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淋巴细胞白血病 (Ph+ ALL) 和 Ph1 样 B-ALL 占大多数病例 “高风险”成人 B-ALL 目前的酪氨酸激酶抑制剂 (TKI) 治疗已改善了治疗结果。 Ph+ ALL，但大多数患者对 TKI 的耐药性迅速发展，Ph1 样 B-ALL 目前正在接受治疗。强化联合化疗，但疾病复发很常见，只有约 25% 的患者能获得 5 年生存率因此，在之前的研究中，Ph+ ALL 和 Ph1 样 B-ALL 的预后仍然很差。显示 Ph+ 和 Ph1 样 ALL 细胞对 CDK6 表达表现出选择性要求，而 CDK4 CDK6 的表达是必不可少的。 G1 期到 S 期细胞周期的转变，并在血液学中具有激酶独立的生长促进作用我们的初步研究表明 CDK6 沉默比 CDK6 酶更有效。抑制小鼠 Ph+ ALL 的抑制作用为了阻断 CDK6 的激酶依赖性和非依赖性作用，我们已开发出 CDK4/6 靶向蛋白水解靶向嵌合体 (PROTAC)，可抑制 CDK4/6 酶体外活性并促进 Ph+ 和 Ph1 样 ALL 细胞中 CDK6 相对于 CDK4 的优先降解，提供对 CDK6 功能的持久抑制在本提案中，我们将评估 CDK6 的需求。 Ph+ 和 Ph1 样 ALL 通过比较 PROTAC YX-2-107 和 CDK6 降解的影响使用 FDA 批准的 CDK4/6 抑制剂 Palbociclib 进行药理学抑制（目标 1.1）。确定与 CDK6 下调相比，CDK6 下调是否能更有效地抑制白血病 CDK6 酶抑制可以通过 CDK6 选择性诱导的基因表达变化来解释这种变化涉及组蛋白脱乙酰酶 1 (HDAC1) 基因和其他几个基因。线粒体代谢途径（目标 1.2 和 1.3）。 CDK6 与 CDK4 靶向的比较以及生物/治疗效果与 Palbociclib 体外相当/优于 Palbociclib 在 Ph+ ALL 的 PDX 中，我们将继续通过药物改进我们的先导化合物 PROTAC YX-2-107 在目标 2 中，我们将评估化学方法以开发具有增强体内功效的衍生物。选择 CDK6 降解 PROTAC 的代谢特性并在 Ph+ 中测试其生物/治疗效果和 Ph1 样 ALL 细胞离体以及在从头注射或复发/TKI 耐药患者来源的小鼠体内总的来说，我们基于 PROTAC 的方法利用了癌症方面的专业知识。卡拉布雷塔和萨尔维诺实验室的生物学和药物化学有望开发出新的药物以及更有效的治疗药物用于治疗临床前 PDX 中的 CDK6 依赖性高危 B-ALL 模型，并有可能应用于临床。