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（由适用提供）：广谱组蛋白脱乙酰基酶抑制剂（HDAC抑制剂或HDIS）是FDA认可的药物，是现代靶向癌症化学疗法的重要元素。不良副作用与这些泛HDI有关，因为它们抑制了具有许多不同细胞功能的多个HDAC。正在开发针对特定HDAC的选择性抑制剂，以最大程度地减少基于机制的毒性。因此，定义单个HDAC在基本细胞机制中的功能的遗传分析对于在癌症治疗中使用它们之前的选择性抑制剂的行为方式至关重要。我们通过一种新型的转录无关机制杀死了HDI，杀死了癌细胞，该机制涉及在循环细胞中选择性触发DNA损伤。这提供了一个治疗窗口，并解释了HDI在有选择地杀死迅速骑自行车的癌细胞和不是正常的非癌细胞。使用新型的选择性抑制剂，我们在DNA复制和复制应力诱导的修复中建立了HDAC1和HDAC2（HDACS1,2）的直接作用。 HDACS1,2，FDA批准的HDI的关键靶标，控制复制叉进程和S期的基因组稳定性。 HDACS1,2靶向组蛋白乙酰化以调节复制过程中新生染色质结构和重塑。总的来说，我们的研究为我们如何看待正常和癌细胞中的HDAC和HDI作用提供了一个新的范式，并为该建议提供了基础。在AIM 1中，我们将通过组蛋白脱乙酰化控制染色质包装和核小体结构来检验HDAC1,2的假设，以允许复制叉进展并维持基因组完整性。还将探索HDACS1,2在确定具有重要功能在DNA复制和维修中通过其脱乙酰基化的非固定蛋白活性的作用。了解HDAC如何促进有效的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，从而最大程度地减少不需要的毒性，同时保持临床有效性。早期B细胞起源（BER-B-ALL）的急性淋巴细胞白血病是最常见的儿科癌症，占成年人急性白血病的20％。 t（9; 22）易位（费城（pH）染色体和编码BCR-ABL）的ber-b均具有最差的临床结局，并且患者对传统疗法的接力有很高的风险。致癌蛋白BCR-ABL增强了DNA修复，以保护白血病细胞免受凋亡。在初步研究中，对HDACS1,2的选择性抑制导致pH+B-all细胞死亡。由于复制和维修需要HDACS1,2，因此我们将测试选择性抑制HDACS1,2覆盖的假设 BCR-ABL驱动的有效修复以损害基因组稳定性并导致pH+BER-B-ALL细胞死亡（AIM 2）。使用小鼠模型，我们将确定HDACS1,2在早期B细胞发育中维持基因组稳定性方面的功能，并评估选择性HDACS1,2抑制是否是治疗早期B细胞衍生的前B-bel-B-all的可行治疗策略。这些研究将显着提高癌症的表观遗传学和治疗领域，并为难以治疗癌症提供治疗选择。