Targeting CDK4 and CDK6 kinases in breast cancer development

靶向乳腺癌发展中的 CDK4 和 CDK6 激酶

• 批准号: 10023399
• 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
• 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/10023399
• 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; 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 subsets; programmed cell death ligand 1; programmed cell death protein 1; response; tumor; tumor heterogeneity; tumor metabolism

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.

项目概要/摘要 该转化提案重点关注使用细胞周期蛋白依赖性激酶 CDK4 和 CDK6 抑制剂 乳腺癌治疗。 CDK4 和 CDK6 是被激活的核心细胞周期机制的组成部分 与其调节亚基 D 型细胞周期蛋白（细胞周期蛋白 D1、D2 和 D3）相互作用。抑制剂 CDK4/6 palbociclib、ribociclib 和 abemaciclib 获得了 FDA 的“突破性疗法”认定 FDA 已批准用于治疗雌激素受体阳性乳腺癌。此外，这些 化合物目前正在针对其他几种癌症类型进行临床试验。大量研究表明 用 CDK4/6 抑制剂治疗人类癌细胞可以阻止肿瘤细胞增殖，并且在某些情况下 导致肿瘤细胞衰老。与 Polyak 博士合作，我们观察到肿瘤细胞表达 CDK4/6 抑制后，高水平的细胞周期蛋白 D3-CDK6 复合物会导致细胞死亡。我们发现细胞周期蛋白 D3- CDK6，但不是我们分析的其他几种类型的细胞周期蛋白 D-CDK4/6 复合物（例如细胞周期蛋白 D1-CDK4）， 在调节肿瘤细胞代谢中发挥限速作用，并保护肿瘤细胞免受高水平的 活性氧。在一项独立研究中，我们发现在小鼠和人类肿瘤细胞中，细胞周期蛋白 D- CDK4 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，我们发现使用 CDK4/6 抑制剂治疗会产生 上调肿瘤细胞中的 PD-L1 蛋白水平。我们还发现，CDK4/6 的联合给药 含有针对程序性细胞死亡蛋白 1 (PD-1) 与其相互作用的抗体的抑制剂 配体 PD-L1 提高了免疫检查点治疗的疗效。在这里提出的研究中，我们将 将这些观察结果扩展到乳腺癌。在目标 1 中，我们将与博士合作。 Polyak 和 Brown 来测试我们的 假设测量人类乳腺癌中的细胞周期蛋白 D3 和 CDK6 水平可能有助于识别 对 CDK4/6 抑制剂治疗特别敏感的乳腺癌病例，如细胞周期蛋白 D3/CDK6 高 CDK4/6 抑制后，肿瘤可能会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 CDK4 的乳腺癌细胞凋亡的方法。我们将解决 这些问题使用人类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。 我们还将与博士合作。 Polyak 和 Brown 解决乳腺肿瘤内和肿瘤间的异质性 癌症，这可能会影响结果。在目标 2 中，我们检验了 CDK4/6 抑制剂治疗的假设 将提高乳腺癌免疫检查点疗法的功效并导致肿瘤消退 并提高了小鼠乳腺癌模型的存活率。我们将使用带有乳房的小鼠来研究这一点 癌症同种异体移植物以及本土三阴性乳腺肿瘤。预计此次事件的总体影响 建议是，它将提供识别对抗乳腺癌药物特别敏感的乳腺癌病例的方法。 CDK4/6 疗法，并建立涉及 CDK4/6 抑制剂的新型高效组合疗法。