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.

项目概要/摘要多发性骨髓瘤是一种无法治愈的浆细胞恶性肿瘤，需要新的治疗方法和精确引导迫切需要采取一些方法。目前的治疗针对的是浆细胞生物学，被认为是所有人都共有的骨髓瘤。然而，对这些治疗的反应差异很大，表明潜在的异质性生物学。最近发现的一种具有重要治疗意义的异质性来源涉及依赖于 Bcl-2 蛋白家族，其中包括 Bcl-2、Bcl-xL 和 Mcl-1。这些蛋白质调节细胞生存，是正在研究用于治疗骨髓瘤的一类新药物的目标。虽然两者都正常浆细胞和骨髓瘤通常依赖 Mcl-1 生存，Mcl-1 是骨髓瘤的一个子集，具有 B 细胞样表型是 Bcl-2 依赖性的，并且对 Bcl-2 特异性抑制剂 Venetoclax 敏感。该 B 细胞表型是值得注意的是，B 细胞也依赖于 Bcl-2，并且 B 细胞恶性肿瘤（例如 CLL）对维奈托克。该提案的目的是检验以下假设：在骨髓瘤的一个子集中，B 细胞转录和信号网络保持活跃并导致 Bcl-2 依赖性和 Venetoclax 对传统浆细胞定向治疗的敏感性和耐药性。拟议的研究将定义骨髓瘤中 Bcl-2 家族依赖性的机制并鉴定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）产生反应。目标 1 将描述其机制 BATF3 活性，一种 AP-1 转录因子，可增加 Bcl-2 依赖性并使骨髓瘤敏感 venetoclax，对 CRISPR 介导的 BATF3 过度表达的细胞进行基因组和表观基因组分析，或击倒。目标 2 将直接探究 Bcl-2 依赖性的起源和对 Venetoclax 的内在耐药性在骨髓瘤中，使用 CRISPR 筛选针对在 Venetoclax 敏感和中差异表达的基因耐药细胞。最后，Aim 3 将利用最先进的质谱流式细胞术对骨髓瘤患者进行离体测试样本开发一种新型生物标志物，可用于未来的精准医学试验以预测反应 Bcl-2、Bcl-xL 和 Mcl-1 抑制剂。这些研究将由 Vikas Gupta 博士进行，他的长期研究职业目标是成为一名独立资助的医师科学家，研究分子发病机制多发性骨髓瘤。他正在寻求 NIH K08 职业发展奖，以获得必要的额外技能为了独立。在担任导师和顾问的多学科专家小组的帮助下，他将接受先进研究技术的培训，例如靶向 CRISPR 筛选、RNA 测序、生物信息学、质谱流式分析以及手稿和资助写作、临床试验方面的指导开发、实验室管理和领导技能。完成此处建议的工作将奠定为未来 R01 应用研究克服 Bcl-2 耐药机制的方法奠定基础家庭抑制剂。