Targeting CDK6 expression/activity in Ph+ and Ph1-like acute lymphoblastic leukemia (ALL)

靶向 Ph 和 Ph1 样急性淋巴细胞白血病 (ALL) 中的 CDK6 表达/活性

基本信息

批准号：
10317798
负责人：
BRUNO CALABRETTA
金额：
$ 64.53万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10317798
关键词：
Acute Acute Lymphocytic Leukemia Adult B-Cell Acute Lymphoblastic Leukemia Biological Biological Response Modifier Therapy Blood CDK4 gene Cancer Biology Catalytic Domain Cell Cycle Cell Cycle Proteins Cell Line Clinic Clinical Combination Drug Therapy Complex Cyclin D1 Cyclin-Dependent Kinase Inhibitor 2A Development Dose Down-Regulation Drug Kinetics Exhibits FDA approved Gene Expression Gene Expression Profile Gene Expression Regulation Generations Genetic Genetic Transcription Goals Growth HDAC1 gene Half-Life Hematologic Neoplasms Human Imatinib In Vitro Intervention Knowledge Laboratories Lead Link Liver MLL-rearranged leukemia Malignant Neoplasms Metabolic Metabolic Pathway Mitochondria Molecular Mus Mutation Nuclear Oral Outcome Patients Ph+ B-ALL Pharmaceutical Chemistry Pharmacology Philadelphia Phosphotransferases Plasma Prognosis Property Protac Recurrent disease Relapse Resistance Resistance development Role Route S Phase Specificity Structure-Activity Relationship Subgroup Testing Therapeutic Agents Therapeutic Effect Tyrosine Kinase Inhibitor acute lymphoblastic leukemia cell advanced breast cancer base cancer therapy cell growth cyclin-dependent kinase 6 effective therapy high risk high throughput screening improved improved outcome in vitro activity in vivo inhibitor/antagonist innovation intraperitoneal leukemia mouse model novel novel therapeutics patient derived xenograft model pre-clinical prototype therapeutically effective validation studies

项目摘要

Abstract Philadelphia-positive acute lymhoblastic leukemia (Ph+ ALL) and Ph1-like B-ALL account for most cases of “high-risk” adult B-ALL. Current therapies with tyrosine kinase inhibitors (TKIs) have improved the outcome of Ph+ ALL, but resistance to TKIs develops rapidly in most patients. Ph1-like B-ALL is currently treated with intensive combination chemotherapy but disease relapse is common with a 5-year survival in only ~25% of patients. As a result, the prognosis of Ph+ ALL and Ph1-like B-ALL remains dismal. In previous studies, we showed that Ph+ and Ph1-like ALL cells exhibit a selective requirement for CDK6 expression while CDK4 expression is dispensable. CDK6 is the catalytic subunit of the cyclin D/CDK6 complex which is essential for the G1 to S-phase cell cycle transition and has kinase-independent growth-promoting effects in hematological malignancies. Our preliminary studies indicate that CDK6 silencing is more effective than CDK6 enzymatic inhibition in suppressing Ph+ ALL in mice. To block kinase-dependent and independent effects of CDK6, we have developed CDK4/6-targeted proteolysis-targeting chimera (PROTACs) that inhibit CDK4/6 enzymatic activity in vitro and promote the preferential degradation of CDK6 over CDK4 in Ph+ and Ph1-like ALL cells, providing durable suppression of CDK6 function. In this proposal, we will assess the requirement of CDK6 in Ph+ and Ph1-like ALL by comparing the effects of CDK6 degradation by PROTAC YX-2-107 and pharmacological inhibition using Palbociclib, an FDA-approved CDK4/6 inhibitor (Aim 1.1). We will also determine whether the more potent leukemia suppression induced by CDK6 down-regulation in comparison to CDK6 enzymatic inhibition can be explained by changes in gene expression induced selectively by CDK6 silencing. Such changes involve the histone deacetylase 1(HDAC1) gene and several others involved in mitochondrial metabolic pathways (Aims 1.2 and 1.3). Although we have been able to achieve high specificity of CDK6 versus CDK4 targeting and biological/therapeutic effects comparable/superior to Palbociclib ex vivo and in PDXs of Ph+ ALL, we will continue to improve our lead compound PROTAC YX-2-107 by medicinal chemistry approaches in order to develop derivatives with enhanced in vivo efficacy. In Aim 2, we will assess metabolic properties of select CDK6-degrading PROTACs and test their biological/therapeutic effects in Ph+ and Ph1-like ALL cells ex vivo and in mice injected with de novo or relapsed/TKI-resistant patient-derived Ph+/Ph1-like ALL cells. Collectively, our PROTAC-based approach which leverages the expertise in cancer biology and medicinal chemistry of the Calabretta and Salvino's laboratories holds promise to develop novel and more effective therapeutic agents for the treatment of CDK6-dependent high-risk B-ALL in pre-clinical PDX models and, potentially, in the clinic.

抽象的费城阳性急性lymhoboblastic白血病（pH+ all）和类似pH1的b-all考虑了大多数情况 “高风险”成人B-all。酪氨酸激酶抑制剂（TKI）的当前疗法已改善 pH+全部，但大多数患者对TKIS的耐药性迅速发展。目前正在接受PH1的B-All治疗强化组合化疗，但疾病缓解很常见，仅在约25％的生存率中，患者。结果，pH+和类似pH1的B-ALL的预后仍然令人沮丧。在以前的研究中，我们表明pH+和pH1样细胞所有细胞均表现出CDK6表达的选择性要求，而CDK4 表达是可分配的。 CDK6是细胞周期蛋白D/CDK6复合物的催化亚基，这对于 G1至S期细胞周期过渡，并在血液学中具有非激酶非依赖性生长促进作用恶性肿瘤。我们的初步研究表明，CDK6沉默比CDK6更有效在抑制小鼠中抑制pH+全部。为了阻止CDK6的激酶依赖性和独立效应，我们已经开发了CDK4/6靶向蛋白水解靶向嵌合体（Protac），可抑制CDK4/6酶促体外活性并促进pH+和pH1样细胞中CDK6的首选降解，提供CDK6功能的持久抑制。在此提案中，我们将评估CDK6的要求通过比较Protac YX-2-107和使用PALBOCICLIB（FDA批准的CDK4/6抑制剂）使用药理抑制作用（AIM 1.1）。我们也会确定与CDK6下调诱导的潜在白血病是否与 CDK6酶促抑制可以通过CDK6选择性诱导的基因表达的变化来解释沉默。这样的变化涉及组蛋白脱乙酰基酶1（HDAC1）基因以及其他几个参与线粒体代谢途径（目标1.2和1.3）。尽管我们能够实现高特异性 CDK6与CDK4的靶向和生物/治疗效果可比/优于palbociclib ex Vivo 在pH+ all的PDX中，我们将继续改善医学上的复合Protac YX-2-107 化学方法是为了开发具有增强体内效率的衍生物。在AIM 2中，我们将评估精选CDK6降解Protac的代谢特性，并在pH+中测试其生物/治疗作用和pH1的所有细胞ex ex ex ex ex ex Vivo，以及注射从头或中继/TKI抗患者衍生的小鼠 pH+/pH1状的所有细胞。总体而言，我们基于Protac的方法利用了癌症的专业知识 Calabretta和Salvino的实验室的生物学和医学化学有望发展新颖以及更有效的治疗剂，用于治疗CDK6依赖性高风险B-all在临床前PDX中模型，并可能在诊所中。