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

• 批准号: 8711359
• 负责人: Siyuan Zhang
• 金额: $ 23.15万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 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/8711359
• 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 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

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.

项目摘要/摘要 剖析Src家族蛋白在乳腺癌脑转移中的作用 张思源，医学博士，德克萨斯大学安德森癌症中心医学博士 我于1998年在北京大学卫生科学中心获得医学博士学位，并于 2005年，新加坡国立大学癌症生物学专业毕业。我的博士训练主要集中在 破译菊内酯抗癌活性的分子机制 天然产品中的成分小黄花。在我发表的9篇论文中，有7篇是第一作者 博士生培训。我加入了德州大学医学博士安德森癌症研究小组 (MDACC)，以追求我的目标，即发现临床影响。我的研究阐明了一个 曲妥珠单抗耐药的关键机制及其临床可翻译新药的开发 曲妥珠单抗耐药患者的联合治疗方案。同时，我也在调查 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 乳腺癌脑转移的基因改变和确立我作为一个独立的 研究人员通过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，重点研究肿瘤转移的机制 转移前微环境；以及(2)基于基础研究结果的翻译研究 识别、设计和临床前测试治疗癌症转移的新的治疗方案。至 实现我的短期和长期职业目标，在K99指导阶段的这笔赠款，我将 在无与伦比的癌症研究培训环境中接受全面培训- MDAC.我将与我的导师合作，并积极参加正式的课程、研讨会和 研讨会拓宽了我的知识和技能，特别是在转基因小鼠模型方面。 科学写作、研究道德、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过渡。 我的研究计划集中在src家族激酶(Sfk)在乳腺癌脑中的作用。 转移。在全世界每年被诊断患有乳腺癌的130万女性中，约有10- 16%的人会发生脑转移。即使在最先进的临床护理下，大脑的总体存活率 转移患者距离确诊时间不到14个月。目前尚无有效的治疗方法。 难治性转移性乳腺癌脑转移患者。因此，新颖而有效 这一人群迫切需要治疗方法。不幸的是，开发出有效的 脑转移瘤的治疗在很大程度上受到缺乏对脑转移瘤的深入了解的阻碍 脑转移的基本机制。我们的初步研究表明，Src家族激酶c-Src 在转移的肿瘤细胞和脑转移微环境中都起着重要的作用。这个 拟议项目的主要目标是使用创新的方法剖析src家庭的作用。 蛋白激酶在脑转移过程中的作用及乳腺癌脑转移新疗法的开发 病人。我们提出三个全面的目标： 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激活在脑转移前的影响 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靶向治疗的临床前疗效 化疗方案在治疗乳腺癌脑转移中的作用。 该项目的成功将促进我从被指导的职位过渡到职业生涯 博士后成为一名有自己研究方向的独立科学家。更多 重要的是，这项研究对乳腺癌脑转移机制的新见解将 指导新的临床可翻译方案的开发，为 治疗一种极难治愈的疾病。