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

基本信息

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
项目类别：
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

项目摘要

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）中，这种肿瘤类型可能适合基于免疫的治疗，转移瘤中恶性细胞的生物学特性而非原发肿瘤的生物学特性导致死亡率。认识到只有约五分之一的患者真正对免疫疗法有反应，这表明需要付出更多努力应致力于了解肿瘤微环境中代谢程序的基本机制。原发肿瘤和远处转移都会影响对免疫治疗的反应，但许多重要的 BET 溴结构域蛋白（包括 BRD2）尚未被探索。体细胞中的 BRD3 和 BRD4 是代谢的新关键调节因子，可能是 TNBC 的免疫疗法中这些转录共调节因子是肿瘤细胞增殖的众所周知的参与者。化，但直到最近才被确定为对新陈代谢和转移至关重要，正如我们在这里所示，个体。 BET 蛋白还控制 PD-L1 表达，这是小分子泛 BET 抑制剂的核心。 (BETi)，例如 JQ1，在多种临床前癌症模型的操作中显示出前景。蛋白质还通过代谢基因和反式活性的转录上调来增加脂肪酸氧化通过驱动 TNBC 转移的方式调节 PPARγ 靶基因（如 PGC-1α）。兴趣，而 2 型糖尿病是一个有用的起点，这些机制至关重要。我们的初步数据表明，BRD2 和 BRD4 各自相反。其他代谢功能：BRD2 共同抑制 PPARγ 靶基因和 OXPHOS 基因转录，但 BRD4 对抗 TNBC 中的糖酵解代谢，这表明适当选择性的 BET 抑制可以。我们的长期目标是了解 BET 溴结构域蛋白如何提高免疫疗法的疗效。重新编程代谢以调节 TNBC 的进展和转移以及免疫治疗反应。这里的目标是通过选择性敲除来解决每个 BET 家族成员的个体功能下一代BETi，定义调节新陈代谢、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 代谢至关重要强有力的初步数据支持三点。具体目标： 1. 确定 BET 蛋白如何控制代谢可塑性以驱动 TNBC 2 的进展。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。我们将确定 BET 蛋白调节的代谢可塑性如何促进抗 PD-1/PD-L1 策略。对患有或未接受二甲双胍治疗的 2 型糖尿病 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结合起来，这些见解将有助于定制下一代 BETi。最大限度地提高免疫疗法组合的治疗效果并最大限度地降低 TNBC 的转移风险。