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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：
10624789
负责人：
Sergi Regot
金额：
$ 49.78万
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/10624789
关键词：
17q 17q23 Automobile Driving Biogenesis Breast Breast Cancer Cell Cell Cycle Progression Cell Proliferation Cell division Cells Centrosome Chemicals Chromosome Segregation Clinic Clinical Collaborations 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 Phosphoric Monoester Hydrolases Phosphotransferases Poly(ADP-ribose) Polymerase Inhibitor Pre-Clinical Model Primary Neoplasm Proliferating Property Proteins Reporting Role TP53 gene Testing Therapeutic Tumor Promotion 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 pharmacologic preservation protein expression synthetic lethal interaction 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.

项目摘要合成致死性的概念已经在临床上通过使用PARP抑制剂治疗 BRCA 1/2功能缺失突变的乳腺癌。然而，只有5-10%的乳腺肿瘤是 BRCA 1/2遗传突变引起的，强调需要确定新的合成致命相互作用，可以在临床上使用。在这个提议中，我们利用了我们最近发现的一种新的合成致命癌症特异性基因改变暴露的相互作用。中心体是微管组织中心，在细胞分裂过程中催化纺锤体的组装，师.中心体复制与细胞周期进程紧密耦合，并由主细胞控制调节激酶（Polo样激酶4）PLK 4。PLK 4活性的化学抑制导致细胞分裂，缺乏中心体复制，产生无中心体的细胞，表现出延迟的有丝分裂纺锤体组装件.尽管大多数癌细胞可以在没有中心体的情况下增殖， PLK 4的抑制导致中心体缺失，选择性地触发癌细胞的有丝分裂灾难过度表达TRIM 37。这具有治疗相关性，因为TRIM 37染色体基因座在50- 100%中扩增。 60%的神经母细胞瘤和~10%的乳腺癌。此外，这一区域的扩增与具有高度重排和不稳定基因组的侵袭性癌症。在本应用程序中，我们将定义如何 TRIM 37过表达促进肿瘤发生并增加对PLK 4抑制剂的脆弱性。我们将还测试了PLK 4抑制在实现选择性杀死人类癌症类器官中的有效性 TRIM 37扩增。目的1将确定TRIM 37过表达如何增加对PLK 4抑制剂的敏感性，并测试是否 TRIM 37驱动的中心体功能障碍通过促进有丝分裂错误而有助于肿瘤发生。17q23 扩增子含有约30个基因，包括TRIM 37和TP 53拮抗磷酸酶PPM 1D。的 PPM 1D过表达的致癌特性已经在几种模型中得到验证。选择性PPM 1D 抑制剂已经开发出来，但PPM 1D如何与17 q23扩增子中编码的其他基因合作，仍然未知。在目标2中，我们确定PPM 1D过表达是否促进TRIM 37介导的基因组表达。不稳定性，并测试PPM 1D抑制是否可以增强PLK 4抑制剂在这些肿瘤中的作用。最后，Aim 3将检查TRIM 37过表达是否赋予乳腺中对PLK 4抑制的敏感性增加，类神经母细胞瘤了解TRIM 37在肿瘤发生中的作用将有助于确定其在肿瘤发生中的作用。过表达推动了侵袭性癌症的发展，并为使用PLK 4 i治疗提供了理论基础用TRIM 37的基因组扩增治疗癌症。