Abstract PL3-1: Biology of myeloma: Basis for novel drugs

Abstract

Abstract The outcome of Multiple Myeloma (MM) patients has significantly improved over the last decade, and this is mainly due to the efficacy of novel drugs, such as Thalidomide, Lenalidomide, and Bortezomib. Nevertheless, the majority of patients relapses and become eventually refractory to all available treatments. Therefore, drugs with novel mechanism of action are urgently needed in order to improve the outcome of relapsed MM patients. The increase knowledge in MM biology is already contributing to a more specific drug design, and we have recently learned that in the pathogenesis of MM, as important as the malignant cells themselves, is their interaction with the microenvironment. MM requires a multistep transformation process that implies the sequential generation of primary Ig translocations, chromosomal instability (including mutations –i.e: RAS-, and deletions – i.e: RB-), and secondary translocations. Most primary immunoglobulin gene translocations occur early in the pathogenesis of MM. These translocations, which are mediated by errors in immunoglobulin heavy-chain switch recombination, result in the juxtaposing of an immunoglobulin enhancer and oncogene. On the basis of IgH translocations, MM patients can be divided into 5 subgroups: 1) D-type cyclins: Cyclin D1 on 11q23, Cyclin D3 on 6p21 and Cyclin D2 on 12p13 (25% of cases); 2) MMSET/FGFR3 proteins (4p16.3) (15%); 3) B-zip transcription factors: c-maf on 16q23 and mafB on 20q11 (15%); 4) other IgH translocations (20%); and 5) No IgH translocations (25%). Secondary oncogenic events may involve genes different from the Ig locus, as well as the 14q32 region, as occur in the c-myc translocations: t(8;14), t(2;8), t(8;22), t(14;20). Some of these molecular events represent potential therapeutic targets. Thus the t(4;14) translocation generates a constitutive activation of the oncogenic receptor tyrosine kinase FGFR3 with subsequent phosphorylation of the antiapoptotic STAT3 signalling pathway. Therefore, the use of inhibitors of the FGFR3 tyrosine kinase as well as inhibitors of cyclin dependent kinases could be attractive therapeutic targets. Similarly C-maf, that is over expressed in MM patients with t(14;16) as well as in some MM cases lacking this translocation, also represents a potential target. The second area of MM pathogenesis that has important implications for treatment intervention is the interaction between the malignant cell and the bone marrow microenvironment. MM cells adhere to the extra cellular matrix proteins and bone marrow stromal cells through a series of adhesion molecules, such as the β1-integrin family (VLA-4, VLA-5 and VLA-6) as well as ICAM-1 and VCAM-1. Adhesion of myeloma cells to BM microenvironment induces a cell-adhesion-mediated drug resistance. Interruption by downregulating the interactions between the tumor cell and its microenvironment can potentially halt MM cell growth and proliferation, and be of benefit to patients with MM. The binding of MM cell to BM microenvironment also induces the transcription and secretion of cytokines (TNFa, IL-6, IGF-1, SDF1a, VEGF), by both the plasma cells and BMSC, triggering signalling pathways (such as the RAF/MEK/MAPK, PI3K/AKT, and JAK/STAT pathways), that promote cell proliferation and prevent apoptosis. In this area several targeted oriented drugs are already at early phases of clinical investigation, and these includes: 1. Agents against receptors present in plasma cells (PC) which can be targeted by specific drugs or monoclonal antibodies: cell death receptors (such as DR4-6, FAS and BCL2); TK receptors, VEGFR; TACI, IL6-R, IGF-1R or the CD56 or CD40 antigens; 2. Inhibitors directed to signalling pathways including Farnesil Transferase (Tipifarnib), RAF (RAF 265), STAT3 (Atiprimod), mTor (RAD001) or AKT (Perifosine); and 3. Drugs that interfere with the interactions between PC and microenvironment such as the new Proteasome inhibitors, such as NPI-0052 and PR-171 (Carfilzomib), novel IMIDs (Pomalidomide), HDAC and Hsp90 inhibitors. Unfortunately, the expectations raised by some of these agents have not been so far confirmed in the clinic. It is probable that these targeted directed drugs will be more effective in science based combinations with other agents which have already shown clear efficacy in MM. Citation Information: Clin Cancer Res 2010;16(7 Suppl):PL3-1