Mayo Clinic Breast Cancer SPORE

计划摘要/摘要 这是梅奥诊所乳腺癌孢子的第三次续签申请，正在提交VISION 通过执行创新的翻译，可以减轻乳腺癌(BC)的负担 研究对妇女具有高度重要性的问题。研究孢子的科学包括三个方面 翻译研究项目。项目1：“雌激素受体阳性的BC易感基因变异对 BC风险和对治疗的反应“。这个项目建立在前一个资助期的工作基础上， 首席调查人员(PI)发现某些BC易感基因(ATM、CHEK2和PALB2)是 主要与ER+BC的风险有关。PIS将评估ATM、BRCA2、CHEK2、 PALB2，并确定a)年龄相关风险、对侧BC和第二癌症(卵巢、 结直肠、胰腺等)，b)这些PV的预后效应和c)变异的临床相关性 ATM、CHEK2和PALB2中的不确定意义。项目2：“改善儿童的内分泌管理 绝经前ER+/HER2-BC提出了一种新的ER靶向药物Z-endoxifen(ENDX)，用于 基于新数据的绝经前ER+BC，ENDX双重靶向ERα和PKCβ1，具有强大的 ERα、Cyclin D1和E2F1蛋白下调。这种双重目标不仅是ENDX独有的，而且是 在临床试验中提出的剂量，ENDX能够完全阻断 绝经前的雌激素水平。项目3：开发一种新型多抗原预防乙肝疫苗 为患有癌前疾病的女性而创作的是基于Mayo研究人员的开创性工作开发的一部小说 针对所有BC亚型共同表达的六种抗原的疫苗。该项目的工作将提供 关键信息，将使研究人员能够a)了解目标抗原在 从正常乳腺组织进展到BC；以及，b)在第一阶段研究中，评估血液和乳腺组织 免疫反应的生物标志物。该项目的成功完成将为第三阶段奠定基础 预防良性乳腺疾病(BBD)妇女BC疫苗的临床试验 有可能显著降低BC的总体发病率和死亡率。这些研究项目是 由三个高度互动的核心支持：核心A：行政核心，核心B：生物显微镜和病理学 核心和核心C：生物统计学、生物信息学和患者登记核心。发展性研究 该计划将继续确定和开发最有希望推进的研究项目 完整的孢子项目和职业提升计划将继续确定和支持教师 BC转译研究中最有潜力成为未来孢子领袖的研究人员。 孢子中的研究人员、核心和研究项目都集成在梅奥癌症诊所 中心。总而言之，我们的孢子将做出发现，并将其转化为临床，以造福于 患有或有患公元前疾病风险的女性。

Program Summary/Abstract This third renewal application of the Mayo Clinic Breast Cancer SPORE is being submitted with the vision that the burden of breast cancer (BC) can be reduced through the performance of innovative translational research addressing issues of high significance for women. The science of the SPORE includes three translational research projects. Project 1: “The influence of variants in ER-positive BC predisposition genes on BC risk and response to therapy”. This project builds upon the work from the prior funding period, where the principal investigators (PIs) identified that certain BC predisposition genes (ATM, CHEK2 and PALB2) were associated mainly with the risk of ER+ BC. The Pis will assess pathogenic variants in ATM, BRCA2, CHEK2, PALB2 and determine a) age-related risks, the risks of contralateral BC and second cancers (ovarian, colorectal, pancreatic etc.), b) the prognostic effects of these PV and c) the clinical relevance of variants of uncertain significance in ATM, CHEK2, and PALB2. Project 2: “Improving the endocrine management of premenopausal ER+/HER2- BC” brings forward a new ER-targeting drug, Z-endoxifen (ENDX), for premenopausal ER+ BC based on new data that ENDX dually targets both ERα and PKCβ1, with potent protein downregulation of ERα, Cyclin D1, and E2F1. This dual targeting is not only unique to ENDX, but at the dosing proposed in the clinical trial, ENDX is able to completely block the stimulatory effects of premenopausal levels of estrogen. Project 3: “Development of a novel multi-antigen BC prevention vaccine for women with premalignant disease” is based on pioneering work of Mayo investigators to develop a novel vaccine that targets six antigens collectively expressed by all BC subtypes. The work in this project will provide critical information that will allow the investigators to a) understand the expression of target antigens during progression from normal breast tissue to BC; and, b) in the phase I study, evaluate blood and breast tissue biomarkers of immune response. Successful completion of this project will establish the parameters for a phase III clinical trial of the vaccine for BC prevention in women with benign breast disease (BBD), with the enormous potential to drive significant reductions in overall BC incidence and mortality. These research projects are supported by three highly interactive cores: Core A: Administrative Core, Core B: Biospecimen and Pathology Core, and Core C: Biostatistics, Bioinformatics, and Patient Registry Core. A Developmental Research Program will continue to identify and develop research projects that hold the greatest promise to advance to full SPORE projects, and a Career Enhancement Program will continue to identify and support faculty investigators in BC translational research that have the greatest potential to become future SPORE leaders. The investigators, cores, and the research programs in the SPORE are all integrated in the Mayo Clinic Cancer Center. Collectively, our SPORE will make discoveries and translate them into the clinic for the benefit of women with, or at risk of BC.