific inhibitor. This B cell phenotype is notable because B cells are also Bcl-2 dependent and B cell malignancies such as CLL are highly sensitive to venetoclax. The objective of this proposal is to test the hypothesis that in a subset of myeloma, B cell transcriptional and signaling networks remain active and contribute to Bcl-2 dependence and venetoclax sensitivity as well as resistance to conventional plasma cell directed therapy. The studies proposed will define the mechanisms of Bcl-2 family dependence in myeloma and identify biomarkers capable of selecting myeloma patients most likely to respond to Bcl-2 inhibitors such as venetoclax. Aim 1 will characterize the mechanisms of BATF3 activity, an AP-1 transcription factor that increases Bcl-2 dependence and sensitizes myeloma to venetoclax, using genomic and epigenomic analyses on cells with CRISPR mediated BATF3 overexpression or knockdown. Aim 2 will directly interrogate the origins of Bcl-2 dependence and intrinsic resistance to venetoclax in myeloma using CRISPR screens targeting genes that are differentially expressed in venetoclax sensitive and resistant cells. Finally, Aim 3 will utilize state of the art mass cytometry on ex vivo tested myeloma patient samples to develop a novel biomarker that could be used for future precision medicine trials to predict response to inhibitors of Bcl-2, Bcl-xL, and Mcl-1. These studies will be conducted by Dr. Vikas Gupta, whose long-term career goal is to become an independently funded physician-scientist studying the molecular pathogenesis of multiple myeloma. He is seeking an NIH K08 career development award to acquire the additional skills necessary for independence. With the help of a multi-disciplinary group of experts serving as mentors and advisors, he will receive hands on training in advanced research techniques such as targeted CRISPR screens, RNA sequencing, bioinformatics, and mass cytometry as well as mentoring in manuscript and grant writing, clinical trial development, laboratory management, and leadership skills. Completion of the work proposed here will lay the foundation for future R01 applications studying approaches to overcome mechanisms of resistance to Bcl-2 family inhibitors.

项目摘要/摘要多发性骨髓瘤是浆细胞无法治愈的恶性肿瘤方法是急需的。当前的治疗目标是所有人都被认为是普遍的等离子体细胞生物学骨髓瘤。但是，对这些治疗的反应是高度可变的，指向潜在的异质性生物学。最近发现具有重要治疗意义的异质性来源涉及依赖于Bcl-2蛋白质的蛋白质，其中包括Bcl-2，Bcl-XL和MCL-1。这些蛋白质调节细胞生存，是研究用于骨髓瘤的新药物的靶标。虽然两者都正常血浆细胞和骨髓瘤通常取决于MCL-1的生存，这是B细胞样的骨髓瘤的一部分表型取决于Bcl-2，并且对Bcl-2特异性抑制剂的Venetoclax敏感。该B细胞表型是值得注意的是，B细胞也与Bcl-2相关，B细胞恶性肿瘤（例如CLL）对 Venetoclax。该提议的目的是检验以下假设：在骨髓瘤的一部分B细胞中转录和信号网络保持活跃，并有助于Bcl-2依赖性和Venetoclax 灵敏度以及对常规浆细胞定向治疗的抗性。提出的研究将定义 Bcl-2家族依赖性在骨髓瘤中的机制并识别能够选择骨髓瘤的生物标志物患者最有可能对BCL-2抑制剂（如Venetoclax）做出反应。 AIM 1将表征 BATF3活性，一种AP-1转录因子，可提高Bcl-2依赖性并使骨髓瘤敏感 Venetoclax，使用CRISPR介导的BATF3过表达的细胞进行基因组和表观基因组分析或击倒。 AIM 2将直接询问Bcl-2依赖性的起源和对Venetoclax的内在抗性在骨髓瘤中，使用CRISPR筛选靶向基因，在Venetoclax敏感和抗性细胞。最后，AIM 3将利用离体测试的最先进的质量细胞仪，骨髓瘤患者样品开发一种新型的生物标志物，该标志物可用于未来的精确医学试验以预测反应以Bcl-2，Bcl-XL和MCL-1的抑制剂。这些研究将由Vikas Gupta博士进行，他的长期职业目标是成为一个独立资助的医师科学家，研究分子发病机理多发性骨髓瘤。他正在寻求NIH K08职业发展奖，以获得必要的其他技能独立。借助由担任导师和顾问的多学科专家小组，他将接受高级研究技术的培训，例如靶向CRISPR屏幕，RNA测序，生物信息学和质量细胞仪以及手稿和赠款写作的指导，临床试验发展，实验室管理和领导技能。在此提议的工作完成未来R01应用程序的基础研究方法，以克服对Bcl-2的抗性机制家庭抑制剂。