Mayo Clinic Breast Cancer SPORE

项目概要/摘要 这是马约诊所乳腺癌孢子的第三次更新申请， 乳腺癌（BC）的负担可以通过创新的翻译性能来减少， 研究对妇女具有重要意义的问题。孢子的科学包括三个 翻译研究项目。项目1：“ER阳性BC易感基因变异对 BC风险和治疗反应”。该项目建立在前一个供资期的工作基础上， 主要研究者（PI）发现，某些BC易感基因（ATM，CHEK 2和PALB 2） 主要与ER+ BC的风险相关。PI将评估ATM，BRCA 2，CHEK 2， PALB 2并确定a）年龄相关的风险，对侧BC和第二种癌症（卵巢癌， 结肠直肠、胰腺等），B）这些PV的预后影响，以及c） 在ATM、CHEK 2和PALB 2中的意义不确定。项目2：“改善儿童的内分泌管理” 绝经前ER+/HER 2- BC”提出了一种新的ER靶向药物Z-内昔芬（ENDX）， 绝经前ER+ BC基于新的数据，ENDX双重靶向ERα和PKCβ1， ERα、Cyclin D1和E2 F1蛋白下调。这种双重目标不仅是ENDX所独有的， 在临床试验中提出的剂量，ENDX能够完全阻断的刺激作用， 绝经前的雌激素水平项目3：“新型多抗原BC预防疫苗的开发 为患癌前病变的妇女”是基于马约研究人员的开创性工作， 疫苗靶向所有BC亚型共同表达的六种抗原。该项目的工作将提供 关键信息，将使研究者a）了解靶抗原的表达， 从正常乳腺组织到BC的进展;和，B）在I期研究中，评估血液和乳腺组织 免疫反应的生物标志物。这一项目的成功完成将为第三阶段确定参数， 在患有良性乳腺疾病（BBD）的妇女中进行预防BC疫苗的临床试验， 有可能推动整体BC发病率和死亡率的显著降低。这些研究项目是 由三个高度互动的核心提供支持：核心A：管理核心，核心B：生物标本和病理学 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SPORE项目和职业提升计划将继续识别和支持教师 BC转化研究的研究人员，最有潜力成为未来的SPORE领导者。 SPORE中的研究者、核心和研究项目都整合在马约癌症诊所中 中心总的来说，我们的SPORE将做出发现，并将其转化为临床，以造福于 患有或有患BC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.