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Targeting CDK4 and CDK6 kinases in breast cancer development

靶向乳腺癌发展中的 CDK4 和 CDK6 激酶

基本信息

批准号：
10261468
负责人：
Peter Sicinski
金额：
$ 35.19万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-11 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10261468
关键词：
Address Affect Allografting Antibodies Apoptosis Blocking Antibodies Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Breast Cancer therapy CDK4 gene Cancer Model Cell Aging Cell Cycle Cell Death Cell Proliferation Clinical Trials Collaborations Complex Complex Analysis Cultured Cells Cyclin D1 Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinase Inhibitor 2A Cyclin-Dependent Kinases Cyclins Cytostatics Development Enrollment Estrogen Therapy Estrogen receptor positive Goals Human In Vitro Inter-tumoral heterogeneity Laboratories Ligands Mammary Neoplasms Measures Mus Nature Outcome Patient-derived xenograft models of breast cancer Patients Pentosephosphate Pathway Phosphotransferases Play Protein Isoforms Proteins Reactive Oxygen Species Refractory Retinoblastoma Protein Role Survival Rate Testing United States Food and Drug Administration Up-Regulation Work Xenograft procedure anti-CTLA4 anti-PD-1 anti-cancer anti-tumor immune response base cancer cell cancer type checkpoint therapy combinatorial cyclin D3 cytotoxic efficacy testing immune checkpoint improved in vivo inhibitor/antagonist malignant breast neoplasm neoplastic cell novel novel therapeutics patient derived xenograft model patient subsets programmed cell death ligand 1 programmed cell death protein 1 response tumor tumor heterogeneity tumor metabolism

项目摘要

Project Summary/Abstract This translational proposal focuses on the use of inhibitors of cyclin-dependent kinases CDK4 and CDK6 for breast cancer treatment. CDK4 and CDK6 are components of the core cell cycle machinery that are activated upon interaction with their regulatory subunits, the D-type cyclins (cyclins D1, D2 and D3). Inhibitors of CDK4/6 palbociclib, ribociclib and abemaciclib received ‘Breakthrough Therapy’ designation status from the FDA and have been approved for treatment of estrogen receptor-positive breast cancers. In addition, these compounds are now in clinical trials for several other cancer types. A large number of studies demonstrated that treatment of human cancer cells with CDK4/6 inhibitors blocks tumor cell proliferation, and in some cases causes tumor cell senescence. Working together with Dr. Polyak, we observed that tumor cells expressing high levels of cyclin D3-CDK6 complexes undergo cell death upon CDK4/6 inhibition. We found that cyclin D3- CDK6, but not several other types of cyclin D-CDK4/6 complexes analyzed by us (such as cyclin D1-CDK4), plays a rate-limiting role in regulating tumor cell metabolism, and protects tumor cells against elevated levels of reactive oxygen species. In an independent study, we found that in mouse and human tumor cells, cyclin D- CDK4 kinase regulates the levels of an immune checkpoint protein, programmed death-ligand 1 (PD-L1). Using mouse cancer models and in vitro cultured cells, we found that treatment with CDK4/6 inhibitors results in upregulation of PD-L1 protein levels in tumor cells. We also found that combined administration of CDK4/6 inhibitors with antibodies that target the interaction between programmed cell death protein 1 (PD-1) and its ligand PD-L1 increased the efficacy of immune checkpoint therapy. In the studies proposed here, we will extend these observations to breast cancers. In Aim 1, we will work with Drs. Polyak and Brown to test our hypothesis that measuring cyclin D3 and CDK6 levels in human breast cancers may allow one to identify breast cancer cases that are particularly sensitive to CDK4/6 inhibitor treatment, as cyclin D3/CDK6-high tumors might undergo tumor cell death and tumor regression upon CDK4/6 inhibition. We will also explore ways to trigger apoptosis of breast cancers expressing predominantly cyclin D1 and CDK4. We will address these issues using xenografts of human breast cancer cell lines and patient-derived breast cancer xenografts. We will also work with Drs. Polyak and Brown to address the intra- and inter-tumoral heterogeneity of breast cancers, which may influence the outcomes. In Aim 2, we test our hypothesis that CDK4/6 inhibitor treatment would increase the efficacy of immune checkpoint therapy for breast cancers and result in tumor regression and improved survival rates in mouse breast cancer models. We will study this using mice bearing breast cancer allografts as well as autochthonous triple-negative breast tumors. The expected overall impact of this proposal is that it will provide means to identify breast cancer cases that are particularly sensitive to anti- CDK4/6 therapy, and establish novel, highly effective combinatorial treatments involving CDK4/6 inhibitors.

