Genome maintenance by Hdacs1,2 and their inhibition for Pre-B leukemia therapy

Hdacs1,2 的基因组维护及其对 Pre-B 白血病治疗的抑制作用

基本信息

批准号：
8888393
负责人：
Srividya Bhaskara
金额：
$ 34.08万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888393
关键词：
Accounting Acetylation Acute Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Adult Advanced Malignant Neoplasm Adverse effects Affect Allogenic Apoptosis B lymphoid malignancy B-Cell Development B-Lymphocytes Cause of Death Cell Cycle Cell Death Cell physiology Cells Cessation of life Chemotherapy-Oncologic Procedure Child Chimeric Proteins Chromatin Chromatin Structure Clinical Clinical effectiveness Code Complement Cutaneous DNA DNA Damage DNA Double Strand Break DNA Repair DNA biosynthesis Deacetylation Defect Depsipeptides Early treatment Elements Epigenetic Process FDA approved Flap Endonucleases Gene Expression Genetic Transcription Genome Genome Stability Goals HDAC1 gene HDAC2 gene Histone Acetylation Histone Deacetylase Inhibitor Histone Deacetylation Histones Individual Knockout Mice Knowledge Leukemic Cell Link Lymphoblastic Leukemia Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Mediating Modeling Molecular Mus Non-Histone Chromosomal Proteins Normal Cell Nucleosomes Oncogenic Outcome Pathway interactions Patients Pharmaceutical Preparations Philadelphia Philadelphia Chromosome Protein Acetylation Proteins Relapse Role S Phase Staging Stress Structure T-Lymphocyte Testing Therapeutic Toxic effect Transplantation Vorinostat Work base bcr-abl Fusion Proteins cancer cell cancer therapy chromatin remodeling conventional therapy design genetic analysis genome integrity high risk inhibitor/antagonist killings leukemia mouse model mutant novel pre-clinical public health relevance repaired research clinical testing response small molecule targeted treatment treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Broad-spectrum histone deacetylase inhibitors (HDAC inhibitors or HDIs) are FDA approved drugs and important elements of modern targeted cancer chemotherapy. Adverse side effects are associated with these pan-HDIs, because they inhibit multiple HDACs with many different cellular functions. Selective inhibitors targeting specific HDACs are being developed to minimize the mechanism-based toxicity. Genetic analysis to define the functions of individual HDACs in basic cellular mechanisms is therefore essential to fully understand the mode-of-action of selective inhibitors prior to using them in cancer therapy. We showed HDIs kill cancer cells through a novel transcription-independent mechanism, which involves triggering DNA damage selectively in cycling cells. This provides a therapeutic window, and explains HDI action in selectively killing rapidly cycling cancer cells and not normal non-cancerous cells. Using novel selective inhibitors, we established a direct role for Hdac1 and Hdac2 (Hdacs1,2) in DNA replication and replication stress induced repair. Hdacs1,2, the key targets of FDA approved HDIs, control replication fork progression and genome stability in S-phase. Hdacs1,2 target histone acetylation to regulate nascent chromatin structure and remodeling during replication. Collectively, our studies provide a new paradigm for how we view HDAC and HDI actions in normal and cancer cells, and provide the basis for this proposal. In Aim 1, we will test the hypothesis that Hdacs1,2 via histone deacetylation control chromatin packaging and nucleosome structure to allow replication fork progression and maintain genome integrity. Roles for Hdacs1,2 in regulating the activities of a non-histone protein with important functions in DNA replication and repair via its deacetylation will also be explored. Understanding how HDACs contribute to efficient DNA replication and repair will provide a rational basis for the design and pre- clinical evaluation of selective HDIs that minimize unwanted toxicity while retaining clinical effectiveness. Acute lymphoblastic leukemia of early Pre-B-cell origin (Pre-B-ALL) is the most common pediatric cancer and accounts for 20% of acute leukemia in adults. Pre-B-ALL with the t(9;22) translocation (the Philadelphia (Ph) chromosome and coding for BCR-ABL) has the poorest clinical outcome and patients are at high risk of relapse with conventional therapies. BCR-ABL, the oncogenic fusion protein, enhances DNA repair to protect leukemic cells from apoptosis. In preliminary studies, selective inhibition of Hdacs1,2 caused death in Ph+Pre- B-ALL cells. Since Hdacs1,2 are required for replication and repair, we will test the hypothesis that selective inhibition of Hdacs1,2 overrides the BCR-ABL-driven efficient repair to compromise genome stability and cause death in Ph+Pre-B-ALL cells (Aim 2). Using mouse models, we will determine the functions for Hdacs1,2 in maintaining genome stability in early B-cell development and evaluate whether selective Hdacs1,2 inhibition is a viable therapeutic strategy for the treatment of early B-cell derived Pre-B-ALL. These studies will significantly advance cancer epigenetics and therapeutic fields, and provide a treatment option for a hard to treat cancer.

