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P4 -TARGETING MULTIPLE MYELOMA BY COMBINING CDK INHIBITORS AND BCL-2 ANTAGONISTS

P4 - 通过结合 CDK 抑制剂和 BCL-2 拮抗剂来靶向多发性骨髓瘤

基本信息

批准号：
8543581
负责人：
STEVEN GRANT
金额：
$ 27.95万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8543581
关键词：
Adherence Apoptosis Apoptotic B lymphoid malignancy BCL2 gene BCL2L11 gene BIK gene BIRC4 gene Bone Marrow Cells Bortezomib CD34 gene CDK4 gene Cancer Center Cell Adhesion Cell Cycle Cell Death Cell Proliferation Cell Survival Cells Cessation of life Chemosensitization Clinical Trials Complex Cyclin-Dependent Kinase Inhibitor Cyclins Cytotoxic agent Dexamethasone Disease Dose Down-Regulation Doxorubicin Drug resistance Elongation Factor Event Exhibits Family Family member Foundations Genes Genetic Goals Growth Factor Hematopoietic Human Induction of Apoptosis Injury Laboratories Laboratory Study Life Link Malignant - descriptor Malignant Neoplasms Mediating Melphalan Mitochondria Modeling Molecular Multiple Myeloma Noxae PMAIP1 gene Pathogenesis Patients Pharmaceutical Preparations Phase I Clinical Trials Phosphorylation Physiological Process Protein Family Proteins RNA Refractory Regimen Reporting Resistance Schedule Stromal Cells Testing Therapeutic Transcription Elongation Transcription Repressor/Corepressor Translating Up-Regulation Validation X-linked IAP Xenograft Model Xenograft procedure base cell transformation clinically relevant cyclin T1 flavopiridol gene repression in vivo inhibitor/antagonist insight interest killings lenalidomide leukemia novel novel strategies novel therapeutics pro-apoptotic protein response roscovitine small molecule stem synergism tool treatment strategy

项目摘要

Evidence linking dysregulation of cell cycle and Bcl-2 family proteins in the molecular pathogenesis of multiple myeloma (MM) has prompted intense interest in cyclin-dependent kinase (CDK) inhibitors and Bcl-2 antagonists in this disease. Furthermore, recent findings suggest that certain CDK inhibitors (e.g., flavopiridol; FP) act as transcriptional repressors by inhibiting the CDK9/cyclinT pTEFB complex, and by extension, phosphorylation ofthe carboxy-terminal domain of RNA Polll. Such agents down-regulate expression of short-lived proteins including Mcl-1, a critical survival factor in MM. Significantly, CDK inhibitors have recently been found to enhance the lethality of Bcl-2 antagonists (e.g. ABT-737) in human leukemia cells by unleashing Bak from Bcl-xL and Mcl-1, leading to a dramatic potentiation of apoptosis. Notably, a novel FP schedule has recently been developed which displays significant activity in another B-cell malignancy (CLL). We therefore hypothesize that clinically relevant CDK inhibitors such as FP, seliciclib (Rroscovitine), and SCH727965, an agent with an 1050 of 1 nM toward CDK9, represent logical candidate agents to enhance the activity of clinically relevant Bcl-2 antagonists (e.g., GX15-070, ABT-737) in MM. Indeed, preliminary evidence suggests a high degree of synergism between FP and GX15070, as well as other CDKI/Bcl-2 antagonist regimens, in MM cells. Evidence also suggests that such regimens induce upregulation of pro-apoptotic proteins (e.g., Bim, NOXA, and BIK) which may cooperate with Mcl-1 downregulation to trigger apoptosis. In specific aim #1, we will employ genetic tools to test the hypothesis that synergistic interactions between CDK inhibitors and Bcl-2 antagonists stem from Mcl-1/XIAP downregulation, upregulation of Bim, NOXA, and BIK, release of Bak and BIM from both Bcl-xL and Mcl-1, Bax/Bak activation, and induction of mitochondrial injury. This information will guide the selection of correlative laboratory studies in subsequent planned clinical trials. In Specific Aim #2, we will determine whether and by what mechanism(s) this strategy overcomes conventional drug resistance, stromal/cell adhesion- or growth factor-mediated drug resistance, and bortezomib or lenalidomide resistance in MM cells. In specific aim #3, we will evaluate the selectivity of this strategy by comparing its activity against primary, patient-derived CDI38* MM versus their normal counterparts (e.g., CDI38", CD34* cells), and testing its in vivo efficacy using flank and systemic xenograft MM models. In Specific Aim #4, we will use this information as a foundation for initiating one or more Phase I trials of CDKIs (e.g., FP) and Bcl-2 antagonists (e.g., GX15-070) in patients with refractory MM. Collectively, these studies will provide a rational foundation for a novel approach to MM therapy in which the activity of clinically relevant Bcl-2 antagonists (e.g., GX15-070 or ABT- 737) is enhanced through rational combination with transcriptionally repressive CDK inhibitors that disrupt the pTEFb complex (e.g., FP, seliciclib, or SCH727965) in patients with refractory MM.

