Abstract 3608: HIF-1α inhibition blocks the cross talk between multiple myeloma plasmacells and tumour microenvironment

Abstract

Multiple Myeloma (MM) is a clonal B-cell malignancy characterized by accumulation of malignant plasma cells (PCs) within the bone marrow (BM) in close contact with stromal cells (SCs) which secrete growth factors and cytokines, promoting tumor cell growth and survival. The rapid progression of MM is dependent upon cellular interactions within the BM microenvironment, and novel agents targeting this interaction appear to be promising therapeutic strategies for the treatment of MM tumor expansion. Unlike most other organs, the BM microenvironment is physiologically hypoxic, a pre-requisite for normal BM hematopoiesis. It is well established that hypoxia is an important selective force in the evolution of tumor cells and a stabilization of HIF-1α protein has been documented in several human cancers. While the role of hypoxia in the pathogenesis of hematologic malignancies has yet to be elucidated, recent animal studies have shown that changes in oxygen levels within the BM microenvironment support the survival and expansion of MM cells. Furthermore, some drugs active in MM, such as Bortezomib and Lenalidomide, are believed to exert their effects in part by interfering with hypoxia-induced signaling cascades. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of HIF-1α in the PCs-BMSCs interplay. To test this hypothesis, we used EZN-2968, a small 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. We have already shown that EZN-2968 is highly specific for HIF-1α mRNA and it results in a long lasting and time dependent inhibition of HIF-1α protein level. Herein, we provide evidence that the interaction between MM cells and BMSCs is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BMSCs were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed that EZN-2968 down-modulates cytokine-induced signaling cascades after a short incubation, and seems to induce a negative modulation of those transcripts previously shown to reflect the activation state of specific tumor cell pathways (cell proliferation and survival). This observation was also supported by gene expression profile experiments. One of the key finding of our study is that PC attachment to the extracellular matrix protein was markedly reduced in the presence of EZN-2968. The effects of HIF inhibition on MM cell adhesion are quite intriguing, since MM pathogenesis is dependent upon the interaction of MM cells with the SCs. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between BMSCs and PCs in MM. We conclude that HIF inhibition may be an attractive therapeutic target for MM. Citation Format: Enrica Borsi, Giulia Perrone, Carolina Terragna, Marina Martello, Angela Flores Dico, Lucia Pantani, Annamaria Brioli, Giovanni Martinelli, Michele Cavo. HIF-1α inhibition blocks the cross talk between multiple myeloma plasmacells and tumour microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3608. doi:10.1158/1538-7445.AM2014-3608