1. ¹Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
2. ²Boston VA Healthcare System, Department of Medicine, Harvard Medical School, MA, USA
3. ³Department of Experimental and Clinical Medicine, University of 'Magna Græcia' and Cancer Center, Catanzaro, Italy
4. ⁴Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA
5. ⁵Callisto Pharmaceuticals Inc., New York, NY, USA

Correspondence: Dr NC Munshi, Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. E-mail: nikhil_munshi@dfci.harvard.edu

Received 29 April 2007; Revised 17 July 2007; Accepted 20 July 2007; Published online 20 September 2007.

Abstract

Atiprimod (Atip) is a novel oral agent with anti-inflammatory properties. Although its in vitro activity and effects on signaling in multiple myeloma (MM) have been previously reported, here we investigated its molecular and in vivo effects in MM. Gene expression analysis of MM cells identified downregulation of genes involved in adhesion, cell-signaling, cell cycle and bone morphogenetic protein (BMP) pathways and upregulation of genes implicated in apoptosis and bone development, following Atip treatment. The pathway analysis identified integrin, TGF- and FGF signaling as well as Wnt/-catenin, IGF1 and cell-cycle regulation networks as being most modulated by Atip treatment. We further evaluated its in vivo activity in three mouse models. The subcutaneous model confirmed its in vivo activity and established its dose; the SCID-hu model using INA-6 cells, confirmed its ability to overcome the protective effects of BM milieu; and the SCID-hu model using primary MM cells reconfirmed its activity in a model closest to human disease. Finally, we observed reduced number of osteoclasts and modulation of genes related to BMP pathways. Taken together, these data demonstrate the in vitro and in vivo antitumor activity of Atip, delineate potential molecular targets triggered by this agent, and provide a preclinical rational for its clinical evaluation in MM.