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: 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
• 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

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.

项目总结/文摘