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

项目总结/摘要 标题：剖析Src家族激酶在乳腺癌脑转移中的作用 主要研究者：张思远，医学博士，哲学博士、德克萨斯大学安德森癌症中心 我拿到了医学博士学位。1998年毕业于北京大学医学部，获博士学位。学位 2005年新加坡国立大学癌症生物学。我的博士培训的重点是 破解parthenetrin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。我是第一作者，在我发表的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的Dihua Yu博士的团队。安德森癌症 （MDACC）在2007年追求我的目标，使临床影响的发现。我的研究阐明了 曲妥珠单抗耐药的关键机制，并导致开发了一种新的临床可翻译的 用于曲妥珠单抗耐药患者的组合方案。同时，我也在研究 乳腺癌脑转移中的PTEN缺失我目前的研究目标是研究某些 乳腺癌脑转移的基因改变，并建立自己作为一个独立的 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，研究转移的机制，重点关注肿瘤转移的贡献。 转移前微环境;（2）转化研究，基于基础研究结果， 鉴定、设计和临床前测试用于治疗癌症转移新治疗方案。到 为了实现我的短期和长期职业目标，在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。我将与我的导师合作，积极参加正式的课程，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。 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 这些技能将进一步促进我作为一名独立科学家的转变。 我的研究计划是集中在Src家族激酶（SFK）在乳腺癌脑中的作用 转移在全球每年130万被诊断患有乳腺癌的女性中，约有10- 16%会发展成脑转移。即使有最先进的临床护理， 转移患者从诊断开始不到14个月。目前还没有有效的治疗方法， 难治性转移性乳腺癌脑转移患者。因此，新颖有效 迫切需要针对这一人群的治疗方法。不幸的是，发展有效的 脑转移的治疗在很大程度上受到缺乏对脑转移的深入了解的阻碍。 脑转移的基本机制。我们的初步研究表明Src家族激酶c-Src 在转移性肿瘤细胞和脑转移微环境中起重要作用。的 该项目的主要目标是使用创新的方法来剖析Src家族的作用 激酶在脑转移过程中的作用，并开发乳腺癌脑转移的新疗法 患者我们提出三个全面目标： 1)目的1（K99期）：确定肿瘤SFK激活在乳腺癌脑中的作用 转移 2)目的2（R 00阶段）：确定SFK激活对脑转移前 微环境对乳腺癌脑转移的影响 3)目的3（R 00期）：研究新型SFK靶向治疗药物的临床前疗效 乳腺癌脑转移的治疗方案。 该项目的成功将促进我的职业转型，从我的位置作为一个导师 博士后，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，为患者提供新的机会。 一种难以治愈的疾病的治疗。

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.