Epigenetic-based therapy of Hodgkin lymphoma

霍奇金淋巴瘤的表观遗传学治疗

基本信息

批准号：
7715214
负责人：
ANAS YOUNES
金额：
$ 6.91万
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：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7715214
关键词：
Age Antigens Apoptosis Autologous Stem Cell Transplantation Azacitidine B-Lymphocytes Biological Markers Biology Biopsy Specimen Blood Blood specimen CCL17 gene CD19 gene CXCR3 gene Cancer Center Cell Line Cell Therapy Cessation of life Clinical Clinical Data Clinical Trials Combined Modality Therapy Core Biopsy Correlative Study Cytotoxic T-Lymphocytes DNA Data Deacetylase Development Disease Doctor of Medicine Enrollment Enzyme-Linked Immunosorbent Assay Epigenetic Process Equilibrium Future Gene Expression Generations Genes Goals Hematologic Neoplasms Histone Deacetylase Inhibitor Histone Deacetylation Histones Hodgkin Disease Human Immune Immune response Immunity Immunohistochemistry Immunologic Monitoring Immunosuppressive Agents Immunotherapy In Vitro Inflammatory Interferons Interleukin-12 Interleukin-13 Interleukin-4 Interleukin-5 LMP1 Lead Life Lymphoma MS4A1 gene Malignant - descriptor Measures Molecular Analysis Molecular Target Oral Pan Genus Partial Remission Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Phenotype Plasma Play Principal Investigator Process Progression-Free Survivals Recurrent disease Reed-Sternberg Cells Refractory Refractory Disease Relapse Reporting Reproduction spores Research Research Ethics Committees Role STAT3 gene STAT6 gene Safety Signal Pathway Specimen Staging Stem cell transplant Stem cells T-Lymphocyte Testing Therapeutic Effect Tissues Toxic effect Treatment Protocols Treatment outcome Tumor Antigens Tumor Suppression University of Texas M D Anderson Cancer Center Validation Vidaza Work angiogenesis base cancer cell cancer therapy career development caspase-3 cell growth chemokine chemotherapy clinical remission cytokine design improved in vivo information gathering inhibitor/antagonist interest mortality neoplastic cell novel peripheral blood pre-clinical prognostic programs promoter protein expression research study response small molecule therapy resistant treatment response treatment strategy tumor

项目摘要

The goal of this proposal is to improve the treatment outcome and cure rate of patients with relapsed Hodgkin lymphoma (HL) using epigenefic-based therapy. We have recently demonstrated a promising single agent activity of the novel oral isotype-selective histone deacetylase (DAC) inhibitor MGCD-0103 in heavily pretreated patients with relapsed HL who had no other curative opfions. This proposal will build on this observafion to design more effective epigenefic-based therapy. Preliminary in vitro studies demonstrate single agent acfivity of the hypomethylafing agent azacifidine (Vidaza) in HL-derived cell lines, and the combinafion of MGCD-0103 and azacifidine produced synergistic antiproliferative effect. Furthermore, correlative studies from the MGCD-0103 clinical trial, and preliminary in vitro experiments suggest that epigenefic therapy may induce favorable immunoregulatory effects by altering cytokine and chemokine expression, and by upregulafing the expression of tumor-associated antigens on the cancer cells. Our central hypothesis is that epigenefic-based therapy has dual therapeufic effect in HL by both a direct anfiproliferafive effect on the malignant Hodgkin and Reed-Sternberg (HRS) cells and by inducing a favorable antitumor immune response leading to durable clinical remissions. To test this hypothesis, this project includes two IRB-approved clinical trials; in the first we use a combined epigenefic treatment strategy using an isotype selective HDAC inhibitor MGCD0103 in combinafion with a hypomethylafing agent (azacitidine), and in the second we use the pan DAC inhibitor panobinostat (LBH589) in the same pafients populafion. We also propose to examine biomarkers in blood and fissue specimens obtained from pafients participating in the clinical trial, and to perform in vitro experiments to rafionally design future second generation epigenefic-based combinafion therapy for pafients with relapsed HL. Our work is organized into 3 specific aims: Aim 1) Determine the safety and efficacy of HDACi-based therapy in patients with relapsed and refractory classical HL. Aim 2) Determine the in vivo antiproliferative and immunomodulatory effects of epigenetic therapy and idenfify potenfial biomarkers of antitumor efficacy using blood and fissue specimens from pafients enrolled on trials in Aim 1. Aim 3) To examine novel epigenefic-based combinafion therapy in vitro to rationally design second generafion clinical trials. RELEVANCE (See Instmctions): Pafients with relapsed HL after having had stem cell transplantafion have no curative opfions. This project explores novel treatment strategies using agents that alter gene expression in the cancer cells to induce their death and to make them more sensifive to other treatment strategies, including chemotherapy and immunotherapy, to improve treatment outcomes for pafients with relapsed HL.

该建议的目的是改善复发患者的治疗结果和治愈率霍奇金淋巴瘤（HL）使用基于表观研究的治疗。我们最近证明了一个有前途的新型口服同种型选择性组蛋白脱乙酰基酶（DAC）抑制剂MGCD-0103的单药活性在经过大量预处理的患者中，没有其他治愈性的HL。该提议将建立在这种观察力的基础上，以设计更有效的基于表面的治疗。初步体外研究在HL衍生的细胞中演示了甲基氟替代剂AZACIFIDINE（VIDAZA）的单剂抗性线，MGCD-0103和Azacifidine的组合产生了协同的抗增殖作用。此外，来自MGCD-0103临床试验的相关研究和初步的体外实验表明表皮治疗可能通过改变细胞因子和趋化因子的表达，并通过上调癌症对肿瘤相关的抗原的表达细胞。我们的核心假设是，基于表面的疗法在HL中都具有双重治疗作用对恶性霍奇金和芦苇 - - 塞伯格（HRS）细胞的直接亚属脂肪酸法和通过诱导有利的抗肿瘤免疫反应，导致持久的临床缓解。测试这个假设，该项目包括两项由IRB批准的临床试验；在第一个中，我们使用一个合并使用同种型选择性HDAC抑制剂MGCD0103在联合使用的表型治疗策略与低甲基氟替代剂（azacitidine），第二个我们使用PAN DAC抑制剂Panobinostat （lbh589）在同一能力人群中。我们还建议检查血液和裂缝中的生物标志物从参与临床试验的能力器获得的标本，并进行体外实验王位设计未来的第二代基于上层遗传学的综合疗法复发HL。我们的工作被组织为3个特定目标：目标1）确定的安全性和功效基于HDACI的疗法，用于复发和难治性经典HL的患者。目标2）确定体内表观遗传疗法的抗增生性和免疫调节作用使用血液和触发标本的抗肿瘤功效，来自AIM 1中的试验的能力标本。AIM3）在体外检查基于新型上学的组合疗法，以合理设计第二代临床试验。相关性（请参阅Instmctions）：具有干细胞移植后HL复发的HL的适应体没有治愈性的作用。这项目使用改变癌细胞中基因表达的药物探索新的治疗策略诱使他们的死亡，并使他们对其他治疗策略更具敏感性，包括化学疗法和免疫疗法，以改善复发性HL的适应体的治疗结果。