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.

项目概要合成致死的概念已通过使用 PARP 抑制剂治疗的临床得到验证。具有 BRCA1/2 功能丧失突变的乳腺癌。然而，只有 5-10% 的乳腺肿瘤由 BRCA1/2 的遗传突变引起，强调需要确定新的合成致死相互作用可以用于临床。在这个提案中，我们利用了我们最近发现的一种新的合成致命物质癌症特异性基因改变所暴露的相互作用。中心体是微管组织中心，在细胞分裂过程中催化有丝分裂纺锤体的组装分配。中心体复制与细胞周期进程紧密耦合并由主控调节激酶（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复制，产生无中心体细胞，表现出有丝分裂纺锤体延迟集会。尽管大多数癌细胞可以在没有中心体的情况下增殖，但我们最近发现抑制 PLK4 会导致中心体耗竭，选择性地引发癌细胞有丝分裂灾难过度表达 TRIM37。这具有治疗相关性，因为 TRIM37 染色体位点在 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袭性癌症。在此应用程序中，我们将定义如何 TRIM37 过表达会促进肿瘤发生并增加对 PLK4 抑制剂的脆弱性。我们将还测试了 PLK4 抑制在实现选择性杀死人类癌症类器官方面的有效性与 TRIM37 放大。目标 1 将确定 TRIM37 过度表达如何增加对 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 拮抗磷酸酶 PPM1D。这 PPM1D 过度表达的致癌特性已在多个模型中得到验证。选择性 PPM1D 抑制剂已经开发出来，但 PPM1D 如何与 17q23 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 PPM1D 过表达是否会促进 TRIM37 介导的基因组稳定性并测试 PPM1D 抑制是否可以增强 PLK4 抑制剂在这些肿瘤中的作用。最后，瞄准 3 将检查 TRIM37 过度表达是否会增加乳腺和乳腺组织对 PLK4 抑制的敏感性。神经母细胞瘤肿瘤类器官。了解 TRIM37 在肿瘤发生中的作用将有助于确定其如何发挥作用过度表达会促进侵袭性癌症的发展，并为在癌症中使用 PLK4i 提供了理论依据。通过 TRIM37 基因组扩增治疗癌症。