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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.

项目总结/文摘