描述（由申请人提供）：广谱组蛋白脱乙酰酶抑制剂（HDAC 抑制剂或 HDIs）是 FDA 批准的药物，是现代靶向癌症化疗的重要组成部分，不良副作用与这些泛 HDIs 相关，因为它们抑制多种 HDAC。因此，针对特定 HDAC 的选择性抑制剂正在开发中，以最大限度地减少基于机制的毒性，从而确定单个 HDAC 在基本细胞机制中的功能对于充分了解这一点至关重要。我们展示了 HDI 在用于癌症治疗之前的作用模式，它通过一种新颖的转录独立机制杀死癌细胞，该机制涉及选择性地触发循环细胞中的 DNA 损伤，这提供了一个治疗窗口，并解释了 HDI。选择性杀死快速循环的癌细胞的作用使用新型选择性抑制剂，我们确定了 Hdac1 和 Hdac2 (Hdacs1,2) 在 DNA 复制和复制应激诱导修复中的直接作用，Hdacs1,2 是 FDA 批准的 HDIs 的关键靶标，控制复制叉。 Hdacs1,2 的进展和基因组稳定性以组蛋白乙酰化为目标来调节复制过程中的新生染色质结构和重塑。我们如何看待 HDAC 和 HDI 在正常细胞和癌细胞中的作用，并为该提案提供基础。在目标 1 中，我们将测试 Hdacs1,2 通过组蛋白脱乙酰化控制染色质包装和核小体结构以允许复制叉进展的假设。还将探讨 Hdacs1,2 在通过脱乙酰化调节在 DNA 复制和修复中具有重要功能的非组蛋白活性中的作用。 HDAC 有助于有效的 DNA 复制和修复，将为选择性 HDI 的设计和临床前评估提供合理的基础，从而最大限度地减少不必要的毒性，同时保留早期前 B 细胞起源的急性淋巴细胞白血病 (Pre-B-ALL)。）是最常见的儿童癌症，占成人急性白血病的 20%，具有 t(9;22) 易位（费城 (Ph) 染色体并编码 BCR-ABL）。 BCR-ABL（致癌融合蛋白）的临床结果最差，患者复发的风险很高。在初步研究中，Hdacs1,2 的选择性抑制导致 Ph+Pre 死亡。 - B-ALL 细胞由于复制和修复需要 Hdacs1,2，因此我们将测试选择性抑制 Hdacs1,2 的假设。 BCR-ABL 驱动的修复会损害有效的基因组稳定性并导致 Ph+Pre-B-ALL 细胞死亡（目标 2），我们将使用小鼠模型确定 Hdacs1,2 在维持早期 B- 基因组稳定性中的功能。细胞发育并评估选择性 Hdacs1,2 抑制是否是治疗早期 B 细胞衍生的 Pre-B-ALL 的可行治疗策略。这些研究将显着推进癌症表观遗传学和治疗领域，并为难以治疗的疾病提供治疗选择。治疗癌症。