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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?

个性化癌症医学的一个基本主题是确定特定的亚群