Targeting SF3B1 for the treatment of MDS

总结 前体mRNA剪接复合体的核心组分剪接体中的体细胞突变是最常见的。 骨髓增生异常综合征（MDS）患者常见的遗传性病变。具体来说，反复出现的误解 SF 3B 1基因突变存在于10-20%的MDS病例中。SF 3B 1的抑制剂已经被 开发并代表MDS治疗的有希望的新前沿。我们建议开发临床前 Sf 3b 1突变模型，以在这些模型中单独或与 阿扎胞苷;并与SF 3B 1抑制剂的I/II期临床试验进行相关研究 H3生物医学H3生物医学已经产生了一种化合物，H3 B 8800，显示出有希望的突变- 在细胞系中的选择性活性，并准备进行临床试验。埃伯特实验室开发了一种 表达Sf 3b 1 K700 E突变的条件性基因敲入小鼠模型，Sf 3b 1 K700 E突变是人类中最常见的突变。 MDS患者。由于在MDS中SF 3B 1突变通常与DNMT 3A突变共同发生，我们将创建 具有条件Sf 3b 1敲入突变和条件Dnmt 3a失活的模型。我们将测试H3 B 8800，并将测试H3 B 8800与阿扎胞苷（一种对MDS有效的药物）的组合， 尤其是TET 2突变的病例。我们将使用基因组识别H3 B 8800的抗性机制- 广泛的CRISPR-Cas9筛选。最后，我们将在一项研究中检查H3 B 8800在MDS患者中的安全性和有效性。 I/II期临床试验。这种一流的药物有可能在很大一部分人中产生重大的临床影响。 由于体细胞突变导致剪接体功能异常的MDS病例。本文中描述的研究 该提案将定义药物在不同遗传背景下的活性，检查药物在不同遗传背景下的活性， 造血干细胞和祖细胞，确定治疗耐药性的机制，以及对 药物的作用方式，并检查患者的治疗效果。

SUMMARY Somatic mutations in the core components of the pre-mRNA splicing complex, the spliceosome, are the most common genetic lesions in patients with myelodsyplastic syndromes (MDS). Specifically, recurrent missense mutations in the SF3B1 gene are present in 10-20% of all MDS cases. Inhibitors of SF3B1 have been developed and represent a promising new frontier for MDS therapy. We propose to develop pre-clinical models of Sf3b1 mutation, to test a novel SF3B1 inhibitor in these models, alone or in combination with azacitidine; and to perform correlative studies on a Phase I/II clinical trial of an SF3B1 inhibitor in collaboration with H3 Biomedicine. H3 Biomedicine has generated a compound, H3B 8800, that shows promising mutant- selective activity in cell lines and that is poised for clinical trials. The Ebert laboratory has developed a conditional knock-in mouse model that expresses the Sf3b1 K700E mutation, the most common mutation in MDS patients. Since SF3B1 mutations commonly co-occur with mutations in DNMT3A in MDS, we will create a model with both conditional Sf3b1 knock-in mutation and conditional Dnmt3a inactivation. We will test H3B 8800 in this model and will test the combination of H3B 8800 with azacitidine, a drug with efficacy in MDS and in TET2-mutated cases in particular. We will identify mechanisms of resistance to H3B 8800 using a genome- wide CRISPR-Cas9 screen. Finally, we will examine the safety and efficacy of H3B 8800 in MDS patients in a phase I/II clinical trial. This first-in-class agent has the potential for major clinical impact in a large fraction of MDS cases with aberrant spliceosome function due to somatic mutations. The studies described in this proposal will define the activity of the drug in different genetic backgrounds, examine the activity of the drug in hematopoietic stem and progenitor cells, identify mechanisms of therapy resistance as well as insights into the mode of action of the drug, and examine therapeutic efficacy in patients.