Clinical Activity of MGCD-0103 in Hodgkin Lymphoma

描述（由申请人提供）：本申请的目的是确定新型口服同型选择性组蛋白脱羧酶（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，并确定复发经典霍奇金淋巴瘤（HL）患者治疗反应的预测标志物。我们的初步体外实验表明，MGCD-0103通过caspase依赖和caspase非依赖机制诱导p21表达和诱导凋亡，在hl来源的细胞系中具有直接的抗增殖活性。此外，MGCD-0103抑制STAT6和TARC的表达，表明MGCD-0103可能在改变t细胞对HL微环境的趋化性中发挥作用。重要的是，我们正在进行的MGCD-0103在复发性HL患者中的II期研究数据显示，在大量预处理的患者中，40%的部分或完全缓解。我们的工作分为三个具体目标：目标1。确定口服HDAC抑制剂MGCD-0103治疗复发性HL患者的安全性和有效性。目标2。确定MGCD-0103治疗对a)选定的血清细胞因子/趋化因子和b)原代HRS细胞和周围反应性炎症细胞的选定分子靶点的体内影响，这些细胞是通过核心针活检获得的，来自Aim 1临床试验的复发性HL患者。目标3。检查分子和生物标志物与临床反应和/或治疗相关毒性之间的相关性。公共卫生相关性：本应用程序中提出的工作旨在通过治疗性地操纵肿瘤细胞的遗传密码以促进其死亡，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起作用，并开发治疗反应的预测标志物。

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.