Clinical Activity of MGCD-0103 in Hodgkin Lymphoma

描述(申请人提供)：这项建议的目标是测定新型口服同型选择性组蛋白脱氨酶(HDAC)抑制剂MGCD-0103的临床活性，并进行相关研究，以了解其作用机制，并找出预测复发经典霍奇金淋巴瘤(HL)患者治疗反应的标志物。我们的初步体外实验表明，MGCD-0103通过caspase依赖和非caspase依赖的机制诱导p21表达和诱导细胞凋亡，从而直接抑制HL来源的细胞株的增殖。此外，MGCD-0103抑制STAT6和TARC的表达，提示MGCD-0103可能在改变T细胞对HL微环境的趋化作用中发挥作用。重要的是，我们正在进行的MGCD-0103在复发性HL患者中的II期研究的数据显示，在经过大量预治疗的患者中，40%的患者部分或完全缓解。我们的工作分为三个具体目标：目的1.确定口服HDAC抑制剂MGCD-0103治疗复发性HL的安全性和有效性。目的2.观察MGCD-0103对复发性HL患者原代HRS细胞及周围炎症细胞分子靶点的影响。目的1.研究分子生物学标志物与临床疗效和/或治疗相关毒性的相关性。公共卫生相关性：本申请中提出的工作旨在通过治疗操纵肿瘤细胞的遗传密码以利于他们的死亡，从而提高复发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，以了解研究药物如何发挥作用，并开发治疗反应的预测标记物。

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.