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Dissecting and Targeting Deregulated Mitochondrial Apoptosis in Human Cancer

剖析和靶向人类癌症中失调的线粒体凋亡

基本信息

批准号：
10474551
负责人：
Loren David Walensky
金额：
$ 103.12万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-24 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10474551
关键词：
Advanced Development Apoptosis Apoptotic BAX gene BCL-2 Protein BCL2 gene Binding Binding Sites Biochemistry Cancer Biology Cells Cellular biology Cessation of life Chemicals Chemistry Chemoresistance Cysteine Development Enzymes Family Goals Human Length Ligands Long-Chain-Acyl-CoA Dehydrogenase MCL1 gene Maintenance Malignant Neoplasms Mediating Metabolic Mitochondria Modification Molecular Molecular Conformation Pathogenesis Pathologic Pathway interactions Pediatric Oncologist Pharmacology Phase Post-Translational Protein Processing Protein Family Proteins Proteomics Regulation Relapse Research Resistance Role Signal Pathway Structure Surface Technology Work apoptosis deregulation cancer therapy fatty acid metabolism fatty acid oxidation in vivo evaluation inhibitor insight interdisciplinary approach monomer mutant next generation novel novel therapeutics programs prototype refractory cancer structural biology tool tumor metabolism

项目摘要

PROJECT SUMMARY/ABSTRACT BCL-2 proteins participate in a dynamic interaction network that determines whether a cell will live or die. Deregulation of this essential signaling pathway underlies the pathogenesis of human cancer and resistance to treatment. The goal of this R35 research program is to elucidate the fundamental protein interaction mechanisms that drive the apoptotic program and harness these insights to develop next-generation cancer treatments. Over the last five years of R35 support, we applied novel chemical tools and a host of analytical technologies to achieve mechanistic discoveries that revealed new druggable binding sites and compounds to target them. We found that covalent modification of distinct cysteines in pro-apoptotic BAX and anti-apoptotic MCL-1 and BFL-1 differentially regulate their apoptotic functions. Our pursuit of covalent ligands that mimic these post-translational modifications are yielding prototype BAX activators and MCL-1 and BFL-1 inhibitors for cancer therapy. Deciphering how BAX and BAK are directly activated, and the conformational mechanisms that underlie their conversion from latent monomers into toxic mitochondrial oligomers, has also been a major focus of our work. Indeed, the elusive structures of the BAX and BAK death channels represent the “holy grail” of apoptosis research. We recently generated the first full-length homogeneous BAX oligomer (BAXO) amenable to structure- function characterizations, providing a glimpse into the macromolecular organization of a functional BAXO species. BAXO and its mutants are enabling us to pinpoint the structural determinants for each step of the BAX- activation pathway and thus inform new control points for pharmacologic activation of apoptosis. In addition to dissecting these high-priority, canonical BCL-2 protein interactions, we have developed proteomic tools to identify non-canonical targets and recently found that MCL-1 directly interacts with the fatty acid oxidation enzyme VLCAD, revealing a dual role for MCL-1 at the intersection of apoptosis and metabolic regulation. We hypothesize that MCL-1-driven cancers rely on both apoptotic suppression and fatty acid metabolism to maximize pathologic survival, potentially explaining why MCL-1 is the most widely expressed anti-apoptotic protein across human cancers. Here, we build on our newest mechanistic insights to interrogate a spectrum of BCL-2 family interactions that drive human cancer and mine each opportunity to pharmacologically subvert them. Specifically, our next set of R35 goals are: (1) identify the structural and functional determinants that mediate the “execution phase” of mitochondrial apoptosis; (2) solve the structure of a BAX oligomer; (3) characterize the non-canonical role of MCL-1 at the intersection of apoptosis and cancer metabolism; and (4) advance the development and in vivo testing of BCL-2 family molecular modulators as next-generation therapies for human cancer. We tackle these goals using multidisciplinary approaches that span chemistry, structural biology, proteomics, biochemistry, cell biology, and in vivo testing. As a chemical biologist and pediatric oncologist, I am committed to transforming our fresh mechanistic insights into new therapies for relapsed and refractory cancers.

项目总结/文摘