Circumventing acquired carboplatin resistance in triple-negative breast cancers

乳腺癌细胞在重要器官中不受控制的生长几乎是造成约40，000例死亡的原因 每年都在美国发生。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）的化疗耐药性。本提案的目的 目的是确定除表皮生长因子受体（EGFR）以外的生物学途径 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 该项目的目的是将结果立即转化为临床环境，并为当前的 转移性疾病患者。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。的 中心假设将通过追求两个具体目标进行测试：1）描绘目标路径， 与阿法替尼协同作用，用于卡铂耐药TNBC的细胞毒性; 2）确定阿法替尼的功效- 在多种不同的TNBC体内模型中，这些目标将通过一个 一组创新的患者来源的异种移植模型（PDX），由卡铂等基因对组成， 敏感的或已经产生卡铂抗性的那些。该研究计划是 这是一项重要的研究，因为它将确定新的治疗靶点，可用于治疗晚期乳腺癌患者。 疾病，然后比较各种靶向组合对手术不可切除的 转移这些努力的预期结果是，我们将确定TNBC PDX的子集， 有利地响应阿法替尼为基础的联合治疗，随后，我们将确定基因组和/或 或抗EGFR反应的蛋白质组学预测因子，其将通过以下方式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。

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.