Mechanisms of BET bromodomain metabolic reprogramming in triple negative breast cancer

三阴性乳腺癌中 BET 溴结构域代谢重编程的机制

• 批准号: 9757730
• 负责人: Gerald V Denis
• 金额: $ 62.5万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-07 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757730
• 关键词: Adipocytes; Affect; Agonist; Animal Model; BRD2 gene; Biology; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast cancer metastasis; Bromodomain; CD8-Positive T-Lymphocytes; Cancer Model; Cell Proliferation; Cell Respiration; Cessation of life; Clinical Research; Combination immunotherapy; Coupled; Coupling; Data; Development; Diagnosis; Disease; Distant Metastasis; Family member; Genes; Genetic Transcription; Glycolysis; Goals; High Prevalence; Immune; Immunotherapy; Incidence; Individual; Investigation; Malignant Neoplasms; Mammary Neoplasms; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Metformin; Molecular; Molecular Target; Neoplasm Metastasis; New Agents; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Outcome; PD-1/PD-L1; PDCD1LG1 gene; PPAR gamma; Pathway interactions; Patients; Postmenopause; Primary Neoplasm; Property; Proteins; Public Health; Publishing; Research; Risk; Role; SLEB2 gene; Signal Transduction; Somatic Cell; T-Lymphocyte; Treatment Efficacy; Tumor Escape; Tumor Immunity; Up-Regulation; Urban Population; Woman; anti-PD-1; base; breast cancer progression; cancer cell; chemotherapy; fatty acid oxidation; hormone therapy; immune checkpoint; improved; inhibitor/antagonist; innovation; insight; interest; knock-down; lipid metabolism; malignant breast neoplasm; mortality; neoplastic cell; next generation; novel strategies; pre-clinical; programs; response; small molecule; targeted treatment; tool; triple-negative invasive breast carcinoma; tumor; tumor metabolism; tumor microenvironment; urban underserved

In triple negative breast cancer (TNBC), a tumor type that may be amenable to immune-based treatment, the biology of malignant cells in metastases drives mortality, rather than the biology of primary tumors. The realization that only about a fifth of patients really respond to immunotherapies suggests that more effort should be dedicated to understanding basic mechanism in the tumor microenvironment. Metabolic programs in both primary tumor and distant metastasis affect responsiveness to immunotherapy, but many important molecular switches of metabolism remain unexplored. The BET bromodomain proteins, comprising BRD2, BRD3 and BRD4 in somatic cells, are new critical regulators of metabolism and could be important targets in immunotherapy for TNBC. These transcriptional co-regulators are well known players in tumor cell prolifer- ation, but are only recently identified as critical for metabolism and metastasis. As we show here, individual BET proteins also control PD-L1 expression, central to immunotherapy. Small molecule pan-BET inhibitors (BETi), such as JQ1, show promise in several pre-clinical cancer models. Manipulation of individual BET proteins also increases fatty acid oxidation by transcriptional upregulation of metabolic genes and transacti- vates PPARγ target genes like PGC-1α, in ways that drive TNBC metastasis. Metabolic reprogramming is of interest, and Type 2 diabetes is a useful place to start. These mechanisms are critically important in metabolism of the TNBC microenvironment. Our preliminary data show that BRD2 and BRD4 oppose each other in metabolic functions: BRD2 co-represses PPARγ target genes and OXPHOS gene transcription, but BRD4 opposes glycolytic metabolism in TNBC. This suggests that properly selective BET inhibition could improve efficacy of immunotherapies. Our long term goal is to understand how BET bromodomain proteins reprogram metabolism to regulate progression and metastasis in TNBC, and immunotherapy responses. The objective here is to resolve the individual functions of each BET family member with selective knockdown and next-generation BETi, to define gene networks that regulate metabolism, metastasis and checkpoint function. The central hypothesis is that BET proteins control a metabolic switch in TNBC metabolism that is critical for metastasis, and can be reprogrammed for immunotherapy benefit. Strong preliminary data support three Specific Aims: 1. Determine how BET proteins control metabolic plasticity to drive progression of TNBC. 2. Determine how BET proteins regulate breast tumor immune escape through the PD-1/PD-L1 axis. 3. Determine how BET protein-regulated metabolic plasticity facilitates anti-PD-1/PD-L1 strategies. We will undertake an observational study of TNBC patients with and without Type 2 diabetes and metformin treatment. We expect to find that a BET protein metabolic switch regulates progression and metastases in TNBC, coupling metabolic reprogramming to checkpoint function. These insights will help tailor next generation BETi to maximize therapeutic efficacy of immunotherapy combinations and minimize metastasis risk in TNBC.

在三阴性乳腺癌（TNBC）（一种可能适合基于免疫的治疗的肿瘤类型）中， 转移瘤中恶性细胞的生物学而不是原发性肿瘤的生物学驱动死亡。的 只有大约五分之一的患者对免疫疗法有反应，这表明更多的努力 应致力于了解肿瘤微环境的基本机制。代谢程序在 原发肿瘤和远处转移都影响免疫治疗的反应性，但许多重要的 代谢的分子开关仍然未被探索。BET布罗莫结构域蛋白，包括BRD 2， 体细胞中的BRD 3和BRD 4是代谢的新的关键调节剂，并且可能是代谢的重要靶点。 TNBC的免疫疗法。这些转录辅助调节因子是众所周知的肿瘤细胞增殖的参与者， 这些蛋白质是代谢的关键，但最近才被确定为代谢和转移的关键。正如我们在这里所展示的， BET蛋白还控制PD-L1表达，这是免疫治疗的核心。小分子泛BET抑制剂 （BETi），如JQ 1，在几种临床前癌症模型中显示出希望。个人BET的操作 蛋白质还通过代谢基因的转录上调增加脂肪酸氧化， 以驱动TNBC转移的方式改变了PPARγ靶基因，如PGC-1α。代谢重编程是 2型糖尿病是一种常见的糖尿病。这些机制对于 TNBC微环境的代谢。我们的初步数据显示，BRD 2和BRD 4分别与 其他代谢功能：BRD 2共抑制PPARγ靶基因和OXPHOS基因转录，但 BRD 4对抗TNBC中的糖酵解代谢。这表明适当的选择性BET抑制可以 提高免疫疗法功效。我们的长期目标是了解BET布罗莫结构域蛋白如何 重编程代谢以调节TNBC的进展和转移以及免疫治疗应答。的 这里的目的是通过选择性敲除来解析每个BET家族成员的个体功能， 下一代BETi，定义调节代谢、转移和检查点功能的基因网络。 中心假设是BET蛋白控制TNBC代谢中的代谢开关，这对于TNBC代谢至关重要。 转移，并且可以重新编程以获得免疫治疗益处。强劲的初步数据支撑三 具体目标：1。确定BET蛋白如何控制代谢可塑性以推动TNBC的进展。2. 确定BET蛋白如何通过PD-1/PD-L1轴调节乳腺肿瘤免疫逃逸。3. 确定BET蛋白调节的代谢可塑性如何促进抗PD-1/PD-L1策略。我们将 对有和无2型糖尿病和二甲双胍治疗的TNBC患者进行观察性研究。 我们期望发现BET蛋白代谢开关调节TNBC的进展和转移， 将代谢重编程与检查点功能偶联。这些见解将有助于定制下一代BETi 以最大化免疫疗法组合的治疗功效并最小化TNBC中的转移风险。