权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

06 Breast Cancer

06 乳腺癌

基本信息

批准号：
9794675
负责人：
KELLY K HUNT
金额：
$ 1.87万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9794675
关键词：
Address American Joint Committee on Cancer Area Basic Science Biological Assay Biological Factors Biological Markers Biology Breast Breast Cancer Patient Breast Cancer Treatment Breast cancer metastasis CCNE1 gene Cancer Center Support Grant Catchment Area Cell Cycle Cells Clinical Clinical Investigator Clinical Research Clinical Trials Collaborations Communication DNA Repair Development Diagnosis Disease ERBB2 gene Early Diagnosis Epithelial Evolution FRAP1 gene Faculty Funding Generations Genetically Engineered Mouse Genets Genomics Goals Grant Incidence Individual Journals Knowledge Laboratories Link Long-Term Effects Longevity Malignant Neoplasms Mammary Neoplasms Maps Measures Mediator of activation protein Medical Oncologist Mesenchymal Metastatic Neoplasm to the Bone Methods MicroRNAs Minor Modeling Molecular Morbidity - disease rate Mutation Nature Neoplasm Metastasis Paper Pathway interactions Patients Peer Review Phenotype Philanthropic Fund Population Population Research Population Study Prevention Primary Neoplasm Publishing Publishing Peer Reviews Research Research Infrastructure Research Personnel Resistance Resource Sharing Signal Transduction Staging System Subgroup Surgical Oncologist System TP53 gene Techniques Technology Texas Therapeutic Translating Translational Research Tumor stage United States Wages Woman advanced disease anticancer research base biomarker-driven burden of illness clinical practice cohort data registry early detection biomarkers effective therapy fundamental research genomic profiles improved innovation interest malignant breast neoplasm member molecular marker mortality neoplasm registry neoplastic cell novel therapeutics outcome forecast overexpression personalized medicine pre-clinical predicting response prognostic programs recruit response biomarker single cell sequencing targeted treatment therapeutic target treatment effect treatment response treatment strategy trend triple-negative invasive breast carcinoma tumor growth tumor heterogeneity tumor initiation tumor progression tumorigenesis vector

项目摘要

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).

项目概要/摘要乳腺癌计划 (BrCP) 由来自 25 个科室的 72 名成员（60 名初级成员、12 名副成员）组成。该项目由乳腺外科肿瘤学家和临床研究员 Kelly K. Hunt 博士领导；坎丹博士 Keyomarsi，实验室研究员； Debu Tripathy 博士，乳腺医学肿瘤学家和临床医生研究者。 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。有 3 个主题：1）遗传改变和乳腺癌进化，2) 已确诊乳腺癌的生物学，以及 3) 乳腺癌的靶向治疗乳腺癌。他们实现了 3 个具体目标：目标 1：阐明分子和基因组进化乳腺癌发生和进展的基础；目标 2：检查信号转导的失调，乳腺癌中的 DNA 修复、细胞周期和分化途径可以提供治疗靶点；目的 3：将科学发现应用于乳腺癌管理和生物测定的新疗法和生物测定中进行创新的临床试验和基于人群的研究，可以减轻德克萨斯州的疾病负担人口。年度直接同行评审资金总额为 540 万美元，其中 320 万美元（60%）来自 NCI 拨款。自上次竞争更新以来，该计划已发表 1,092 篇已发表论文： 562 篇（51%）代表项目内合作，360 (33%) 代表项目间合作，695 (64%) 代表外部合作。 46% 的文章发表在 IF >5 的期刊上，18% 的文章发表在 IF >5 的期刊上曾出现在 IF >10 的期刊上，包括 Cancer Discov、Cell、JAMA、J Clin Oncol、Lancet Oncol、Nature、 Nat Genet 和 N Engl J Med。计划成员使用所有 14 个共享资源。在最后的资助期内，研究极大地影响了乳腺癌骨转移治疗的临床实践。另一项发展是 Neo-Bioscore 分期系统，该系统在之前验证的基础上进行了改进 CPS+EG系统并允许其应用于ERBB2阳性疾病患者。 CPS+EG系统影响了将生物因素纳入第八版美国联合委员会癌症乳腺癌分期系统。计划成员还取得了一些有影响力的发现提高我们对导致乳腺癌亚型的机制的理解，特别是那些患有有限的乳腺癌亚型的机制治疗选择。通过针对三阴性乳腺癌的项目间合作进行的研究证明了共同的进化谱系以及非克隆细胞的少数亚群，表明大多数拷贝数畸变是在肿瘤进化的最早阶段获得的（Gao R et al, 纳特·热内特，2016）；揭示了上皮-间质转化、治疗耐药性和转移（Zhang J et al, Nat Cell Biol, 2013）；并将 iDAPK1 确定为三重疾病的新型治疗策略通过调节 mTOR/S6 通路来治疗具有 p53 突变的阴性乳腺癌（Zhao J 等人，J Clin Invest， 2015）。