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（由适用提供）：每年诊断出大约12,000名AML的新患者，并因AML继电器和/或治疗的毒性而死亡9,000例。为AML开发新颖，有针对性和更安全的疗法有未满足的需求。在所有成年AML中，大约50％的核型（NK）和其中三分之一具有内部串联复制（ITD）的表达FLT3，这与临床结果差有关。 AML茎/早期祖细胞能够具有有限的自我更新和增殖，并且是相对不适治疗的。典型的Wnt-�-Catenin途径对于AML茎/祖细胞的自我更新，生长和存活至关重要。在AML中，放松管制的Wnt信号传导抑制了 - 蛋白质的降解，从而导致核定位增加和 - 钙蛋白与两部分TCF/LEF转录因子的相互作用。这导致调节与AML茎/祖细胞生长和存活有关的基因。衔接蛋白TBL1（透明蛋白样蛋白1）是 - - 卡丁蛋白介导的靶基因转录，需要 促进AML表型。我们的初步研究表明，BC2059（€-CAT Pharmaceuticals）是一种新颖的小分子，蒽醌氧化物 - 氧化物 - 有可能破坏TBL1与€catenin的结合，从而促进了蛋白酶体降解 - 蛋白酶体降解� -Catenin。这代表了一种新颖而创新的方法，可衰减 - 帕宁蛋白的核水平和转录活性。我们的初步发现还表明，BC2059在体外和体内抗AML活性对培养和原代人NK-AML爆炸祖细胞（BPC）（包括表达FLT3-ITD）的培养和原发性抗AML活性，而没有诱导的宿主毒性。此外，我们的初步研究表明，与组蛋白脱乙酰基酶抑制剂（HDI）panobinostat（PS）或FLT3拮抗剂AC-220共同治疗增强了BC2059诱导的人AML BPC的细胞凋亡。因此，我们建议检验以下假设：BC2059介导的 - - 连宁水平/活性的敲低将与组蛋白脱乙酰基酶抑制剂（HDI）协同相互作用。 或flt3拮抗剂在使用或不使用（w/wo）flt3-itd的情况下对AML发挥抗AML效果。该提案的目的是：目标1：进一步阐明BC2059的体外生长抑制作用，分化和凋亡作用以及在培养的和原发性人类AML BPC中的基本机制，并评估了BC2059对老鼠模型中的人体AML的体内效率。目标2：确定与BC2059和HDI对人AML BPC共同处理的体外和体内效率。 AIM 3：确定BC2059的体外和体内抗AML效率以及对表达FLT3-ITD的培养和原代人AML BPC的FLT3拮抗剂。这些临床前研究将产生体外和体内数据的支持性，作为基于BC2059的临床翻译的概念概念，用于AML w/wo flt3-itd表达。