Targeting Posttranslational Modifications in Breast Carcinogenesis

靶向乳腺癌发生中的翻译后修饰

基本信息

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
项目类别：
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

项目摘要

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). ! ! !

靶向乳腺癌的翻译后修饰三重负乳腺癌（TNBC）的预后不良，不适合内分泌或Her2-- 靶向疗法。而新批准的PARP抑制剂（PARPI），例如Olaparib和Talazoparib提供大约15-20％的TNBC患者的BRCA1缺乏症患者的希望很大，需要一种新型可能受益于剩余的80-85％BRCA1专业TNBC患者的策略是紧迫而重要的。这该项目的目标是确定Krüppel样因子4（KLF4）和Poly-ADP-之间的相互作用的影响。乳腺肿瘤进展和转移中的核糖聚合酶1（PARP1），并进一步发展一个小分子与PARPI合成抗TNBC治疗的KLF4抑制剂。该提议基于我们的原始发现KLF4充当介导DNA损伤响应（DDR）/DNA修复的关键信号节点，其中PARP1的KLF4的聚（ADP-核糖基）（parylation）决定了KLF4的染色质募集这反过乳腺癌的进展/转移和药物敏感性。这些发现导致了我们的中心假设 PARP1对KLF4的失调会导致基因组不稳定性和肿瘤促进进展/转移，并且新开发的KLF4抑制剂对KLF4的封锁协同，使PARPI有效地杀死TNBC细胞。三提出了具体目的，以阐明通过PARP1调节KLF4的重要性和机制：（1）至确定PARP1调节KLF4介导的基因组稳定性和致癌的机制通过策划募集KLF4为染色质；（2）确定身体和临床 KLF4抚养在乳腺肿瘤进展/转移中的相关性；（3）验证治疗 KLF4抑制剂在使用人乳房治疗中与Olaparib/talazoparib协同作用在抗TNBC治疗中肿瘤器官和患者衍生的Xenographictic（PDXS）。呢呢呢