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    • 10. 发明申请
    • NEW METHOD FOR TREATING MULTIPLE MYELOMA
    • 治疗多发性骨髓瘤的新方法
    • WO2018078083A1
    • 2018-05-03
    • PCT/EP2017/077573
    • 2017-10-27
    • INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE)UNIVERSITÉ PARIS DIDEROT - PARIS 7ECOLE PRATIQUE DES HAUTES ETUDESASSISTANCE PUBLIQUE-HÔPITAUX DE PARIS (APHP)
    • BORIES, Jean-ChristopheFERMAND, Jean-PaulARNULF, BertrandSONG, Xuiyi
    • A61K31/554A61K31/506A61K45/06A61P35/00
    • The present invention relates to a method of treating multiple myeloma. The inventors analyzed two sets of 18 and 40 samples from symptomatic t(4; 14) MM at presentation by exome or RNA sequencing, respectively. They confirm the high mutational rates in the NRAS, KRAS, BRAF and FGFR3 genes which have been previously described, and strongly suggests that these events are mutually exclusive in t(4;14) MM. Mutations in ATM/ATR, MAPK and MYCBP2 occur at relatively high frequencies (11.4%, 14% and 8% respectively), while very few t(4;14) patients carry alterations in FAM46C or CCND1. Mutations in PRKD2, the gene coding for the PKD2 serine/threonine kinase, affect around 11.4% of the cases and this alteration is associated with progression to symptomatic myeloma in one patient. The inventors also tested the inhibition of PKD2 activity by kb NB 142-70 and the inhibition of PKD 1, PKD2 and PKD3 by CRT0066101 and observed that these agents induced cell growth arrest and apoptosis of tumor plasma cells in vitro. These results show that PKD2 and others members of the PKD family is a therapeutic target in patients with MM. Thus, the present invention relates to a PKD inhibitor for use in the treatment of multiple myeloma.
    • 本发明涉及治疗多发性骨髓瘤的方法。 本发明人分别通过外显子组或RNA测序分析了来自症状性t(4; 14)MM的两组18和40个样品。 他们证实了先前描述的NRAS,KRAS,BRAF和FGFR3基因的高突变率,并强烈表明这些事件在t(4; 14)MM中是相互排斥的。 ATM / ATR,MAPK和MYCBP2突变发生频率相对较高(分别为11.4%,14%和8%),而极少数t(4; 14)患者携带FAM46C或CCND1改变。 PRKD2中的突变(编码PKD2丝氨酸/苏氨酸激酶的基因)影响了约11.4%的病例,并且这种改变与一名患者发展为症状性骨髓瘤有关。 本发明人还测试了由kb NB 142-70对PKD2活性的抑制和CRT0066101对PKD1,PKD2和PKD3的抑制,并观察到这些试剂在体外诱导了肿瘤浆细胞的细胞生长停滞和凋亡。 这些结果显示PKD2和PKD家族的其他成员是MM患者的治疗靶标。 因此,本发明涉及用于治疗多发性骨髓瘤的PKD抑制剂。