Treatment of Lymphoid and Myeloid Malignancies by Immunomo-dulatory Drugs
Treatment of Lymphoid and Myeloid Malignancies by Immunomo-dulatory Drugs
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DOI：
10.2174/1871529x18666180522073855
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发表时间：
2019-01-01
影响因子：
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通讯作者：
Fuchs, Ota
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文献类型：
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作者：
Fuchs, Ota
沙利度胺及其衍生物(来那度胺、泊马度胺、阿瓦度胺、盐酸伊贝多胺、CC-885和CC-90009)属于免疫调节药物家族。来那度胺(CC5013，Revlimid(R))被美国FDA和EMA批准用于治疗多发性骨髓瘤(MM)患者、染色体5q缺失的低或中等风险输血依赖骨髓增生异常综合征(MDS)[del(5q)]，以及Bortezomib治疗后复发和/或难治性套细胞淋巴瘤。来那度胺也已在临床试验中进行了研究，并显示出良好的治疗慢性淋巴细胞白血病(CLL)和非霍奇金淋巴瘤(NHL)的活性。来那度胺具有抗炎和抑制血管生成的作用。泊马度胺(CC4047，Imnovid(R)[EU]，Pomalyst(R)[USA])被批准用于对硼替佐米和来那度胺不敏感的高级MM。其他IMIDS正处于临床试验的第一和第二阶段。Cereblon(CRBN)似乎在淋巴和髓系血液系统恶性肿瘤的IMiDS作用中起着重要作用。Cereblon是cullin-4真正有趣的新基因(Ring)E3泛素连接酶CRL4(CRBN)的底物受体。这种E3泛素连接酶在没有来那度胺的情况下泛素化CRBN本身和CRL4CRBN复合体的其他成分。来那度胺的存在改变了CRL4CRBN的特异性，CRL4CRBN泛素化两个转录因子IKZF1(Ikaros)和IKZF3(Aiolos)，以及酪蛋白激酶1α(CK1α)，并标记它们在蛋白酶体中的降解。这两种转录因子(IKZF1和IKZF3)都能刺激MM细胞的增殖并抑制T细胞。低CRBN水平与MM细胞对来那度胺不敏感有关。来那度胺减少了与Cereblon结合的ArgAerte-2蛋白的表达。ArgAerte-2似乎是MM细胞中对抗IMiDS耐药的重要药物靶点。来那度胺还减少了MM细胞中basigin和单羧酸转运蛋白1的表达。低表达Ikaros、Aiolos和basigin的MM细胞对来那度胺更为敏感。CK1α基因(CSNK1A1)位于del(5q)MDS常见缺失区(CDR)的5q32上。抑制CK1α使Del(5q)MDS细胞对来那度胺增敏。CK1α也介导恶性浆细胞在MM中的存活，但抑制CK1α不仅对del(5q)MDS是一种潜在的新疗法，而且对MM也是一种潜在的新疗法。在DEL(5q)的MDS患者中，来那度胺治疗后的输血独立性(TI)超过60%，而在核型正常的低危MDS患者中，仅有25%的TI和发生中性粒细胞减少和血小板减少的反应持续时间显著缩短。到目前为止，来那度胺反应的生物标志物缺乏是目前MDS患者面临的主要问题。
Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid (R)) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid (R) [EU], Pomalyst (R) [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4(CRBN). This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1 alpha (CK1 alpha) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1 alpha gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1 alpha sensitizes del(5q) MDS cells to lenalidomide. CK1 alpha mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1 alpha is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.