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

• 批准号: 8487128
• 负责人: Dai Horiuchi
• 金额: $ 11.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487128
• 关键词: Apoptosis; Apoptotic; Automobile Driving; BCL1 Oncogene; BCL2 gene; BCL2L11 gene; Biological; Biology; Breast Cancer Cell; CDC2 Protein Kinase; Cancer cell line; Cell Culture Techniques; Cell Cycle; Cell Death; Cell Line; Cells; Clinical; Clinical Research; Clinical Trials; Collaborations; Critiques; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Diversity Library; Epidermal Growth Factor Receptor; Epithelial Cells; Estrogen Receptors; Family member; Genetic; Human; Individual; Knowledge; Lead; Lymphoma; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Mammary gland; Mentors; Messenger RNA; Mitochondria; Mitotic; Modeling; Molecular; Mus; Oncogene Proteins; 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; Writing; base; cellular engineering; chemical genetics; clinically relevant; combinatorial; design; effective therapy; high throughput screening; inhibitor/antagonist; insight; killings; malignant breast neoplasm; meetings; member; mouse model; novel; novel therapeutics; outcome forecast; overexpression; public health relevance; receptor; research study; small hairpin RNA; small molecule; therapeutic target; tool; transcription factor; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor xenograft; tumorigenic

DESCRIPTION (provided by applicant): 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 patients¿ 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-throughput 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.

描述（由申请人提供）：目前没有针对三阴性（TN）乳腺癌的靶向治疗策略，三阴性（TN）乳腺癌是最难治疗的乳腺癌形式，不过度表达人表皮生长因子受体2（HER 2），缺乏雌激素和孕酮受体的表达。因此，迫切需要加深我们对这种侵袭性乳腺癌亚型的理解，并确定临床相关的治疗干预靶点。我们最近发现，致癌转录因子MYC以及MYC依赖性信号通路在原发性人类三阴性乳腺肿瘤中显著上调。此外，我们发现MYC激活与患者预后不良相关，这表明MYC通路可能在驱动这些侵袭性肿瘤的形成中发挥重要作用。我们如何杀死MYC驱动的TN肿瘤？由于MYC是一种转录因子，因此合理设计的可以直接抑制其活性的小分子抑制剂不能用于临床使用。选择性杀死MYC驱动的肿瘤的替代方法是利用“合成-致死”相互作用的存在。我们的研究小组以前采取了细胞周期偏向的方法，发现抑制有丝分裂激酶细胞周期蛋白依赖性激酶（CDK）1导致过度表达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。我们随后使用这种方法来治疗具有升高的MYC表达的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，重要的是，可以靶向选择性杀死MYC驱动的肿瘤。本研究的目的1将进一步研究小分子CDK抑制对MYC驱动的TN癌症的临床潜力，特别是与抗凋亡BCL-2成员的临床抑制剂组合。这是基于我们的新假设，因为CDK抑制上调BIM并激活线粒体内源性途径，所以CDK和抗凋亡BCL-2家族成员的抑制剂的组合使用可显著提高细胞死亡率。目的2将表征新发现的MYC激活和Pim 1抑制之间的合成-致死相互作用，Pim 1是一种非必需的激酶，先前显示与MYC遗传相互作用。目标3将进行高通量小分子筛选，以鉴定能够在乳腺细胞中诱导MYC依赖性合成致死性的潜在先导分子。我们将使用模型人乳腺上皮细胞、遗传定义的癌细胞系和一组新型人鼠原位肿瘤移植模型的组合来进行这些实验。如果成功，这项研究不仅将扩大我们对MYC生物学的了解，还将为TN肿瘤患者提供新的治疗概念。