细胞周期失调和 Bcl-2 家族蛋白在分子发病机制中的关联证据多发性骨髓瘤 (MM) 引起了人们对细胞周期蛋白依赖性激酶 (CDK) 抑制剂和 Bcl-2 的浓厚兴趣本病的拮抗剂。此外，最近的研究结果表明某些 CDK 抑制剂（例如，黄吡醇； FP) 通过抑制 CDK9/cyclinT pTEFB 复合物作为转录阻遏物，并通过 RNA Poll 羧基末端结构域的延伸、磷酸化。此类药物下调包括 Mcl-1 在内的短寿命蛋白的表达，Mcl-1 是 MM 的关键生存因子。值得注意的是，CDK 抑制剂最近发现可增强 Bcl-2 拮抗剂（例如 ABT-737）对人类白血病的杀伤力通过从 Bcl-xL 和 Mcl-1 中释放 Bak 来诱导细胞凋亡，从而显着增强细胞凋亡。值得注意的是，一个最近开发了新的 FP 时间表，它在另一个 B 细胞中显示出显着的活性恶性肿瘤（CLL）。因此，我们假设临床相关的 CDK 抑制剂，例如 FP、seliciclib (Rroscovitine)， SCH727965，一种对 CDK9 具有 1050 1 nM 的试剂，代表逻辑候选增强 MM 中临床相关 Bcl-2 拮抗剂（例如 GX15-070、ABT-737）活性的药物。事实上，初步证据表明 FP 和 GX15070 之间存在高度协同作用，并且其他 CDKI/Bcl-2 拮抗剂方案，用于 MM 细胞。有证据还表明，此类方案会诱导上调促凋亡蛋白（例如 Bim、NOXA 和 BIK）可能与 Mcl-1 下调协同作用来触发细胞凋亡。在具体目标#1中，我们将使用遗传工具来检验以下假设： CDK 抑制剂和 Bcl-2 拮抗剂之间的协同相互作用源于 Mcl-1/XIAP 下调， Bim、NOXA 和 BIK 上调，Bak 和 BIM 从 Bcl-xL 和 Mcl-1、Bax/Bak 中释放激活和诱导线粒体损伤。该信息将指导相关产品的选择随后计划的临床试验中的实验室研究。在具体目标 #2 中，我们将确定是否以及通过该策略克服传统耐药性、基质/细胞粘附或生长的机制是什么因子介导的耐药性，以及 MM 细胞中的硼替佐米或来那度胺耐药性。在具体目标#3中，我们将通过将其活性与主要的、源自患者的活性进行比较来评估该策略的选择性 CDI38* MM 与正常对应物（例如 CDI38"、CD34* 细胞）的比较，并测试其体内功效使用侧腹和全身异种移植 MM 模型。在具体目标 #4 中，我们将使用此信息作为为启动一项或多项 CDKI（例如 FP）和 Bcl-2 拮抗剂（例如 GX15-070）I 期试验奠定基础难治性 MM 患者。总的来说，这些研究将为小说提供合理的基础 MM 治疗方法，其中临床相关 Bcl-2 拮抗剂（例如 GX15-070 或 ABT- 737) 通过与转录抑制性 CDK 抑制剂合理组合来增强难治性 MM 患者的 pTEFb 复合物（例如 FP、seliciclib 或 SCH727965）。