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.
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.
| Younes, Anas; Oki, Yasuhiro; Bociek, R Gregory et al. (2011) Mocetinostat for relapsed classical Hodgkin's lymphoma: an open-label, single-arm, phase 2 trial. Lancet Oncol 12:1222-8 |
| Buglio, Daniela; Mamidipudi, Vidya; Khaskhely, Noor M et al. (2010) The class-I HDAC inhibitor MGCD0103 induces apoptosis in Hodgkin lymphoma cell lines and synergizes with proteasome inhibitors by an HDAC6-independent mechanism. Br J Haematol 151:387-96 |
