Impact of chromosomal instability on sensitivity to microtubule-targeting drugs in breast cancer

染色体不稳定性对乳腺癌微管靶向药物敏感性的影响

基本信息

批准号：
10305657
负责人：
Mark E Burkard
金额：
$ 53.3万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-07 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305657
关键词：
Address Affect Antineoplastic Agents Archives Biological Biological Assay Biological Markers Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Cancer Control Cancer Patient Cell Culture Techniques Cell Death Cell division Cell model Cells Chromosomal Instability Chromosomes Clinical Cultured Cells DNA copy number DNA sequencing Data Defect Drug Targeting Drug resistance Ensure Epothilones Exhibits FDA approved Genetic Transcription Goals Human Human Cell Line Interphase Ixabepilone Knowledge Laboratories Malignant Neoplasms Mammary Neoplasms Measures Metastatic breast cancer Methods Microtubule Stabilization Microtubules Mitosis Mitotic Mitotic spindle Modeling Morphology Organoids Paclitaxel Patient Selection Patient-Focused Outcomes Patients Pharmaceutical Preparations Physiological Poison Public Health Recording of previous events Research Sampling Standardization Testing Tumor Biology Tumor Suppression Vinca Alkaloids Vinorelbine Work anti-cancer antitumor effect base cancer biomarkers cancer therapy chemotherapy clinically relevant digital docetaxel drug mechanism drug sensitivity improved ineffective therapies malignant breast neoplasm member mouse model overtreatment predicting response predictive marker response standard of care standardize measure targeted agent targeted cancer therapy targeted treatment taxane transcriptome sequencing tumor

项目摘要

Project Summary Several microtubule-targeted drugs are commonly used to treat breast cancer, but for many patients they do not work. The long-term goal of this research is to accurately predict which patients will benefit from microtubule-targeted drugs including paclitaxel, docetaxel, vinorelbine, eribulin, and ixabepilone. Multiple lines of evidence from our laboratories and others support the idea that chromosomal instability (CIN) is the key feature of cancer governing response to paclitaxel and other anti-microtubule drugs. The central hypothesis is that breast tumors with the highest levels of pre-existing CIN are most sensitive to the enhanced CIN caused by microtubule-targeted therapies. Our preliminary data show that paclitaxel causes CIN due to multipolar spindles in patient tumors, that similar concentrations of other anti-microtubule drugs cause multipolar spindles in cultured cells, and that CIN measured by interphase FISH correlates with taxane response in metastatic breast cancer. Aim 1 will determine whether clinically useful microtubule poisons universally induce multipolar spindles. Paclitaxel, docetaxel, eribulin, vinorelbine, and ixabepilone will be tested for effects on mitotic spindle morphology and function in cell models, mouse models, and in samples obtained from human breast cancer in patients receiving these treatments as single agents as part of the standard of care. This aim will thereby determine whether these microtubule-targeted drugs have similar or disparate biologic effects on cancer. Aim 2 will determine which types and degrees of CIN confer sensitivity to diverse microtubule targeted agents. Four models of CIN will be used to generate specific mitotic defects including multipolar divisions, polar chromosomes, lagging chromosomes, and chromosome bridges at defined rates, and these will be tested for sensitivity to microtubule-targeted drugs in multiple models. Patient-derived primary organoid breast cancer cultures with defined mechanisms of CIN will be tested in parallel. Aim 3 will establish a standardized method to quantify CIN to use as a biomarker in human breast cancer. The four CIN models will be used to compare proposed methods to quantify CIN including interphase FISH, bulk DNA and RNA sequencing, and digital karyotypes from low-pass single-cell DNA sequencing. We anticipate that this will provide a basis to accurately infer CIN from the thousands of sequenced tumors for which data is publically available. These measures of CIN will also be evaluated for their ability to predict taxane response in metastatic breast cancer patients, employing archived tumor samples, to verify ability to predict response to paclitaxel. The work is significant because it will advance our knowledge of the mechanism of widely used cancer drugs as well as how CIN, a common feature of tumor biology, affects response to these agents. It ensures clinical relevance by incorporating both models and human samples in each aim. Ultimately the knowledge gained will allow for accurate prediction of patients who will and will not benefit from widely used treatments, and thereby has the potential to address the ongoing problem of overtreatment and ineffective treatment of cancer.

项目概要几种微管靶向药物通常用于治疗乳腺癌，但对于许多患者来说不工作。这项研究的长期目标是准确预测哪些患者将从中受益微管靶向药物包括紫杉醇、多西紫杉醇、长春瑞滨、艾日布林和伊沙匹隆。多条线路来自我们实验室和其他实验室的大量证据支持染色体不稳定性 (CIN) 是关键这一观点癌症控制紫杉醇和其他抗微管药物反应的特征。中心假设是预先存在 CIN 水平最高的乳腺肿瘤对 CIN 增强最敏感通过微管靶向疗法。我们的初步数据表明，紫杉醇由于多极引起 CIN 患者肿瘤中的纺锤体，类似浓度的其他抗微管药物会导致多极纺锤体在培养细胞中，通过间期 FISH 测量的 CIN 与转移性紫杉烷反应相关乳腺癌。目标 1 将确定临床上有用的微管毒物是否普遍诱发多极主轴。将测试紫杉醇、多西紫杉醇、艾日布林、长春瑞滨和伊沙匹隆对有丝分裂纺锤体的影响细胞模型、小鼠模型以及从人类乳腺癌中获得的样品中的形态和功能作为标准护理的一部分，接受这些单一药物治疗的患者。这一目标将由此确定这些微管靶向药物对癌症是否具有相似或不同的生物学作用。目的 2 将确定哪些类型和程度的 CIN 赋予对不同微管靶向药物的敏感性。四 CIN 模型将用于产生特定的有丝分裂缺陷，包括多极分裂、极分裂以规定的速率检测染色体、滞后染色体和染色体桥，并对这些进行测试多种模型中对微管靶向药物的敏感性。患者来源的原发性类器官乳腺癌具有明确 CIN 机制的培养物将同时进行测试。目标3将建立标准化方法量化 CIN 以用作人类乳腺癌的生物标志物。将使用四个 CIN 模型进行比较提出的量化 CIN 的方法包括间期 FISH、批量 DNA 和 RNA 测序以及数字化低通单细胞 DNA 测序的核型。我们预计这将为准确地从数以千计的已测序肿瘤（其数据已公开）中推断出 CIN。这些措施 CIN 还将评估其预测转移性乳腺癌患者紫杉烷反应的能力，使用存档的肿瘤样本来验证预测紫杉醇反应的能力。这项工作意义重大因为它将增进我们对广泛使用的抗癌药物的机制以及 CIN（一种肿瘤生物学的共同特征影响对这些药物的反应。它通过以下方式确保临床相关性在每个目标中结合模型和人类样本。最终所获得的知识将允许准确预测将或不会从广泛使用的治疗中受益的患者，从而具有有望解决癌症过度治疗和无效治疗的持续问题。