Epigenetic-based therapy of Hodgkin lymphoma

这项建议的目标是提高复发患者的治疗结果和治愈率 霍奇金淋巴瘤(HL)使用基于表观的治疗。我们最近展示了一种很有前途的 新型口服同型选择性组蛋白脱乙酰酶抑制剂MGCD-0103的单药活性 在没有其他治疗方案的复发HL患者中，经过严格的预治疗。这项提议将 在此观察的基础上，设计更有效的表观药物治疗。初步的体外研究 亚甲基化药物阿扎非定对HL细胞的单药活性研究 MGCD-0103与阿扎西替丁合用具有协同抗增殖作用。 此外，MGCD-0103临床试验的相关研究和初步的体外实验 提示表没食子儿茶素没食子酸酯治疗可能通过改变细胞因子和细胞因子诱导良好的免疫调节作用 趋化因子的表达，并通过上调肿瘤相关抗原的表达 细胞。我们的中心假设是，基于表吉奈菲的治疗对HL具有双重治疗作用， 对恶性Hodgkin和Reed-Sternberg(HRS)细胞的直接抗增殖作用 诱导良好的抗肿瘤免疫反应，导致持久的临床缓解。为了测试这一点 假设，这个项目包括两个IRB批准的临床试验；在第一个试验中，我们使用联合 同型选择性HDAC抑制剂MGCD0103联合应用表观治疗策略 一种次甲基安非他明(阿扎替丁)，在第二种方法中，我们使用了PAN DAC抑制剂潘诺比妥 (LBH589)在相同的情侣中流行。我们还建议检查血液和骨骼中的生物标志物。 从参与临床试验的患者身上获得的标本，并进行体外实验以 合理设计未来第二代基于表观依从性的综合治疗 复发的霍奇金淋巴瘤。我们的工作组织成3个具体目标：目标1)确定其安全性和有效性 基于HDACi的复发性难治性经典型HL患者的治疗。目的2)体内测定 表观遗传治疗的抗增殖和免疫调节作用及其潜在生物标志物的确定 使用参加AIM 1试验的患者的血液和裂口标本的抗肿瘤效果。目的3)至 体外研究新的表观药物联合疗法合理设计二类药物 临床试验。 相关性(请参阅实例)： 干细胞移植后复发的HL患者没有治愈的机会。这 该项目探索新的治疗策略，使用改变癌细胞中基因表达的试剂来 诱导他们死亡，并使他们对其他治疗策略更加敏感，包括 化疗和免疫治疗，以改善复发HL患者的治疗结果。

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.