Dual LSD1 and HDAC Inhibition for Cancer Therapy

LSD1 和 HDAC 双重抑制用于癌症治疗

基本信息

批准号：
8326765
负责人：
Melissa Marie Singh
金额：
$ 5.57万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8326765
关键词：
Acetylation Address Affect Apoptosis Apoptotic Area Binding Brain Neoplasms Caspase Inhibitor Cell Death Cell Line Cell Survival Chromatin Chromatin Structure Clinical Complex DNA Fragmentation DNA Methylation DNA Modification Process Data Diagnosis Disease Drug Combinations Enzyme Inhibition Enzymes Epigenetic Process Family Flavins Gene Expression Gene Targeting Genes Genetic Transcription Glioblastoma HDAC1 gene Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Human Development Immunohistochemistry In Situ Nick-End Labeling In Vitro Inhibition of Apoptosis Knowledge Life Expectancy Link Lysine Malignant Neoplasms Malignant neoplasm of brain Methylation Modeling Molecular Monitor Monoamine Oxidase Monoamine Oxidase Inhibitors Nucleic Acid Regulatory Sequences Pathway interactions Patients Process Property Proteins Public Health Research Role Solid Neoplasm Surrogate Markers Testing Therapeutic Effect Tranylcypromine Treatment Protocols Work Xenograft Model Xenograft procedure amine oxidase anticancer research base cancer therapy caspase-3 cell growth chemotherapeutic agent chromatin immunoprecipitation demethylation effective therapy efficacy testing histone acetyltransferase in vivo inhibitor/antagonist mouse model neoplastic cell novel outcome forecast protein expression research study tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Aberrant epigenetic alterations are important mechanisms in the development of human cancers. The misregulation of histone deacetylases (HDAC), which often leads to the silencing of gene expression, is linked to cancer progression and research in recent years has focused on reversing these changes in gene expression through inhibition of HDACs. Clinical use of several HDAC inhibitors (HDACi) shows promise towards treatment of a variety of cancers, but these agents are less effective as monotherapies in solid tumors, highlighting the need to find rational combinations of chemotherapeutic agents for the treatment of these tumors. The objective of this application is to identify an effective therapy for glioblastoma, a particularly aggressive type of brain tumor with poor prognosis, that targets a combination of histone modifying enzymes and understand the mechanism(s) by which inhibition of these enzymes enhances tumor cell death. Based upon our preliminary data which demonstrate that combined inhibition of HDACs and LSD1 in glioblastoma cell lines leads to enhanced apoptotic cell death, we hypothesize that LSD1 and HDACs regulate the expression genes involved in apoptosis and inhibition of LSD1 and HDACs leads to changes in gene expression to enhance tumor cell death in vitro and in vivo. The hypothesis will be tested by pursuing two specific aims: 1) Determine the mechanism(s) by which inhibition of LSD1, by knockdown and pharmacological inhibitors, in combination with HDACi promotes apoptotic cell death and, 2) Evaluate the therapeutic effects of the combination of LSD1 inhibitors and HDACi in a glioblastoma mouse model. For the completion of Aim I, targeted array-based qPCR will be used to identify changes in pro- and anti-apoptotic genes that are regulated by LSD1 and HDACs. The involvement of the identified genes in the apoptosis induced by HDAC and LSD1 inhibition and how HDACs and LSD1 regulate these genes will be assessed. For Aim II, we will use an intracranial xenograft model of glioblastoma to evaluate the efficacy of combined HDAC and LSD1 inhibition in vivo and evaluate the mechanism(s) of apoptosis as defined by Aim I. These studies will provide a greater understanding of how apoptosis is regulated in glioblastoma which will enable us to develop more effective therapies for the treatment of this deadly disease.

描述（由申请人提供）：异常的表观遗传改变是人类癌症发展的重要机制。通常导致基因表达沉默的组蛋白脱乙酰基酶（HDAC）的正常调节与癌症的进展和研究有关，近年来的重点是通过抑制HDAC来逆转基因表达的这些变化。多种HDAC抑制剂（HDACI）的临床使用显示出对各种癌症的治疗有望，但是由于实体瘤中的单疗法，这些药物的有效性较小，这突出了需要找到化学治疗剂治疗这些肿瘤的理性组合。该应用的目的是确定一种有效的胶质母细胞瘤疗法，胶质母细胞瘤是一种特别是预后较差的脑肿瘤类型，其靶向组合组蛋白修饰酶，并了解这些酶抑制这些酶会增强肿瘤细胞死亡的机制。 Based upon our preliminary data which demonstrate that combined inhibition of HDACs and LSD1 in glioblastoma cell lines leads to enhanced apoptotic cell death, we hypothesize that LSD1 and HDACs regulate the expression genes involved in apoptosis and inhibition of LSD1 and HDACs leads to changes in gene expression to enhance tumor cell death in vitro and in vivo.该假设将通过追求两个具体目的来检验：1）确定通过敲低和药理抑制剂抑制LSD1的机制，与HDACI结合使用HDACI促进了凋亡细胞死亡，以及评估LSD1抑制剂和HDACI组合的治疗作用。为了完成AIM I，基于靶向阵列的QPCR将用于识别由LSD1和HDAC调节的促凋亡基因和抗凋亡基因的变化。 HDAC和LSD1抑制引起的凋亡中鉴定基因的参与以及HDAC和LSD1如何调节这些基因。对于AIM II，我们将使用颅内异种移植模型的胶质母细胞瘤模型来评估HDAC和LSD1抑制在体内的疗效，并评估AIM I所定义的凋亡的机制，这些研究将在对glioblastoma中进行更大的治疗方法，从而使您对这种疾病进行了更大的治疗方法，从而使您更加有效地受到治疗。