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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：
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.

项目总结