Clinical Activity of MGCD-0103 in Hodgkin Lymphoma

MGCD-0103 在霍奇金淋巴瘤中的临床活性

基本信息

批准号：
7529307
负责人：
ANAS YOUNES
金额：
$ 25.02万
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：
2008
资助国家：
美国
起止时间：
2008-07-08 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7529307
关键词：
Adverse effects Antigens Apoptosis B-Lymphocytes Biological Markers Biopsy Biopsy Specimen Blood CCL17 gene CDKN1A gene Cardiotoxicity Caspase Cell Line Cells Cessation of life Chemotaxis Clinical Clinical Trials Core Biopsy Correlative Study Coupled DNA Data Development Diarrhea Disease remission Drug effect disorder Epigenetic Process Fatigue Future Genes Genetic Code Goals Histone Deacetylation Histones Hodgkin Disease Hypermethylation Immunity Immunologic Monitoring In Vitro In complete remission Induction of Apoptosis Inflammatory Interleukin-6 Investigation Malignant - descriptor Molecular Molecular Analysis Molecular Target Oral Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase II Clinical Trials Phenotype Play Process Public Health Rate Reed-Sternberg Cells Relapse Reporting Role STAT6 gene Safety Sampling Serum Staging T-Lymphocyte TNFSF10 gene Toxic effect Vorinostat Work angiogenesis base cancer therapy cell growth chemokine cytokine improved in vivo inhibitor/antagonist interest lymph nodes neoplastic cell novel oncoprotein p21 promoter receptor research study response

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to determine the clinical activity of the novel oral isotype-selective histone deacytelase (HDAC) inhibitor MGCD-0103 and perform correlative studies to understand its mechanisms of action and to identify predictive markers for treatment response in patients with relapsed classical Hodgkin lymphoma (HL). Our preliminary in vitro experiments have demonstrated a direct antiproliferative activity of MGCD-0103 in HL-derived cell lines by inducing p21 expression and induction of apoptosis by caspase-dependent and caspase-independent mechanisms. Furthermore, MGCD-0103 inhibited STAT6 and TARC expression, suggesting that MGCD-0103 may play a role in altering T-cell chemotaxis to the HL microenvironment. Importantly, data from our ongoing phase II study of MGCD-0103 in patients with relapsed HL have demonstrated 40% partial or complete remissions in heavily pretreated patients. Our work is organized into 3 specific aims: Aim 1. Determine the safety and efficacy of the oral HDAC inhibitor MGCD-0103 in patients with relapsed HL. Aim 2. Determine the in vivo effect of MGCD-0103 therapy on a) selected serum cytokines/chemokines and b) selected molecular targets in primary HRS cells and the surrounding reactive inflammatory cells obtained by core needle biopsies from patients with relapsed HL entered on clinical trial in Aim 1. Aim 3. Examine the correlation between molecular and biologic markers and clinical response and/or treatment-related toxicity. PUBLIC HEALTH RELEVANCE: The work proposed in this application is aimed at improving the cure rate of patients with relapsed Hodgkin lymphoma by therapeutically manipulating the genetic code of the tumor cells to favor their death. Furthermore, we propose to perform studies on patients' blood and lymph node biopsies to understand how the study drug works and to develop predictive markers for treatment response.

描述（由申请人提供）：该提案的目的是确定新型的口服同种型选择性组蛋白脱氧酶（HDAC）抑制剂MGCD-0103的临床活动，并执行相关研究，以了解其作用机制，并鉴定具有复发性经典Hodgkin Hodgkin Lymphla瘤患者的预测标记。我们的初步体外实验表明，通过诱导p21表达并诱导caspase依赖性和caspase独立的机制诱导P21表达和诱导凋亡的HL衍生细胞系中MGCD-0103的直接抗增殖活性。此外，MGCD-0103抑制了STAT6和TARC的表达，这表明MGCD-0103可能在将T细胞趋化性改变对HL微环境中起作用。重要的是，我们正在进行的MGCD-0103的II期研究中的数据对复发性HL患者的数据显示出40％的部分或完全缓解的患者。我们的工作分为3个特定目标：目标1。确定口服HDAC抑制剂MGCD-0103对复发HL患者的安全性和功效。 Aim 2. Determine the in vivo effect of MGCD-0103 therapy on a) selected serum cytokines/chemokines and b) selected molecular targets in primary HRS cells and the surrounding reactive inflammatory cells obtained by core needle biopsies from patients with relapsed HL entered on clinical trial in Aim 1. Aim 3. Examine the correlation between molecular and biologic markers and clinical response and/or treatment-related毒性。公共卫生相关性：本应用中提出的工作旨在通过治疗方法操纵肿瘤细胞的遗传密码来改善复发性霍奇金淋巴瘤患者的治愈率。此外，我们建议对患者的血液和淋巴结活检进行研究，以了解该研究药物的工作原理并开发预测性标记以进行治疗反应。