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

Dissecting the Role of Src Family Kinases in Breast Cancer Brain Metastasis

剖析 Src 家族激酶在乳腺癌脑转移中的作用

基本信息

批准号：
8091662
负责人：
Siyuan Zhang
金额：
$ 10.7万
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：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8091662
关键词：
Area Astrocytes Basic Science Biological Factors Blood - brain barrier anatomy Brain Brain Part Breast Cancer Cell Breast Cancer Treatment Cancer Biology Cancer Patient Cancer cell line Cell Line Cell Proliferation Cephalic Clinic Clinical Congenic Mice Data Development Diagnosis Disease Doctor of Medicine Doctor of Philosophy ERBB2 gene Educational workshop Endothelial Cells Environment Event Excision Extravasation Funding Genetically Engineered Mouse Glioblastoma Goals Grant Health Sciences Human In Vitro Incidence Infiltration Knock-out Knockout Mice Knowledge Lead Leadership Malignant Neoplasms Mediating Mentors Metastatic Neoplasm to the Breast Metastatic malignant neoplasm to brain Methodology Microarray Analysis Modeling Molecular Mutation Neoplasm Metastasis Operative Surgical Procedures Organ PTEN gene Paper Patient Care Patients Pharmaceutical Preparations Phase Play Population Positioning Attribute Postdoctoral Fellow Process Property Publishing Radiation therapy Refractory Regimen Relapse Research Research Ethics Research Personnel Resistance Role SRC gene Scientist Singapore Steroids Tanacetum parthenium Testing Texas Therapeutic Tight Junctions Training Translational Research Trastuzumab Treatment Protocols Universities University of Texas M D Anderson Cancer Center Vascular Endothelial Growth Factors Vascular Permeabilities Woman Writing anticancer research base career career development clinical care clinical efficacy combinatorial design effective therapy immunodeficient mouse model improved in vivo inhibitor/antagonist innovation insight kinase inhibitor lapatinib malignant breast neoplasm mouse model neoplastic cell novel novel therapeutics overexpression paracrine parthenolide pre-clinical preclinical efficacy research clinical testing skills src-Family Kinases success therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): I received my M.D. in 1998 from Peking University Health Science Center and a Ph.D. degree in Cancer Biology from the National University of Singapore in 2005. My Ph.D. training was focused on deciphering the molecular mechanisms of the anti-cancer activity of parthenolide - an active component in natural product feverfew. I was the first author in 7 of the 9 papers I published during Ph.D. training. I joined Dr. Dihua Yu's group at The University of Texas M.D. Anderson Cancer (MDACC) in 2007 to pursue my goal of making discoveries of clinical impact. My research elucidated a key mechanism of trastuzumab resistance and led to the development of a novel clinically-translatable combinatorial regimen for trastuzumab-resistant patients. Meanwhile, I am also investigating the role of PTEN loss in breast cancer brain metastasis. My current research goal is to study the role of certain genetic alterations in breast cancer brain metastasis and establish myself as an independent researcher through K99 funding. My long-term research goal will be focused on two important areas: (1) Basic research, investigate the mechanisms of metastasis by focusing on the contribution of the pre-metastatic microenvironment; and (2) Translational research, based on basic research findings to identify, design and pre-clinically test novel therapeutic regimens for treatment of cancer metastasis. To achieve my short-term and long-term career goals, during the K99 mentored phase of this grant, I will receive comprehensive training based in an unmatched training environment for cancer research- MDACC. I will cooperate with my mentors and actively participate in formal courses, workshops and seminars to broaden my knowledge and skills, particularly in genetically-engineered mouse models. The career development training in scientific writing, research ethics, lab management and leadership skills will further facilitate my transition as an independent scientist. My research plan is focused on the role of Src family kinases (SFK) in breast cancer brain metastasis. Among 1.3 million women diagnosed with breast cancer every year worldwide, about 10- 16% will develop brain metastases. Even with most advanced clinical care, the overall survival for brain metastasis patients is less than 14 months from diagnosis. At present, no effective treatment exists for patients with refractory metastatic breast cancer brain metastasis. Therefore, novel and effective therapeutic approaches are urgently needed for this population. Unfortunately, developing effective therapeutics for brain metastasis is largely hampered by a shortage of in-depth understanding of the basic mechanisms of brain metastasis. Our preliminary studies suggest that Src family kinase c-Src plays an important role in both metastatic tumor cells and brain metastasis microenvironments. The major goal of the proposed project is to use innovative approaches to dissect the role of Src family kinases in the brain metastasis process and develop novel therapies for breast cancer brain metastasis patients. We propose three comprehensive aims: 1) Aim 1 (K99 phase): Determine the role of tumor SFK activation in breast cancer brain metastasis. 2) Aim 2 (R00 Phase): Determine the impact of SFK activation in the brain pre-metastatic microenvironment on breast cancer brain metastasis. 3) Aim 3 (R00 Phase): Investigate the pre-clinical efficacy of novel SFK-targeting therapeutic regimens in the treatment of breast cancer brain metastasis. Success of the project will promote my career transition from my position as a mentored postdoctoral fellow to becoming an independent scientist with my own research direction. More importantly, novel insights from this study into the mechanisms of breast cancer brain metastasis will guide the development of novel clinically-translatable regimens that offer fresh opportunities for the treatment of a devastatingly intractable disease. PUBLIC HEALTH RELEVANCE: For breast cancer patients, no effective treatments exist for patients with refractory breast cancer brain metastasis. Using innovative approaches, the proposed project aims to decipher mechanisms of brain metastasis by focusing on both metastatic breast cancer cells and the brain metastasis microenvironment. Ultimately, we will design and perform pre-clinical testing on novel combinatorial therapies for breast cancer brain metastasis that can be smoothly transitioned into the clinic.

