Identification of novel therapeutic strategies targeting genetic abnormalities

The critical role of cyclin D dysregulation in the pathogenesis of MM highlights the importance of the cyclin D/RB pathway, and suggests that there may be a therapeutic window in targeting this pathway for all molecular subtypes of MM (Figure 11.2). For example, epigenetic silencing of cyclin-dependent protein kinase (CDK) inhibitor mRNA expression might be reversed by histone deacetylase inhibitors (suberoylanilide hydroxamic acid, depsipeptide) or inhibitors of DNA methyl transferase (5 aza-2'deoxy-cytidine). To target cyclin D per se, there are a number of possible strategies, including modulation of mRNA translation (e.g. desferroxamine, eicosapenta-enoic acid), post-translational modifications (ubiquitination and proteasomal degradation), enzyme function (selective CDK inhibitors), and perhaps even inhibition of expression

TC5 16q23 c-maf 20q11 mafB

TC5 16q23 c-maf 20q11 mafB

Fig. 11.2 Cyclin dysregulations as protential therapeutic targets in MM

With greater understanding of the specific dysregulations induced in the different groups in myeloma, it should be possible to develop strategies to correct the defects in these pathways.

phase

phase

Fig. 11.2 Cyclin dysregulations as protential therapeutic targets in MM

With greater understanding of the specific dysregulations induced in the different groups in myeloma, it should be possible to develop strategies to correct the defects in these pathways.

of cyclin D mRNA (the TC2 group may be particularly dependent on interaction with bone marrow stromal cells for the ectopic expression of cyclin D1). Additional specificity may be achieved by targeting the genes that are directly dysregulated by translocations. This seems to be especially true in the case of the t(4;14), where two enzymes are overexpressed: FGFR3, a tyrosine kinase receptor, and MMSET, which has homology to histone methyltransferases. As a surface receptor, FGFR3 may be targeted by monoclonal antibodies, and as a tyrosine kinase by selective tyrosine kinase inhibitors. Preclinical studies have validated FGFR3 as a therapeutic target in t(4;14) MM, inhibitors of histone methyltransferases are being developed, and studies are under way to validate MMSET as a target in t(4;14) MM.

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