Targeting Posttranslational Modifications in Breast Carcinogenesis

靶向乳腺癌发生中的翻译后修饰

• 批准号: 10523396
• 负责人: Yong Wan
• 金额: $ 46.22万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523396
• 关键词: 3-Dimensional; ADP ribosylation; Affect; Apoptosis; BRCA1 gene; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer therapy; Breast Carcinogenesis; Cell division; Cells; Chromatin; Computer Models; Cryoelectron Microscopy; DNA Damage; DNA Repair; DNA damage checkpoint; Data; Development; ERBB2 gene; Endocrine; Exhibits; GKLF protein; Generations; Genetic Transcription; Genome Stability; Genomic Instability; Goals; Human; Immunohistochemistry; Impairment; Knock-in; Maintenance; Malignant - descriptor; Mammary Neoplasms; Mammary Tumorigenesis; Mediating; Modeling; Molecular; Neoplasm Metastasis; Oncogenic; Organoids; Pathologic; Physiological; Play; Poly(ADP-ribose) Polymerases; Post-Translational Protein Processing; Prognosis; RNA Interference; Role; Signal Transduction; Structure; Testing; The Cancer Genome Atlas; Therapeutic Intervention; Transcriptional Regulation; Work; base; carcinogenesis; clinically relevant; drug sensitivity; genome integrity; in vivo; inhibitor; malignant breast neoplasm; novel; novel strategies; patient derived xenograft model; protein complex; recruit; response; small molecular inhibitor; small molecule inhibitor; synergism; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor initiation; tumor progression; tumorigenesis

Targeting Posttranslational Modifications in Breast Cancer Triple negative breast cancers (TNBCs) have a poor prognosis and are not amenable to endocrine- or HER2- targeted therapies. While the newly approved PARP inhibitors (PARPi) such as olaparib and talazoparib provide a glint of hope to the approximately 15-20% of TNBC patients with BRCA1-deficiency, the need for a novel strategy that could benefit the remaining 80-85% BRCA1-proficient TNBC patients is urgent and significant. The goal of this project is to determine the impact of interplay between Krüppel-like factor 4 (KLF4) and poly-ADP- ribose polymerase 1 (PARP1) in breast tumor progression and metastasis, and further develop a small molecule inhibitor of KLF4 that synergizes with PARPi for anti-TNBC treatment. This proposal is based on our original discovery that KLF4 acts as a critical signaling node in mediating DNA damage response (DDR)/DNA repair, wherein the Poly-(ADP-ribosyl)ation (PARylation) of KLF4 by PARP1 dictates the chromatin recruitment for KLF4 that, in turn, governs KLF4 transcriptional function with respect to the maintenance of genome stability, tumor progression/metastasis and drug sensitivity in breast cancer. These findings led to our central hypothesis that dysregulation of KLF4 by PARP1 results in genome instability and tumor promotes progression/metastasis, and blockade of KLF4 by newly developed KLF4 inhibitor synergizes PARPi for efficient killing of TNBC cells. Three specific aims are proposed to elucidate the importance and mechanisms regulating KLF4 by PARP1: (1) To determine the mechanism by which PARP1 regulates KLF4-mediated genome stability and carcinogenesis through orchestrating the recruitment of KLF4 to chromatin; (2) To determine the physiological and clinical relevance of KLF4 PARylation in breast tumor progression/metastasis; and (3) To validate the therapeutic intervention of KLF4 inhibitor in synergizing with olaparib/talazoparib in anti-TNBC treatment using human breast tumor organoid and patient-derived xenografts (PDXs). ! ! !

乳腺癌中的靶向翻译后修饰 三阴性乳腺癌(TNBCs)预后不良，对内分泌或HER2不敏感。 有针对性的治疗。而新批准的PARP抑制剂(PARPI)，如olaparib和talazoparib提供 对大约15%-20%患有BRCA1缺乏症的TNBC患者来说，一线希望，需要一种新的 能够使其余80%-85%精通BRCA1的TNBC患者受益的战略迫在眉睫，意义重大。这个 本项目的目标是确定Krüppel样因子4(KLF4)和多聚ADP之间的相互作用的影响。 核糖聚合酶1(PARP1)在乳腺肿瘤进展和转移中的作用，并进一步形成小分子 KLF4的抑制剂，与PARPI协同用于抗TNBC治疗。这项建议是基于我们最初的 发现KLF4在介导DNA损伤反应(DDR)/DNA修复中起关键信号节点的作用， 其中，PARP1对KLF4的多(ADP-核糖基)聚合(PAR化)决定了KLF4的染色质募集 这反过来又控制着KLF4在维持基因组稳定性、肿瘤等方面的转录功能 乳腺癌的进展/转移与药物敏感性这些发现导致了我们的中心假设 PARP1对KLF4的失调导致基因组不稳定，肿瘤促进进展/转移，以及 用新开发的KLF4抑制剂阻断KLF4可以协同PARPI有效地杀伤TNBC细胞。三 具体目的是阐明PARP1调控KLF4的重要性和机制：(1) 确定PARP1调节KLF4介导的基因组稳定性和致癌的机制 通过协调KLF4向染色质的募集；(2)测定生理和临床 KLF4 PAR化与乳腺肿瘤进展/转移的相关性；(3)验证治疗 KLF4抑制剂对奥拉帕利布/他唑帕利布协同抗人乳腺肿瘤的干预作用 肿瘤类器官和患者来源的异种移植物(PDX)。 好了！ 好了！ 好了！