个人描述(申请人提供)：1998年在北京大学卫生科学中心获得医学博士学位，2005年在新加坡国立大学获得肿瘤生物学博士学位。我的博士培训重点是破译巴特内酯抗癌活性的分子机制--这是天然产品三叶草中的一种活性成分。我在博士生培训期间发表的9篇论文中，有7篇是第一作者。2007年，我加入了德州大学安德森癌症医学部(MDACC)余迪华博士的团队，以追求我的目标，即发现具有临床影响的成果。我的研究阐明了曲妥珠单抗耐药的关键机制，并导致了一种新的临床可翻译的联合方案的开发，用于曲妥珠单抗耐药患者。同时，我也在研究PTEN缺失在乳腺癌脑转移中的作用。我目前的研究目标是研究某些基因改变在乳腺癌脑转移中的作用，并通过K99基金确立自己的独立研究人员身份。我的长期研究目标将集中在两个重要领域：(1)基础研究，通过关注转移前微环境的贡献来研究转移的机制；(2)转化研究，基于基础研究结果，识别、设计和临床前测试治疗癌症转移的新治疗方案。为了实现我的短期和长期职业目标，在这笔赠款的K99指导阶段，我将接受基于无与伦比的癌症研究培训环境-MDACC的全面培训。我将与我的导师合作，并积极参加正式的课程、研讨会和研讨会，以拓宽我的知识和技能，特别是在基因工程小鼠模型方面。科学写作、研究道德、实验室管理和领导技能方面的职业发展培训将进一步促进我作为一名独立科学家的过渡。我的研究计划集中在src家族激酶(Sfk)在乳腺癌脑转移中的作用。在全球每年130万被诊断为乳腺癌的女性中，约有10%-16%会发生脑转移。即使有了最先进的临床护理，脑转移患者从确诊到总体生存时间也不到14个月。目前，难治性转移性乳腺癌脑转移患者尚无有效的治疗方法。因此，迫切需要新的有效的治疗方法来治疗这一人群。不幸的是，由于缺乏对脑转移基本机制的深入了解，开发有效的脑转移治疗方法在很大程度上受到了阻碍。我们的初步研究表明，Src家族激酶c-Src在肿瘤转移细胞和脑转移微环境中都发挥着重要作用。该项目的主要目标是使用创新的方法来剖析Src家族激酶在脑转移过程中的作用，并为乳腺癌脑转移患者开发新的治疗方法。我们提出三个全面的目标： 1)目的1(K99期)：确定肿瘤SFK活化在乳腺癌脑转移中的作用。 2)目的2(R00期)：确定脑转移前微环境中SFK的激活对乳腺癌脑转移的影响。 3)目的3(R00期)：探讨新型SFK靶向治疗方案治疗乳腺癌脑转移的临床前疗效。该项目的成功将促进我的职业生涯从一个有指导的博士后研究员的职位过渡到成为一名有自己研究方向的独立科学家。更重要的是，这项研究对乳腺癌脑转移机制的新见解将指导开发新的临床可翻译方案，为治疗这种毁灭性的顽固性疾病提供新的机会。公共卫生相关性：对于乳腺癌患者，目前还没有针对难治性乳腺癌脑转移患者的有效治疗方法。利用创新的方法，拟议的项目旨在通过同时关注转移性乳腺癌细胞和脑转移微环境来破译脑转移的机制。最终，我们将设计并执行针对乳腺癌脑转移的新型组合疗法的临床前测试，这些疗法可以顺利过渡到临床。