Inhibiting tumor growth and metastasis in highly aggressive breast cancers with centrosome amplification

通过中心体扩增抑制高度侵袭性乳腺癌的肿瘤生长和转移

基本信息

批准号：
10670436
负责人：
Ozgur Sahin
金额：
$ 33.2万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670436
关键词：
4T1 Acetylation Apoptosis Apoptotic BCL2 gene Binding Proteins Biological Assay Breast Breast Cancer Model Breast Cancer Patient CDC2 gene CRISPR/Cas technology Cell Death Cell Death Induction Cell Line Cell Polarity Cell division Cells Centrosome Clathrin Clinic Clustered Regularly Interspaced Short Palindromic Repeats Data Defect Distant Metastasis Experimental Models Extracellular Matrix Focal Adhesions Genetic Goals Golgi Apparatus Growth HDAC2 gene High Prevalence Immunocompetent Immunofluorescence Immunologic In Vitro Integrins Interphase Interphase Cell Invaded Knock-out Legal patent Lung Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Mediating Methods Microtubules Mission Mitosis Mitotic Mitotic spindle Modeling Molecular Mouse Mammary Tumor Virus Mutation Neoplasm Metastasis Noninfiltrating Intraductal Carcinoma Normal Cell Organoids Output Ovarian Patient-Focused Outcomes Phenotype Physiological Primary Neoplasm Prognosis Prostate Proteins Public Health Research Role TP53 gene Testing Therapeutic Toxic effect Transgenic Mice Tubulin Tumor-Derived United States National Institutes of Health Xenograft procedure advanced breast cancer aggressive breast cancer cancer cell cell motility clinically relevant disability high risk improved in vivo inhibitor innovation live cell imaging malignant breast neoplasm migration mortality mouse model mutant novel overexpression patient derived xenograft model patient subsets polarized cell polyoma middle tumor antigen pre-clinical prevent success therapeutic target three dimensional cell culture trafficking triple-negative invasive breast carcinoma tumor tumor growth tumor progression

项目摘要

PROJECT SUMMARY Centrosome amplification (CA) is highly prevalent in cancer and strongly associated with tumor progression and worse prognosis in several different cancers, including breast, prostate, ovarian and lung. Centrosome amplified cells also demonstrate increased motility and invasiveness leading to metastasis. Moreover, CA is associated with genetic aberrations, such as p53 mutation that are commonly observed in aggressive forms of cancers, such as the triple negative breast cancer (TNBC). Our long-term goal is to target the growth and metastatic dissemination of aggressive breast tumors with CA that will ultimately lead to improved patient outcome. The overall objectives of this project are to (i) inhibit tumor growth in breast cancer models with CA via inducing centrosome de-clustering and formation of multipolar spindles upon targeting transforming acidic coiled-coil 3 (TACC3), and to (ii) block local invasion and metastatic dissemination in CA models by preventing cell polarization, migration and invasion upon inhibition of TACC3. The central hypothesis is that TACC3 inhibition will, on one hand, prevent active clustering of amplified centrosomes into two spindle poles during mitotic cell division leading to multipolar mitosis and apoptotic cell death in p53 altered cells, and on the other hand disrupts centrosome and Golgi re-orientation, microtubule nucleation and cell polarization in interphase cells leading to decreased migration. The rationale for this project is that TACC3 inhibition represents a unique opportunity to eliminate the most aggressive tumors that have supernumerary centrosomes, while sparing the normal cells. The central hypothesis will be tested by pursing two specific aims: 1.) To inhibit tumor growth in aggressive breast cancer models with CA by targeting TACC3, and 2.) To prevent metastasis in aggressive breast cancer models with CA by targeting TACC3. State-of-the-art experimental settings with translatable approaches will be employed, including tumor organoids, patient- derived xenografts and immunocompetent transgenic mouse model of advanced breast cancer that we characterized in terms of CA. The research proposed in this project is innovative as it aims to study mitosis/interphase-specific interactomes of TACC3 that are essential for TACC3-mediated cell division in mitotic cells and cell polarity in interphase cells that we propose to block using our novel and highly potent TACC3 inhibitor as well as using CRISPR-mediated knock-out. The proposed project is significant because it is expected to provide key mechanistic and phenotypic pre-clinical data to support the notion that targeting TACC3 concomitantly inhibits tumor growth and metastasis in breast cancer models with CA, which will then dramatically reduce mortality rates among patient subpopulation with highly aggressive cancers.

项目概要中心体扩增（CA）在癌症中非常普遍，并且与肿瘤进展密切相关几种不同癌症的预后较差，包括乳腺癌、前列腺癌、卵巢癌和肺癌。中心体扩增的细胞还表现出增加的运动性和侵袭性，导致转移。此外，CA 是与遗传畸变相关，例如在攻击性形式中常见的 p53 突变癌症，例如三阴性乳腺癌（TNBC）。我们的长期目标是实现增长和具有 CA 的侵袭性乳腺肿瘤的转移性传播，最终将改善患者的病情结果。该项目的总体目标是 (i) 抑制 CA 乳腺癌模型中的肿瘤生长通过靶向转化酸性诱导中心体去簇和多极纺锤体的形成卷曲螺旋 3 (TACC3)，并 (ii) 通过以下方式阻断 CA 模型中的局部侵袭和转移性播散抑制 TACC3 后可防止细胞极化、迁移和侵袭。中心假设是一方面，TACC3 抑制将阻止扩增的中心体主动聚集成两个纺锤体极在有丝分裂细胞分裂过程中，p53 改变的细胞会导致多极有丝分裂和细胞凋亡另一方面破坏中心体和高尔基体的重新定向、微管成核和细胞极化间期细胞导致迁移减少。该项目的基本原理是 TACC3 抑制代表了一个独特的机会来消除具有多余的最具侵袭性的肿瘤中心体，同时保留正常细胞。中心假设将通过追求两个具体的目标：1.) 通过靶向 TACC3 抑制具有 CA 的侵袭性乳腺癌模型中的肿瘤生长，2.) 通过靶向 TACC3 来预防患有 CA 的侵袭性乳腺癌模型的转移。最先进的将采用可转化方法的实验环境，包括肿瘤类器官、患者衍生的晚期乳腺癌异种移植物和免疫活性转基因小鼠模型以 CA 为特征。该项目提出的研究具有创新性，因为它旨在研究 TACC3 的有丝分裂/间期特异性相互作用组对于 TACC3 介导的细胞分裂至关重要我们建议使用我们的新型高效药物来阻断有丝分裂细胞和间期细胞的细胞极性 TACC3 抑制剂以及使用 CRISPR 介导的基因敲除。拟议的项目意义重大，因为预计将提供关键的机制和表型临床前数据来支持靶向的观点 TACC3 同时抑制 CA 乳腺癌模型中的肿瘤生长和转移，然后显着降低患有高度侵袭性癌症的患者亚群的死亡率。