Journal Article Novel therapeutic approaches to achieve the cure of multiple myeloma


93E ( 2 )  , pp.17 - 23 , 2017-04-01 , The Chiba Medical Society
[SUMMARY] Multiple Myeloma(MM)is a malignancy of plasma cells, which remains fatal in spite of recently emerging agents such as proteasome inhibitors and immunomodulatory drugs. The difficulty of the treatment of MM is due to the complex genetic and biological features of this disease and the acquired drug resistance in the context of bone marrow microenvironment. In order to conquer this cancer, we have investigated three promising strategies: targeting the IRE1α-XBP pathway in the unfolded protein response against ER stress, targeting the PI3K/Akt pathway in signal transduction, and targeting histone methyltransferases EZH2 and EZH1 in epigenetic modulation. We propose new combination treatments of novel small molecule inhibitors with proteasome inhibitors which are currently key tools for MM therapy. Based on our data, here we discuss the potential novel therapeutic approaches to achieve the cure of patients with MM.
[要旨] 形質細胞の悪性腫瘍である多発性骨髄腫は未だ治癒困難な血液がんである。骨髄腫細胞は多様な遺伝子変異やシグナル伝達経路を持ち,また骨髄微小環境に守られて薬剤耐性を獲得している。我々は今までに,骨髄腫細胞生存の鍵である小胞体ストレス応答を標的にしたIRE1α-XBP1阻害剤,重要なシグナル伝達経路を標的とした新規選択的Akt阻害剤,エピジェネティック機構を標的としたヒストンメチル化酵素EZH2とEZH1の共阻害剤について,骨髄腫の前臨床での治療効果とそのメカニズムを明らかにし,特にこれらの新規薬剤とプロテアソーム阻害剤による併用療法が有望であることを示してきた。本総説ではこれらの知見を元に,多発性骨髄腫の治癒に向けた新規分子標的療法について概説したい。

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