Translational Research in Breast Cancer

摘要 在治疗转移性乳腺癌方面缺乏进展是由于许多基本的治疗障碍。这些 包括对治疗脆弱性知识不足、缺乏可靠的预测生物标志物、无法 靶向常见的肿瘤抑制基因丢失，无法靶向非蛋白激酶或配体的癌基因- 依赖转录因子，由于克隆进化和肿瘤异质性而产生的耐药性，以及未能安装 对肿瘤的免疫反应。这种孢子更新集中在这些障碍上，通过阐明交叉- 削减目标和协调一致的方法，以提高核心利用效率并促进项目间 协作。这三个完整的项目包括研究如何靶向因 PTPN12或NF1抑癌基因在乳腺癌中的缺失及一种有前景的新抑癌基因的开发 MYC阳性乳腺癌的治疗途径。在执行这些项目期间，我们将：a)部署 蛋白基因组学方法用于监测激酶靶标和抗性途径；b)建立高质量 临床试验资格和分层的生物标志物；c)调查疾病监测方法 循环肿瘤细胞(CTCs)和循环肿瘤DNA(CTDNA)；d)纳入免疫学方法 通过提高肿瘤浸润性淋巴细胞的质量和数量进入治疗方案；e)嵌入我们的 孢子生物标记物计划进入早期临床试验，为第三阶段试验的设计提供信息；以及f)促进 学术界、NCI支持的合作团体、行业和倡导者之间的合作研究 组。 这些目标由三个重新格式化的核心来实现，并增加了一个专门的、高度合格的 以病理学和生物库为核心的分子研究病理学家，增加了更深层次的生物信息学 信息学和生物统计核心的专业知识，以及一名新的孢子主管以及更多的倡导者和 行政核心顾问委员会成员。职业提升与发展研究 项目将由经验丰富的领导层指导，并将一如既往地巩固我们孢子的未来。 有了这一强大的增强计划，我们将在全国范围内倡导在晚期癌症治疗方面取得进展 乳腺癌，坚信治愈是近期的可能。

Abstract Lack of progress in curing metastatic breast cancer is due to a number of fundamental treatment barriers. These include insufficient knowledge of therapeutic vulnerabilities, lack of reliable predictive biomarkers, inability to target common tumor suppressor gene loss, inability to target oncogenes that are not protein kinases or ligand- dependent transcription factors, resistance due to clonal evolution and tumor heterogeneity, and failure to mount an immune response against the tumor. This SPORE renewal focuses on these obstacles by articulating cross- cutting objectives and aligned approaches that increase the efficiency of core utilization and promote inter-project collaboration. The three full Projects include studies on how to target the derepressed kinases consequent upon loss of the PTPN12 or the NF1 tumor suppressors in breast cancer, and the development of a promising new therapeutic approach for MYC-positive breast cancer. During the execution of these Projects we will: a) deploy proteogenomic approaches for monitoring kinase targets and resistance pathways; b) establish high-quality biomarkers for clinical trial eligibility and stratification; c) investigate disease-monitoring approaches with circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA); d) incorporate immunological approaches into treatment regimens by increasing the quality and quantity of tumor infiltrating lymphocytes; e) embed our SPORE biomarker program into early phase clinical trials to inform the design of Phase 3 trials; and f) promote collaborative research between Academia, NCI-Supported Cooperative Groups, Industry, and Advocacy Groups. These objectives are served by three reformatted Cores, with the addition of a dedicated and highly-qualified molecular research pathologist for the Pathology and Biobanking Core, the addition of deeper bioinformatics expertise to the Informatics and Biostatistics Core, and a new SPORE director plus additional advocates and advisory board members for the Administration Core. The Career Enhancement and Developmental Research Programs will be guided by highly experienced leadership and, as before, will cement the future of our SPORE. With this powerful enhanced program we will advocate nationally for progress in the treatment of advanced breast cancer, with the conviction that a cure is a near-term possibility.