Epigenetic-based therapy of Hodgkin lymphoma

这项建议的目的是改善复发性乳腺癌患者的治疗效果和治愈率。 霍奇金淋巴瘤（HL）使用基于表观遗传学的治疗。我们最近展示了一个有希望的 新型口服同种型选择性组蛋白脱乙酰酶（DAC）抑制剂MGCD-0103的单药活性 在没有其他治疗方案的重度预治疗复发HL患者中。这项建议会 在此基础上设计更有效的表观遗传疗法。初步体外研究 证明了低甲基化剂阿扎胞苷（Vidaza）在HL衍生细胞中的单药活性 MGCD-0103与阿扎胞苷联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体外实验 表明表观遗传疗法可能通过改变细胞因子和细胞因子来诱导有利的免疫调节作用， 趋化因子表达，并通过上调癌细胞上肿瘤相关抗原的表达， 细胞我们的中心假设是，基于表观遗传学的治疗在HL中具有双重治疗效果， 对恶性Hodgkin和Reed-Sternberg（HRS）细胞的直接抗增殖作用， 诱导有利的抗肿瘤免疫应答，导致持久的临床缓解。为了验证这一 假设，该项目包括两个IRB批准的临床试验;在第一个，我们使用一个组合 使用同种型选择性HDAC抑制剂MGCD 0103与 一种低甲基化剂（阿扎胞苷），第二种我们使用泛DAC抑制剂帕比司他 （LBH 589）在同一人群中。我们还建议检查血液和裂隙中的生物标志物， 从参与临床试验的患者中获得的样本，并进行体外实验， 为患有以下疾病的患者合理设计未来的第二代基于表观遗传学的组合疗法 复发性HL我们的工作分为3个具体目标：目标1）确定 复发性和难治性经典HL患者的HDACi治疗。目的2）确定体内 表观遗传治疗的抗增殖和免疫调节作用，并证实了 使用目标1中试验患者的血液和裂隙标本进行抗肿瘤疗效研究。目标3） 在体外研究新的基于表观遗传学的组合疗法以合理设计第二代 临床试验 相关性（见说明）： 干细胞移植后复发的HL患者没有治愈的机会。这 该项目探索了新的治疗策略，使用改变癌细胞基因表达的药物， 诱导他们死亡，并使他们对其他治疗策略更敏感，包括 化疗和免疫治疗，以改善复发性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.