小柯机器人

美国纪念斯隆凯特琳癌症研究中心Eytan M. Stein等研究人员合作揭示menin抑制剂KMT2A重排或NPM1突变型白血病中的应用。这一研究成果于2023年3月15日在线发表在国际学术期刊《自然》上。

研究人员表示，靶向关键的表观遗传调节器可以逆转癌症中的异常转录，从而恢复正常组织功能。menin与赖氨酸甲基转移酶2A（KMT2A，一个表观遗传调节器）的相互作用是KMT2A重排或核仁磷酸蛋白1基因（NPM1）突变引起的急性白血病中的一个依赖性因素。KMT2A重排发生在高达10%的急性白血病中，并有不良预后，而NPM1突变发生在高达30%的急性骨髓性白血病中，形成最常见的基因改变。

研究人员报道了第一个人体一期临床试验的结果，该试验研究了revumenib（SNDX-5613），一种有效的、选择性的menin-KMT2A相互作用的口服抑制剂，用于复发或难治性急性白血病患者（ClinicalTrials.gov, NCT04065399）。结果表明，在疗效分析人群中，revumenib治疗与3级或更高的治疗相关不良事件发生频率低，完全缓解或部分血液学恢复的完全缓解率（CR/CRh）为30%。心电图上无症状的QT间期延长被确定为唯一的剂量限制性毒性。对以前多种治疗方法难治的白血病出现了缓解。研究人员用敏感的临床检测方法证明了残余疾病的清除，并确定了分化为正常造血细胞的标志，包括分化综合征。这些数据确立了将menin抑制作为易感急性白血病亚型的一种治疗策略。

附：英文原文

Title: The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia

Author: Issa, Ghayas C., Aldoss, Ibrahim, DiPersio, John, Cuglievan, Branko, Stone, Richard, Arellano, Martha, Thirman, Michael J., Patel, Manish R., Dickens, David S., Shenoy, Shalini, Shukla, Neerav, Kantarjian, Hagop, Armstrong, Scott A., Perner, Florian, Perry, Jennifer A., Rosen, Galit, Bagley, Rebecca G., Meyers, Michael L., Ordentlich, Peter, Gu, Yu, Kumar, Vinit, Smith, Steven, McGeehan, Gerard M., Stein, Eytan M.

Issue&Volume: 2023-03-15

Abstract: Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1,2,3. The interaction of menin with lysine methyltransferase2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin1 gene (NPM1)4,5,6. KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin–KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.

DOI: 10.1038/s41586-023-05812-3

Source: https://www.nature.com/articles/s41586-023-05812-3

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