06 Breast Cancer

项目摘要/摘要 乳腺癌计划(BrCP)由来自25个部门的72名成员组成(60名初级成员，12名副成员)。 该项目由乳腺外科肿瘤学家兼临床研究员凯利·K·亨特博士领导；坎丹博士 Keyomarsi，实验室调查员；Debu Trithy博士，乳腺内科肿瘤学家和临床 调查员。BrCP的主要科学目标是阐明癌症进化和转移的机制。 这可以转化为乳腺癌患者的新治疗策略。它有三个主题：1)遗传 改变和乳腺癌的演变，2)已建立的乳腺癌的生物学，和3)靶向治疗 乳腺癌。它们导致了三个特定的目标：目标1：阐明分子和基因组进化 乳腺癌发生和发展的基础；目标2：检查信号转导的放松调控， 乳腺癌中可提供治疗靶点的DNA修复、细胞周期和分化途径；目的 3：利用科学发现开发新的治疗方法和生物检测方法，用于乳腺癌治疗和 进行创新的临床试验和基于人群的研究，以减轻德克萨斯州的疾病负担 人口。每年直接同行评审的资金总额为540万美元，其中320万美元(60%)来自NCI的拨款。 自上次竞争续签以来，该计划已发表了1092篇论文：562篇(51%)代表 方案内协作，360个(33%)表示方案间协作，695%() 代表外部协作。46%的文章出现在期刊上，IF&>5%和18% 已经出现在IF&GT；10的期刊上，包括癌症发现，细胞，JAMA，J Clin Onol，Lancet Onol，自然， Nat Genet和N Engl J Med.计划成员使用所有14个共享资源。在上一次拨款期间， 研究在很大程度上影响了乳腺癌骨转移的临床治疗。 另一个发展是Neo-Bioscore分期系统，它在之前验证的基础上进行了改进 CPS+EG系统，并允许其在ERBB2阳性疾病患者中应用。CPS+EG系统 影响将生物因素纳入第八版美国气候变化联合委员会 癌症乳腺癌分期系统。计划成员还做出了几项有影响力的发现， 提高我们对导致乳腺癌亚型的机制的了解，特别是那些 治疗选择。通过方案间合作对三阴性乳腺癌进行的研究 展示了一个共同的进化谱系以及少数非克隆细胞亚群，这表明 大多数拷贝数偏差是在肿瘤进化的最早阶段获得的(Gao R等人， Nat Genet，2016)；揭示了上皮-间充质转化、治疗耐药和 转移(Zhang J et al，NAT Cell Biol，2013)；并将iDAPK1确定为三重肿瘤的一种新的治疗策略。 通过调节mTOR/S6通路获得p53突变的阴性乳腺癌(赵J等，J Clin Invest， 2015年)。

PROJECT SUMMARY/ABSTRACT The Breast Cancer Program (BrCP) consists of 72 members (60 primary, 12 associate) from 25 departments. The program is led by Dr. Kelly K. Hunt, breast surgical oncologist and clinical investigator; Dr. Khandan Keyomarsi, laboratory-based investigator; and Dr. Debu Tripathy, breast medical oncologist and clinical investigator. The major scientific goal of the BrCP is to elucidate mechanisms of cancer evolution and metastasis that can be translated into new treatment strategies for breast cancer patients. There are 3 themes: 1) Genetic Alterations and Breast Cancer Evolution, 2) Biology of Established Breast Cancer, and 3) Targeted Therapy in Breast Cancer. They have led to 3 specific aims: Aim 1: to elucidate the molecular and genomic evolutionary basis of breast cancer development and progression; Aim 2: to examine the deregulation of signal transduction, DNA repair, cell-cycle, and differentiation pathways in breast cancer that could provide therapeutic targets; Aim 3: to leverage scientific discoveries into novel therapeutics and bioassays for breast cancer management and conduct innovative clinical trials and population-based studies that can reduce the burden of disease in the Texas population. The annual direct peer-reviewed funding totals $5.4M, of which $3.2M (60%) is from NCI grants. Since the last competitive renewal, the program has authored 1,092 published papers: 562 (51%) represent intra-programmatic collaborations, 360 (33%) represent inter-programmatic collaborations, and 695 (64%) represent external collaborations. Forty-six percent of articles have appeared in journals with IF >5 and 18% have appeared in journals with IF >10, including Cancer Discov, Cell, JAMA, J Clin Oncol, Lancet Oncol, Nature, Nat Genet, and the N Engl J Med. Program members use all 14 shared resources. During the last grant period, research substantially influenced the clinical practice for treatment of bone metastasis from breast cancer. Another development was the Neo-Bioscore staging system, which improves upon the previously validated CPS+EG system and allows its application in patients with ERBB2-positive disease. The CPS+EG system influenced the incorporation of biological factors into the eighth edition of the American Joint Committee on Cancer breast cancer staging system. Program members have also made several impactful discoveries that improve our understanding of the mechanisms leading to subtypes of breast cancer, especially those with limited therapeutic options. Studies carried out via inter-programmatic collaborations on triple-negative breast cancers demonstrate a common evolutionary lineage along with a minor subpopulation of nonclonal cells, suggesting that the majority of copy-number aberrations are acquired at the earliest stages of tumor evolution (Gao R et al, Nat Genet, 2016); unveiling a molecular link among epithelial-mesenchymal transition, therapy resistance, and metastasis (Zhang J et al, Nat Cell Biol, 2013); and identifying iDAPK1 as a novel therapeutic strategy in triple- negative breast cancers with p53 mutations by modulating the mTOR/S6 pathway (Zhao J et al, J Clin Invest, 2015).