Circumventing acquired carboplatin resistance in triple-negative breast cancers

规避三阴性乳腺癌的获得性卡铂耐药性

基本信息

批准号：
10159229
负责人：
Joshua (Chuck) Harrell
金额：
$ 34.75万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10159229
关键词：
Apoptosis Apoptotic Biological Breast Cancer Cell Bypass Cancer Patient Carboplatin Cells Cellular Stress Cellular Stress Response Cessation of life Characteristics Chemoresistance Clinic Clinical Combined Modality Therapy Data Set Development Disease Disease Management Drug Combinations Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Estrogens FDA approved Genes Genetic Genomics Goals Growth Health Human In Vitro Individual Interferometry Knowledge Mammary Neoplasms Mediating Mediator of activation protein Metastatic breast cancer Mission Modeling Neoplasm Metastasis Operative Surgical Procedures Organ Organism Outcome Pathway interactions Patient-derived xenograft models of breast cancer Patients Pharmaceutical Preparations Pharmacology Prognosis Proteomics Receptor Inhibition Research Research Proposals Resistance Sampling Signal Pathway Signal Transduction Speed Testing Therapeutic Translating Translations United States United States National Institutes of Health Unresectable Work advanced disease base cancer cell compare effectiveness cytotoxic cytotoxicity in vivo Model inhibitor/antagonist innovation malignant breast neoplasm molecular drug target new therapeutic target novel strategies novel therapeutic intervention patient derived xenograft model response safety testing targeted treatment transcriptome sequencing treatment response triple-negative invasive breast carcinoma tumor

项目摘要

The uncontrolled growth of breast cancer cells in vital organs is attributable to nearly all the ~40,000 deaths that happen each year in the United States. The long-term goal of this project is to identify new therapeutic strategies to overcome chemotherapy resistance in triple-negative breast cancers (TNBC). The objective of this proposal is to identify biological pathways that can be targeted in addition to the epidermal growth factor receptor (EGFR) to promote apoptosis of disseminated cancer cells. The central hypothesis is that EGFR inhibition leads to activation of cellular stress responses that can be targeted with pro-apoptotic agents. The goal at the completion of this project is for the results to immediately translate to the clinical setting and provide options for current patients with metastatic disease. The proposed work will also develop a unique dataset that can be used for further research towards identifying and developing targeted inhibitors that bypass carboplatin-resistance. The central hypothesis will be tested by pursuing two specific aims: 1) Delineate targetable pathways that are synergistic with Afatinib for cytotoxicity of carboplatin-resistant TNBCs; 2) Determine the efficacy of Afatinib- synergsitic combinations in multiple diverse in vivo models of TNBC. These aims will be pursued using an innovative set of patient-derived xenograft models (PDX) which consist of isogenic pairs that are carboplatin- sensitive or those that have been generated to be carboplatin-resistant. This research proposal is significant because it will identify new therapeutic targets that can be used to treat patients with advanced disease, and then compare the effectiveness of various targeted combinations on surgically unresectable metastases. The expected outcome of these efforts is that we will identify subsets of TNBC PDXs that will favorably respond to Afatinib-based combination therapies, and subsequently that we will identify genomic and/ or proteomic predictors of anti-EGFR response that will make a positive impact on disease management by identifying patients that may benefit from this treatment approach.

乳腺癌细胞在重要器官中不受控制的生长几乎是导致约 40,000 例死亡的原因美国每年都会发生。该项目的长期目标是确定新的治疗策略克服三阴性乳腺癌（TNBC）的化疗耐药性。本提案的目的目的是确定除表皮生长因子受体 (EGFR) 之外还可以靶向的生物途径促进播散性癌细胞的凋亡。中心假设是 EGFR 抑制导致激活可以用促凋亡剂靶向的细胞应激反应。完成时的目标该项目的目的是让结果立即转化为临床环境，并为当前的治疗提供选择患有转移性疾病的患者。拟议的工作还将开发一个独特的数据集，可用于进一步研究以确定和开发绕过卡铂耐药性的靶向抑制剂。这中心假设将通过追求两个具体目标来检验：1）描绘可目标路径与阿法替尼对卡铂耐药 TNBC 的细胞毒性具有协同作用； 2) 确定阿法替尼的功效- TNBC 多种不同体内模型中的协同组合。这些目标将通过一套创新的患者来源的异种移植模型（PDX），由卡铂同基因对组成敏感的或已产生的卡铂耐药的。这项研究计划是意义重大，因为它将确定可用于治疗晚期患者的新治疗靶点疾病，然后比较各种靶向组合对手术无法切除的患者的有效性转移。这些努力的预期结果是，我们将确定 TNBC PDX 的子集，这些子集将对基于阿法替尼的联合疗法有良好反应，随后我们将确定基因组和/ 或抗 EGFR 反应的蛋白质组学预测因子，这将对疾病管理产生积极影响确定可能从这种治疗方法中受益的患者。