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

描述（由申请人提供）：我获得了医学博士学位。1998年毕业于北京大学医学部，获博士学位。2005年获得新加坡国立大学癌症生物学学位。我的博士培训的重点是破译小白菊抗癌活性的分子机制-小白菊是天然产品小白菊的一种活性成分。我在博士期间发表的9篇论文中有7篇是第一作者。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曲妥珠单抗耐药患者组合方案。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遗传改变在乳腺癌脑转移中的作用，并通过K99基金建立自己作为独立研究人员的地位。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机制;和（2）转化研究，基于基础研究结果来识别、设计和临床前测试治疗癌症转移的新型治疗方案。为了实现我的短期和长期职业目标，在K99指导阶段，我将在一个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，工作坊和研讨会，以扩大我的知识和技能，特别是在基因工程小鼠模型。在科学写作，研究伦理，实验室管理和领导技能的职业发展培训将进一步促进我作为一个独立的科学家过渡。 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。在全世界每年130万被诊断患有乳腺癌的女性中，约10 - 16%会发生脑转移。即使有最先进的临床护理，脑转移患者的总生存期也不到14个月。目前，对于难治性转移性乳腺癌脑转移的患者没有有效的治疗方法。因此，迫切需要新的和有效的治疗方法，这一人群。不幸的是，开发有效的治疗脑转移的药物在很大程度上受到缺乏对脑转移的基本机制的深入了解的阻碍。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。我们提出三个全面目标： 1)目的1（K99期）：探讨肿瘤SFK激活在乳腺癌脑转移中的作用。 2)目的2（R00阶段）：确定脑转移前微环境中SFK活化对乳腺癌脑转移的影响。 3)目的3（R00期）：研究新型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我作为一个指导博士后研究员的位置，成为一个独立的科学家与我自己的研究方向。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新的临床可翻译方案的开发，为治疗难治性疾病提供新的机会。 公共卫生相关性：对于乳腺癌患者，难治性乳腺癌脑转移患者没有有效的治疗方法。使用创新的方法，拟议的项目旨在通过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，我们将设计并进行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。

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.