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：
8547028
负责人：
Siyuan Zhang
金额：
$ 22.63万
依托单位：
UNIVERSITY OF NOTRE DAME
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 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8547028
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 abstracting 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

Project Summary/Abstract Title: Dissecting the Role of Src Family Kinases in Breast Cancer Brain Metastasis PI: Siyuan Zhang, M.D., Ph.D., The University of Texas M.D. Anderson Cancer Center 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.

项目概要/摘要标题：剖析 Src 家族激酶在乳腺癌脑转移中的作用 PI：张思源，医学博士、哲学博士，德克萨斯大学 M.D. 安德森癌症中心 1998年获北京大学医学部医学博士学位，1998年获北京大学医学部博士学位。学位 2005 年获得新加坡国立大学癌症生物学博士学位。培训重点是破译小白菊内酯抗癌活性的分子机制 - 一种活性物质天然产物小白菊中的成分。期间发表的 9 篇论文中有 7 篇是第一作者博士训练。我加入了德克萨斯大学 M.D. Anderson 癌症中心于迪华博士的团队（MDACC）于 2007 年实现我的目标，即做出具有临床影响的发现。我的研究阐明了一个曲妥珠单抗耐药的关键机制，并导致了一种新型临床可转化药物的开发针对曲妥珠单抗耐药患者的联合治疗方案。同时，我也在研究角色的作用乳腺癌脑转移中 PTEN 缺失。我目前的研究目标是研究某些因素的作用乳腺癌脑转移的基因改变并使我自己成为一个独立的人研究员通过K99资助。我的长期研究目标将集中在两个重要领域： (1)基础研究，重点研究转移机制的贡献转移前微环境； (2) 转化研究，以基础研究成果为基础识别、设计和临床前测试用于治疗癌症转移的新治疗方案。到为了实现我的短期和长期职业目标，在这笔资助的 K99 指导阶段，我将在无与伦比的癌症研究培训环境中接受全面的培训- MDACC。我会与我的导师合作，积极参加正式课程、研讨会和研讨会以扩大我的知识和技能，特别是在基因工程小鼠模型方面。科学写作、研究伦理、实验室管理和领导力方面的职业发展培训技能将进一步促进我作为一名独立科学家的转变。我的研究计划重点是 Src 家族激酶 (SFK) 在乳腺癌脑中的作用转移。全球每年有 130 万女性被诊断患有乳腺癌，其中约 10- 16%会发生脑转移。即使采用最先进的临床护理，大脑的总体存活率转移患者距诊断时间不足 14 个月。目前尚无有效治疗方法难治性转移性乳腺癌脑转移患者。因此，新颖有效该人群迫切需要治疗方法。不幸的是，开发有效的脑转移的治疗在很大程度上因缺乏对脑转移的深入了解而受到阻碍脑转移的基本机制。我们的初步研究表明 Src 家族激酶 c-Src 在转移性肿瘤细胞和脑转移微环境中发挥重要作用。这拟议项目的主要目标是使用创新方法来剖析 Src 家族的作用脑转移过程中的激酶并开发乳腺癌脑转移的新疗法患者。我们提出三个综合目标： 1）目标1（K99期）：确定肿瘤SFK激活在乳腺癌脑中的作用转移。 2) 目标 2（R00 阶段）：确定 SFK 激活对转移前大脑的影响微环境对乳腺癌脑转移的影响。 3）目标3（R00阶段）：研究新型SFK靶向治疗药物的临床前疗效治疗乳腺癌脑转移的方案。该项目的成功将促进我从导师职位的职业转变博士后成为一名有自己研究方向的独立科学家。更多的重要的是，这项研究对乳腺癌脑转移机制的新见解将指导新型临床可转化治疗方案的开发，为临床治疗提供新的机会治疗一种毁灭性的难治性疾病。