The role of TRIM37 in driving tumorigenesis and cancer-specific vulnerability to PLK4 inhibition

TRIM37 在驱动肿瘤发生和癌症特异性对 PLK4 抑制的脆弱性中的作用

基本信息

批准号：
10340029
负责人：
Sergi Regot
金额：
$ 66.5万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10340029
关键词：
17q 17q23 Automobile Driving Biogenesis Breast Breast Cancer Cell Cell Cycle Progression Cell Proliferation Cell division Cells Centrosome Chemicals Chromosomes Clinic Clinical Coupled Data Defect Development Down-Regulation Exhibits Failure Functional disorder Gene Amplification Genes Genetic Genome Genomic Instability Genomics Goals Heterogeneity Human Hypersensitivity Inherited Malignant Neoplasms Mammary Neoplasms Mediating Microtubule-Organizing Center Microtubules Mitotic Mitotic spindle Modeling Molecular Mutation Neuroblastoma Oncogenes Oncogenic Organelles Organoids PLK1 gene PPM1D gene Pharmacology Phosphoric Monoester Hydrolases Phosphotransferases Pre-Clinical Model Primary Neoplasm Proliferating Property Proteins Reporting Role TP53 gene Testing Therapeutic Work aurora B kinase brca gene cancer cell cancer therapy cell killing effectiveness testing genetic approach genetic manipulation imaging approach inhibitor loss of function mutation malignant breast neoplasm neoplastic cell novel novel therapeutics overexpression patient derived xenograft model preservation protein expression tumor tumorigenesis ubiquitin ligase ubiquitin-protein ligase

项目摘要

Project Summary The concept of synthetic lethality has been validated clinically with the use of PARP inhibitors in treating breast cancers with loss-of-function mutations in BRCA1/2. Nevertheless, only 5-10% of breast tumors are caused by inherited mutations in BRCA1/2, highlighting a need to identify new synthetic lethal interactions that can be exploited clinically. In this proposal, we capitalize on our recent discovery of a new synthetic lethal interaction that is exposed by a cancer-specific genetic alteration. Centrosomes are microtubule-organizing centers that catalyze the assembly of the mitotic spindle during cell division. Centrosome duplication is tightly coupled to cell cycle progression and controlled by the master regulatory kinase (Polo-like kinase 4) PLK4. Chemical inhibition of PLK4 activity leads to cell division in the absence of centrosome duplication, producing centrosome-less cells that exhibit delayed mitotic spindle assembly. Although most cancer cells can proliferate in the absence of centrosomes, we recently discovered that inhibition of PLK4 leads to centrosome depletion that selectively triggers mitotic catastrophe in cancer cells overexpressing TRIM37. This has therapeutic relevance as the TRIM37 chromosomal locus is amplified in 50- 60% of neuroblastomas and ~10% of breast cancers. In addition, amplification of this region is associated with aggressive cancers with highly rearranged and unstable genomes. In this application, we will define how TRIM37 overexpression promotes tumorigenesis and increases the vulnerability to PLK4 inhibitors. We will also test the effectiveness of PLK4 inhibition in achieving selective killing of human cancer organoids with TRIM37 amplification. Aim 1 will determine how TRIM37 overexpression increases the sensitivity to PLK4 inhibitors and test if TRIM37-driven centrosome dysfunction contributes to tumorigenesis by promoting mitotic errors. The 17q23 amplicon contains ~30 genes, including TRIM37 and the TP53-antagonizing phosphatase PPM1D. The oncogenic properties of PPM1D overexpression have been validated in several models. Selective PPM1D inhibitors have been developed, but how PPM1D cooperates with other genes encoded in the 17q23 amplicon remains unknown. In Aim 2, we determine if PPM1D overexpression promotes TRIM37-mediated genomic instability and test if PPM1D inhibition can potentiate the action of PLK4 inhibitors in these tumors. Finally, Aim 3 will examine if TRIM37 overexpression confers increased sensitivity to PLK4 inhibition in breast and neuroblastoma tumor organoids. Understanding the role of TRIM37 in tumorigenesis will help define how its overexpression drives the development of aggressive cancers and provide a rationale for the use of PLK4i in the treatment of cancers with genomic amplification of TRIM37.

项目摘要通过使用PARP抑制剂在治疗中，合成致死性的概念已在临床上得到了验证 BRCA1/2中具有功能丧失突变的乳腺癌。然而，只有5-10％的乳腺肿瘤是由BRCA1/2中的遗传突变引起的，强调需要确定新的合成致命相互作用可以在临床上被利用。在此提案中，我们利用了最近发现的新合成致死通过癌症特异性遗传改变暴露的相互作用。中心体是微管组织中心，可在细胞中催化有丝分裂主轴的组装分配。中心体重复紧密耦合到细胞周期进程，并由主控制调节激酶（Polo样激酶4）PLK4。 PLK4活性的化学抑制导致细胞分裂缺乏中心体重复，产生延迟有丝分裂主轴的无中心体细胞集会。尽管大多数癌细胞都可以在没有中心体的情况下增殖，但我们最近发现 PLK4的抑制会导致中心体耗竭，可有选择地触发癌细胞中有丝分裂灾难过表达的TRIM37。这具有治疗性相关性，因为TRIM37染色体基因座在50-- 60％的神经母细胞瘤和约10％的乳腺癌。此外，该区域的扩增与具有高度重排和不稳定基因组的侵略性癌症。在此应用程序中，我们将定义如何 TRIM37过表达促进肿瘤发生，并增加对PLK4抑制剂的脆弱性。我们将还可以测试PLK4抑制在实现人类癌器官选择性杀死的有效性使用TRIM37扩增。 AIM 1将决定TRIM37过表达如何增加对PLK4抑制剂的敏感性并测试是否 TRIM37驱动的中心体功能障碍通过促进有丝分裂错误促进肿瘤发生。 17q23 扩增子包含约30个基因，包括TRIM37和TP53抗磷酸酶PPM1D。这 PPM1D过表达的致癌特性已在几种模型中得到验证。选择性PPM1D 已经开发了抑制剂，但是PPM1D如何与17q23 Amplicon中编码的其他基因合作仍然未知。在AIM 2中，我们确定PPM1D过表达是否促进了TRIM37介导的基因组不稳定性和测试PPM1D抑制是否会增强PLK4抑制剂在这些肿瘤中的作用。最后，瞄准 3将检查TRIM37是否赋予对乳腺PLK4抑制的敏感性是否增加神经母细胞瘤肿瘤器官。了解TRIM37在肿瘤发生中的作用将有助于定义其过表达驱动了侵略性癌症的发展，并为使用PLK4I提供了理由对TRIM37基因组扩增的癌症的处理。