Targeted Therapy for AML Stem Cells

AML干细胞的靶向治疗

• 批准号: 9068839
• 负责人: KAPIL BHALLA
• 金额: $ 33.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-08 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068839
• 关键词: Acute Myelocytic Leukemia; Adaptor Signaling Protein; Adult Acute Myeloblastic Leukemia; Anthraquinones; Apoptosis; Apoptotic; Attenuated; Binding; Blast Cell; Cessation of life; Clinical; Clinical Data; Cyclin D1; Data; Diagnosis; FLT3 gene; Felis catus; Gene Targeting; Genes; Genetic Transcription; Growth; Health; Histone Deacetylase Inhibitor; Human; In Vitro; Intervention; Karyotype; Mediating; Nuclear; Outcome; Oximes; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Proteins; Refractory; Relapse; Signal Transduction; Stem cells; TCF Transcription Factor; Testing; Toxic effect; Transducin; Translations; Treatment-related toxicity; Up-Regulation; WNT Signaling Pathway; analog; base; in vitro activity; in vivo; innovation; knock-down; leukemic stem cell; mouse model; mutant; novel; preclinical study; self-renewal; small molecule; small molecule inhibitor; stem; survivin; targeted treatment

DESCRIPTION (provided by applicant): Approximately 12,000 new patients of AML are diagnosed each year and 9,000 die due to AML relapse and/or toxicity of the therapy. There is an unmet need to develop novel, targeted and safer therapies for AML. Of all adult AML, approximately 50% have normal karyotype (NK) and one-third of these express FLT3 with internal tandem duplication (ITD), which is associated with a poor clinical outcome. AML stem/early progenitor cells are capable of limitless self-renewal and proliferation, and are relatively treatment-refractory. The canonical WNT- ¿-catenin pathway is essential for self-renewal, growth and survival of AML stem/progenitor cells. In AML, deregulated WNT signaling inhibits degradation of ¿-catenin, causing increased nuclear localization and interaction of ¿-catenin with the bipartite TCF/LEF transcription factor. This results in up regulation of genes involved in the growth and survival of AML stem/progenitor cells. An adaptor protein TBL1 (Transducin ¿-like protein 1) is required for ¿-catenin mediated transcription of target genes that promote the AML phenotype. Our preliminary studies demonstrate that BC2059 (¿-Cat Pharmaceuticals), a novel, small molecule, anthraquinone oxime-analog, potently disrupts the binding of TBL1 with ¿-catenin, promoting the proteasomal degradation ¿-catenin. This represents a novel and innovative approach to attenuate the nuclear levels and transcriptional activity of ¿-catenin. Our preliminary findings also demonstrate that BC2059 exerts in vitro and in vivo anti-AML activity against cultured and primary human NK-AML blast progenitor cells (BPCs), including those expressing FLT3-ITD, without inducing host toxicity. Additionally, our preliminary studies show that co- treatment with the histone deacetylase inhibitor (HDI) panobinostat (PS) or FLT3 antagonist AC-220 enhances BC2059-induced apoptosis of human AML BPCs. Therefore, we propose to test the hypothesis that BC2059 mediated knockdown of ¿-catenin levels/activity would synergistically interact with a histone deacetylase inhibitor (HDI) or FLT3 antagonist in exerting anti-AML efficacy against AML with or without (w/wo) FLT3-ITD. The aims of the proposal are: AIM 1: To further elucidate the in vitro growth inhibitory, differentiation and apoptotic effects of BC2059, and the underlying mechanisms, in cultured and primary human AML BPCs, as well as evaluate the in vivo efficacy of BC2059 against established human AML in mouse models. AIM 2: To determine the in vitro and in vivo efficacy of co-treatment with BC2059 and HDI against human AML BPCs. AIM 3: To determine the in vitro and in vivo anti-AML efficacy of BC2059 and a FLT3 antagonist against cultured and primary human AML BPCs expressing FLT3-ITD. These pre-clinical studies will generate the supportive in vitro and in vivo data as proof-of-concept for the clinical translation of BC2059-based therapy for AML w/wo FLT3-ITD expression.

描述（由申请人提供）：每年约有 12,000 名新的 AML 患者被诊断出来，其中 9,000 名患者因 AML 复发和/或治疗毒性而死亡。其中，开发新的、有针对性的、更安全的 AML 疗法的需求尚未得到满足。成人 AML，大约 50% 具有正常核型 (NK)，其中三分之一表达具有内部串联重复 (ITD) 的 FLT3，这与AML 干细胞/早期祖细胞具有无限的自我更新和增殖能力，并且相对难以治疗。 -连环蛋白途径对于 AML 干细胞/祖细胞的自我更新、生长和存活至关重要。在 AML 中，失调的 WNT 信号传导会抑制 ¿ -连环蛋白，导致 ¿ 的核定位和相互作用增加-catenin 与二分 TCF/LEF 转录因子这会导致参与 AML 干细胞/祖细胞生长和存活的基因上调。 ¿ 需要接头蛋白 TBL1（转导蛋白 ¿ 样蛋白 1）。 -连环蛋白介导的靶基因转录 我们的初步研究表明，BC2059（¿-Cat Pharmaceuticals）是一种新型小分子蒽醌肟类似物，可有效破坏 TBL1 与 ¿ -连环蛋白，促进蛋白酶体降解 ¿ -连环蛋白。这代表了一种降低 ¿ 的核水平和转录活性的新颖且创新的方法。我们的初步研究结果还表明，BC2059 对培养的和原代人 NK-AML 母细胞祖细胞 (BPC)（包括表达 FLT3-ITD 的细胞）发挥体外和体内抗 AML 活性，且不会诱导宿主毒性。与组蛋白脱乙酰酶抑制剂 (HDI) 帕比司他 (PS) 或 FLT3 拮抗剂 AC-220 联合治疗可增强 BC2059 诱导的细胞凋亡因此，我们建议检验 BC2059 介导 ¿ 的敲低的假设。 -连环蛋白水平/活性将与组蛋白脱乙酰酶抑制剂 (HDI) 协同相互作用 或 FLT3 拮抗剂在有或没有（w/wo）FLT3-ITD 的情况下对 AML 发挥抗 AML 功效 该提案的目的是： 目的 1：进一步阐明 BC2059 的体外生长抑制、分化和凋亡作用，以及培养和原代人类 AML BPC 中的潜在机制，以及评估 BC2059 在小鼠模型中针对已建立的人类 AML 的体内功效 AIM 2：确定。 BC2059 和 HDI 联合治疗对人 AML BPC 的体外和体内功效 目的 3：确定 BC2059 和 FLT3 拮抗剂对表达 FLT3 的培养和原代人 AML BPC 的体外和体内抗 AML 功效。 -ITD。这些临床前研究将产生支持性的体外和体内数据，作为基于 BC2059 的 AML 疗法临床转化的概念验证。有/无 FLT3-ITD 表达。