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: 10652411
• 负责人: Joshua (Chuck) Harrell
• 金额: $ 34.05万
• 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/10652411
• 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

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造成死亡的全部原因