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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：
7975995
负责人：
STEVEN GRANT
金额：
$ 28.2万
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：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7975995
关键词：
Adherence Apoptosis Apoptotic B lymphoid malignancy BCL2L11 gene BIK gene BIRC4 gene Bone Marrow Cells Bortezomib CD34 gene Cell Adhesion Cell Cycle Cell Death Cell Survival Cells Cessation of life Chemosensitization Clinical Trials Complex Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases 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 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.

细胞周期失调与Bcl-2家族蛋白在前列腺癌分子发病机制中的关联证据