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

• 批准号: 10714928
• 负责人: Joshua (Chuck) Harrell
• 金额: $ 3.44万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 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/10714928
• 关键词: Apoptosis; Apoptotic; Biological; Breast Cancer Cell; Bypass; Cancer Patient; Carboplatin; Cells; Cellular Stress; 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; 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; Prognosis; Proliferating; 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; cancer cell; compare effectiveness; cytotoxic; cytotoxicity; efficacy evaluation; in vivo Model; inhibitor; innovation; malignant breast neoplasm; molecular drug target; new therapeutic target; novel strategies; novel therapeutic intervention; patient derived xenograft model; pharmacologic; response; safety testing; targeted treatment; transcriptome sequencing; treatment response; triple-negative invasive breast carcinoma; tumor

Project Summary/Abstract 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.

项目摘要/摘要 乳腺癌细胞在重要器官中的不受控制的生长可归因于几乎所有的~4万人死亡 在美国每年都会发生。该项目的长期目标是确定新的治疗策略。 以克服三阴性乳腺癌(TNBC)的化疗耐药。这项提议的目的是 是确定除了表皮生长因子受体(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，抑制EGFR会导致 激活细胞应激反应，可以用促凋亡剂作为靶点。完成时的目标 该项目的目的是将结果立即转化为临床环境，并为当前的 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 进一步研究寻找和开发可绕过卡铂耐药的靶向抑制剂。这个 中心假设将通过追求两个具体目标来检验：1)描绘以下目标路径 与阿法替尼对卡铂耐药的TNBCs的细胞毒性的协同作用；2)测定阿法替尼的疗效。 在多种不同的TNBC体内模型中的协同组合。这些目标将通过一个 一套创新的患者来源的异种移植模型(PDX)，由卡铂等基因对组成 敏感的或已产生卡铂抗药性的药物。这项研究建议是 意义重大，因为它将确定新的治疗靶点，可用于治疗晚期糖尿病患者 然后比较各种靶向联合治疗不能手术切除的疗效 转移瘤。这些努力的预期结果是，我们将确定将 对基于Afatinib的联合疗法有良好的反应，随后我们将确定基因组和/或 或蛋白质组学预测的抗EGFR反应将对疾病管理产生积极影响，通过 确定可能从这种治疗方法中受益的患者。