Exploiting synthetic-lethal interactions to target triple-negative breast cancers

利用合成致死相互作用来靶向三阴性乳腺癌

基本信息

批准号：
9070742
负责人：
Dai Horiuchi
金额：
$ 24.43万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9070742
关键词：
Apoptosis Apoptotic Automobile Driving BCL1 Oncogene BCL2 gene BCL2L11 gene Biological Biology Breast Cancer Cell Breast Cancer cell line Breast Epithelial Cells CDC2 Protein Kinase Cancer cell line Cell Culture Techniques Cell Cycle Cell Death Cell Line Cells Clinical Clinical Research Clinical Trials Collaborations Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Diversity Library Epidermal Growth Factor Receptor Estrogen Receptors Family member Genetic Human Knowledge Lead Lymphoma Malignant Neoplasms Malignant neoplasm of prostate Mammary Neoplasms Mammary gland Mentors Messenger RNA Mitochondria Mitotic Modeling Molecular Mus Oncogenes Oncogenic Pathway interactions Patients Phase Phenotype Phosphotransferases Play Progesterone Receptors Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-myc RNA Interference Reporting Research Role Signal Pathway Signal Transduction Testing Therapeutic Therapeutic Intervention Up-Regulation base cancer subtypes cellular engineering chemical genetics clinically relevant combinatorial design effective therapy genetic approach high throughput screening inhibitor/antagonist insight killings malignant breast neoplasm member mouse model novel novel therapeutics outcome forecast overexpression receptor research study small hairpin RNA small molecule small molecule inhibitor targeted treatment tool transcription factor treatment strategy triple-negative invasive breast carcinoma tumor tumor xenograft tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT No targeted therapeutic strategies are currently available against triple-negative (TN) breast cancer, the most difficult-to-treat form of breast cancer, which does not overexpress human epidermal growth factor receptor 2 (HER2) and lacks the expression of the estrogen and progesterone receptors. Thus, there is an urgent need in deepening our understanding of this aggressive breast cancer subtype and identifying clinically relevant targets for therapeutic intervention. We have recently discovered that an oncogenic transcription factor MYC as well as the MYC-dependent signaling pathways are significantly up-regulated in primary human triple-negative breast tumors. In addition, we found that MYC activation is associated with patientsʼ poor prognosis suggesting that the MYC pathways may play a fundamental role in driving the formation of these aggressive tumors. How can we kill MYC-driven TN tumors? Because MYC is a transcription factor, rationally designed small molecule inhibitors that can directly inhibit its activity are not available for clinical use. An alternative approach in selectively killing MYC-driven tumors is to exploit the existence of “synthetic-lethal” interactions. Our group previously took a cell cycle-biased approach and discovered that inhibition of the mitotic kinase cyclin-dependent kinase (CDK) 1 resulted in apoptosis in cells engineered to overexpress MYC. The mechanism of such cell death involved an up-regulation of a pro-apoptotic BCL-2 family member BIM. We subsequently used this approach to treat TN cell lines and xenograft tumors with elevated MYC expression. These observations suggest that MYC-dependent synthetic-lethal interactions exist, and importantly, can be targeted to selectively kill MYC-driven tumors. Aim 1 of this proposed research will further study the clinical potential of small molecule CDK inhibition against MYC-driven TN cancers particularly in combination with clinical inhibitors of anti-apoptotic BCL-2 members. This is based on our novel hypothesis that, because CDK inhibition up-regulates BIM and activates mitochondrial intrinsic pathway, the combined use of the inhibitors for CDK and anti-apoptotic BCL-2 family members may significantly enhance the rate of cell death. Aim 2 will characterize a newly discovered synthetic-lethal interaction between MYC activation and inhibition of Pim1, a non-essential, kinase previously shown to genetically interact with MYC. Aim 3 will conduct a high-throughout small molecule screen to identify potential lead molecules capable of inducing MYC-dependent synthetic lethality in mammary cells. We will carry out these experiments using a combination of model human mammary epithelial cells, genetically defined cancer cell lines, and a panel of novel human-in-mouse orthotopic tumor grafts models. If successful, the proposed research will not only expand our knowledge on MYC biology but will also provide novel therapeutic concepts to be tested again patients with TN tumors.

项目概要/摘要目前尚无针对三阴性（TN）乳腺癌的靶向治疗策略，最难治疗的乳腺癌，不会过度表达人类表皮生长因子受体 2 (HER2) 且缺乏雌激素和孕激素受体的表达，因此，存在一种受体 2 (HER2)。迫切需要加深我们对这种侵袭性乳腺癌亚型的了解并识别我们最近发现了一种致癌性的治疗干预的临床相关目标。转录因子 MYC 以及 MYC 依赖性信号通路在此外，我们发现 MYC 激活与原发性人类三阴性乳腺肿瘤相关。患者的不良预后表明 MYC 通路可能在驱动这些侵袭性肿瘤的形成。我们怎样才能杀死MYC驱动的TN肿瘤？因为MYC是一个经过合理设计的转录因子。目前尚无可直接抑制其活性的小分子抑制剂可供临床使用。选择性杀死 MYC 驱动的肿瘤的方法是利用“合成致死”相互作用的存在。我们的小组之前采用了细胞周期偏向的方法，发现有丝分裂激酶的抑制细胞周期蛋白依赖性激酶 (CDK) 1 导致过表达 MYC 的细胞凋亡。这种细胞死亡的机制涉及促凋亡 BCL-2 家族成员 BIM 的上调。随后使用这种方法治疗 MYC 表达升高的 TN 细胞系和异种移植肿瘤。这些观察结果表明，MYC 依赖性合成致死相互作用存在，而且重要的是，可以靶向选择性杀死 MYC 驱动的肿瘤。这项研究的目标 1 将进一步研究小分子 CDK 的临床潜力抑制 MYC 驱动的 TN 癌症，特别是与临床抗凋亡抑制剂联合使用 BCL-2 成员基于我们的新假设，因为 CDK 抑制会上调 BIM 和激活线粒体内在途径，CDK抑制剂与抗凋亡抑制剂联用 BCL-2家族成员可能会显着提高细胞死亡率，Aim 2将成为新的特征。发现 MYC 激活和 Pim1 抑制之间的合成致死相互作用，Pim1 是一种非必需的、先前显示与 MYC 存在遗传相互作用的激酶 Aim 3 将进行高通量小规模相互作用。分子筛选，以确定能够诱导 MYC 依赖性合成致死性的潜在先导分子我们将使用人类乳腺模型的组合来进行这些实验。上皮细胞、基因定义的癌细胞系和一组新型人鼠原位肿瘤如果成功，拟议的研究不仅将扩展我们对 MYC 生物学的了解，而且还将扩展我们对 MYC 生物学的了解。还将提供新的治疗概念，以供 TN 肿瘤患者再次测试。