MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies.

MnSOD-K68-Ac 重新编程 ER 乳腺恶性肿瘤中的谱系可塑性开关/干性。

基本信息

批准号：
10817556
负责人：
David Gius
金额：
$ 5.07万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2021-01-09 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10817556
关键词：
Acetylation Address Alleles Allografting Antineoplastic Agents Bioenergetics Breast Breast Cancer Cell Breast Carcinogenesis CDK4 gene Cell Survival Cells Cellular Metabolic Process Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Complex Dependence Development Drug Metabolic Detoxication Endocrine Enzyme Induction Enzymes Epigenetic Process Equilibrium Estrogen Receptors Estrogen Therapy Estrogen receptor positive Exhibits Fasting Fatty acid glycerol esters Fulvestrant Genes Genetic Human Impairment Implant In Vitro Infection Knock-in Mouse Laboratories Lysine MCF7 cell Malignant Neoplasms Mammary Neoplasms Medicine Metabolic Metabolic stress Metabolism Mitochondria Modeling Molecular Mouse Mammary Tumor Virus Mus Nature Nutrient Oncogenic Oxygen Pathway interactions Peroxidases Phenotype Physiological Physiology Play Process Progression-Free Survivals Property Proteins Reactive Oxygen Species Receptor Signaling Recurrence Research Research Proposals Resistance Resistance development Risk Role SOD2 gene Sampling Signal Transduction Stains Subgroup Superoxides T47D Tamoxifen Testing Therapeutic Tumor Suppressor Proteins Tumor stage Tumor-Derived Woman Xenograft procedure breast malignancies cancer cell carcinogenesis carcinogenicity cell growth experimental study feeding genomic data high risk hormone therapy human model in vivo in vivo Model inhibitor knock-down malignant breast neoplasm mammary mimetics mitochondrial metabolism molecular marker monomer mouse model mutant neoplastic cell novel therapeutic intervention oncogene addiction patient derived xenograft model patient subsets programs stemness targeted agent therapy resistant tissue culture tissue/cell culture tumor tumor initiation tumorigenesis tumorigenic

项目摘要

Summary - A fundamental theme in personalized cancer medicine is to identify specific subgroups of patients, based on molecular biomarkers and/or tumor signatures, which will subsequently benefit from new therapeutic strategies, including targeted agents. An important, and longstanding, example of this concept is the dependency of a subgroup of breast malignancies on the estrogen receptor (ER) as well as the ER signaling axis. In this regard, there is a subgroup of women with ER+ luminal B human breast malignancies that exhibit a significant risk of recurrence due to the development of resistance to endocrine therapy, including Tamoxifen. To address this, there is an ongoing search to define the pathways or molecular mechanism(s) leading to the resistance to endocrine therapy. A second significant theme in cancer medicine is based on the idea of “oncogene addiction”, a phenomenon that implies while tumors contain multiple genetic, epigenetic, signaling, and metabolic abnormalities and despite this tumor complexity, cell growth and survival can often be impaired by the targeting of a single driver gene/protein. As such, the phenomenon of oncogene addiction in specific cancers, including luminal B breast carcinogenesis, provides a scientific rational to identify carcinogenic drivers in the process luminal B resistance to endocrine therapies. Metabolic stress, due to aberrant reactive oxygen ROS levels, is a hallmark of cancer that disrupts mitochondrial physiology and metabolism leading to an oncogenic addition-like phenotype and resistance to endocrine therapy. Based on these observations, it is proposed that K68 acetylation (K68-Ac) promotes a newly discovered monomeric form of MnSOD, distinct from the established ROS detoxification role of tetrameric MnSOD, reprograms cellular and mitochondrial metabolism leading to oncogenic and tumor resistance phenotype. Finally, will targeting the MnSOD-K68-Ac axis, using a chemical MnSOD mimic (GC4419), convert endocrine resistance tumors to a sensitive phenotype?

摘要 - 个性化癌症医学的一个基本主题是确定特定的亚组基于分子生物标志物和/或肿瘤特征的患者，这将随后受益来自新的治疗策略，包括靶向药物，这是一个重要且长期存在的例子。这个概念的核心是乳腺恶性肿瘤亚组对雌激素受体的依赖性 (ER) 以及 ER 信号轴在这方面，有一个女性亚群具有 ER+ 管腔。 B 由于发展而表现出显着复发风险的人类乳腺恶性肿瘤对内分泌治疗（包括他莫昔芬）的耐药性为了解决这个问题，正在进行一项研究。确定导致内分泌治疗耐药的途径或分子机制 A。癌症医学的第二个重要主题是基于“癌基因成瘾”的想法，这种现象意味着肿瘤包含多种遗传、表观遗传、信号传导和代谢尽管肿瘤非常复杂，但细胞生长和存活通常会受到以下因素的损害：单一驱动基因/蛋白质的靶向。因此，癌基因成瘾现象在特定癌症，包括管腔 B 型乳腺癌的发生，为识别癌症提供了科学依据 Luminal B 对内分泌治疗的抵抗过程中的致癌驱动因素，由于活性氧 ROS 水平异常，是破坏线粒体的癌症的一个标志生理和代谢导致致癌加成样表型和耐药性基于这些观察，提出 K68 乙酰化（K68-Ac）。促进新发现的 MnSOD 单体形式，与已建立的 ROS 不同四聚体 MnSOD 的解毒作用，重新编程细胞和线粒体代谢最后，将使用 MnSOD-K68-Ac 轴作为靶点。化学 MnSOD 模拟物 (GC4419)，将内分泌耐药肿瘤转化为敏感表型？