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.