Induction of an anti-angiogenesis factor, Thrombospondin 1 (TSP-1), by a novel histone deacetylase inhibitor, MGCD0103, in human cancer cells in vitro and in vivo

739 MGCD0103 is a novel non-hydroxamate histone deacetylase inhibitor which specifically targets HDAC1, 2, 3 and 11. Previously, we have shown that MGCD0103 has broad-spectrum antitumor activities in preclinical animal models and its preliminary clinical activity has been shown in multiple Phase II trials in patients with relapsed or refractory Hodgkin’s lymphoma or Non-Hodgkin lymphoma , high-risk myelodysplastic syndrome (MDS) and acute myologenous leukemia (AML). To further understand the mechanism of action of MGCD0103, we investigated the anti-angiogenesis activity and specific components of the angiogenesis pathways that were modulated by MGCD0103. We found MGCD0103 significantly inhibits tubule growth of cultured human endothelial cells in a dose-dependent manner in vitro. In addition, MGCD0103 can induce transcription of an anti-angiogenesis factor, thrombospondin 1 (TSP-1), in human cancer cells in vitro independent of their tissue origins. Synergistic induction of TSP-1 was observed in human cancer cells treated with MGCD0103 in combination of a DNA demethylation agent in vitro. Microarray analysis of peripheral blood mononuclear cells or bone marrow mononuclear cells from five AML patients, who were treated with MGCD0103 either alone or in combination with Vidaza, revealed that the upregulation of expression of TSP-1 in patients with clinical response (n=2) but not in those without response (n=3). Using real time RT-PCR analysis on more clinical samples from patients treated with a combination of Vidaza and MGCD0103 , we further observed induction of TSP-1 transcription in the AML patients with clinical response but not in those without response. The utility of TSP-1 expression as a potential biomarker of MGCD0103 in clinical trials will be discussed.