项目总结/摘要该翻译建议集中于使用细胞周期蛋白依赖性激酶CDK 4和CDK 6的抑制剂，乳腺癌的治疗CDK 4和CDK 6是被激活的核心细胞周期机制的组分，在与它们的调节亚基D型细胞周期蛋白（细胞周期蛋白D1、D2和D3）相互作用时。的抑制剂 CDK 4/6 palbociclib、ribociclib和abemaciclib获得了“突破性治疗”的认定资格。 FDA已批准用于治疗雌激素受体阳性乳腺癌。另外这些化合物目前正在对其他几种癌症进行临床试验。大量研究表明，用CDK 4/6抑制剂治疗人类癌细胞可以阻断肿瘤细胞增殖，在某些情况下，导致肿瘤细胞衰老。与Polyak博士合作，我们观察到表达高水平的细胞周期蛋白D3-CDK 6复合物在CDK 4/6抑制时经历细胞死亡。我们发现细胞周期蛋白D3- CDK 6，而不是我们分析的其他几种类型的细胞周期蛋白D-CDK 4/6复合物（如细胞周期蛋白D1-CDK 4），在调节肿瘤细胞代谢中起限速作用，并保护肿瘤细胞免受高水平的活性氧物质。在一项独立的研究中，我们发现在小鼠和人类肿瘤细胞中，细胞周期蛋白D- CDK 4激酶调节免疫检查点蛋白，程序性死亡配体1（PD-L1）的水平。使用小鼠癌症模型和体外培养的细胞，我们发现用CDK 4/6抑制剂治疗导致肿瘤细胞中PD-L1蛋白水平的上调。我们还发现，CDK 4/6联合给药具有靶向程序性细胞死亡蛋白1（PD-1）及其受体之间相互作用的抗体的抑制剂，配体PD-L1增加了免疫检查点疗法的功效。在本研究中，我们将将这些观察结果扩展到乳腺癌。在目标1中，我们将与Polyak博士和Brown博士合作，假设测量人类乳腺癌中细胞周期蛋白D3和CDK 6水平可以帮助人们识别对CDK 4/6抑制剂治疗特别敏感的乳腺癌病例，如细胞周期蛋白D3/CDK 6高在CDK 4/6抑制后，肿瘤可能经历肿瘤细胞死亡和肿瘤消退。我们还将探索触发主要表达细胞周期蛋白D1和CDK 4的乳腺癌细胞凋亡的方法。我们将解决这些问题使用人乳腺癌细胞系的异种移植物和患者来源的乳腺癌异种移植物。我们还将与Polyak和Brown博士合作，解决乳腺癌的肿瘤内和肿瘤间异质性，癌症，这可能会影响结果。在目标2中，我们检验了我们的假设，CDK 4/6抑制剂治疗将增加乳腺癌免疫检查点疗法的疗效，并导致肿瘤消退并提高了小鼠乳腺癌模型的存活率。我们将使用小鼠进行研究，癌症同种异体移植物以及自体三阴性乳腺肿瘤。预期的整体影响这项提案将提供一种方法来确定对抗- CDK 4/6治疗，并建立新的，高效的组合治疗涉及CDK 4/6抑制剂。