Therapeutic rescue of the transcriptional repressor Capicua to inhibit lung cancer metastasis

项目摘要摘要 候选人：Ross Okimoto医学博士是一位医学肿瘤学家，他相信专注于疾病的基础科学研究可以 改善癌症患者的预后。冈本博士的长期目标是领导一个独立的实验室 旨在识别和定位癌症转移的分子基础的转译研究计划。 冈本博士最近在《自然遗传学》和《美国国家科学院院刊》上发表了两篇第一作者论文，展示了他作为 转化型癌症研究员。这份K08应用程序对他正在进行的职业发展至关重要，为他提供了 1)癌基因介导的正常和恶性转录调控方面的关键指导和培训 进展；2)先进的显微技术；以及3)使用针对疾病的临床前工具来增强 治疗性建模并实现临床翻译。 研究：转移占癌症相关死亡的90%，但抑制癌症扩散的能力 由于缺乏有利于转移的靶点和重述人类疾病的强大的临床前模型而受阻。穿过 建立了体内直视肺癌转移模型，Okimoto博士最近发现转录 抑制因子Capicua(CIC)抑制肺癌转移。因为候选人发现CIC表达式是 在ERK激活后减少，他假设抑制ERK可以恢复CIC的表达，以阻止转移。 具体目标如下：1)测试CIC是否是ERK信号的直接物理和功能底物； 2)检测抑制MEK-ERK是否能恢复CIC的表达，从而抑制小鼠原位肿瘤转移。 指导和培训：Okimoto博士的培训将通过正式的课程和指导下完成 指导世界领导人，包括Trever Bivona，MD，PhD，一位具有分子专业知识的胸部肿瘤学家 有针对性的治疗。比沃纳博士得到了美国国立卫生研究院的广泛研究支持(3 NCI资助的R01‘S和DP2董事 新创新者奖)，并在过去五年中指导了五名研究员实现独立。冈本医生将会是 由转录转移调控专家Zena Werb博士共同指导。沃布博士是该奖项的获奖者 加州大学旧金山分校2015年终身导师成就奖，表彰她对指导年轻医生的奉献- 科学家走向独立。除了他的指导委员会，冈本博士还组建了一个词级团队 医生-科学家顾问包括，Kevin Shannon，MD(小鼠模型和MAPK信号转导方面的专家)，Andrei Goga， 医学博士(致癌转录控制)和Neil Shah，医学博士(临床前/临床治疗学)提供 指导，并确保他成功地转变为一名独立的内科科学家。 环境：候选人的培训和研究将在加州大学旧金山分校进行 世界著名的转化医学和研究中心。Okimoto博士将获得所有 在一个整合良好的医生社区中完成拟议实验所需的机构资源 还有科学家。拟议研究的成功完成将为临床前使用提供理论基础。 批准的MEK-ERK抑制剂在治疗选择很少的患者群体中阻止肺癌转移。

Project Summary Abstract Candidate: Ross Okimoto, MD is a medical oncologist who believes that disease focused basic science research can improve outcomes for patients with cancer. Dr. Okimoto's long-term goal is to lead an independent laboratory-based translational research program aimed at identifying and targeting the molecular underpinnings of cancer metastasis. With two recent first author publications in Nature Genetics and PNAS, Dr. Okimoto has demonstrated potential as a translational cancer researcher. This K08 application will be critical for his ongoing career development, providing him with key mentorship and training in 1) oncogene mediated transcriptional regulation of normal and malignant progression; 2) advanced microscopy techniques; and 3) employing disease specific preclinical tools to enhance therapeutic modeling and enable clinical translation. Research: Metastasis accounts for >90% of cancer related death, yet the ability to inhibit the spread of cancer is hindered by the lack of pro-metastatic targets and robust preclinical models that recapitulate human disease. Through development of an in vivo orthotoptic lung cancer metastasis model, Dr. Okimoto recently found that the transcriptional repressor, Capicua (CIC), suppresses lung cancer metastasis. Since the candidate found that CIC expression is decreased upon ERK activation, he hypothesizes that ERK inhibition can restore CIC expression to block metastasis. The following specific aims are proposed: 1) to test if CIC is a direct physical and functional substrate of ERK signaling; 2) to test if MEK-ERK inhibition restores CIC expression to inhibit metastasis in a well-defined orthotopic mouse model. Mentorship and Training: Dr. Okimoto's training will be accomplished through formal coursework and under direct mentorship of world leaders including Trever Bivona, MD, PhD, a thoracic oncologist with expertise in molecular targeted therapies. Dr. Bivona has extensive research support from the NIH (3 NCI-funded R01's and the DP2 Directors New Innovator's Award), and has mentored five fellows to independence within the past five years. Dr. Okimoto will be co-mentored by Zena Werb, PhD, an expert in transcriptional metastatic regulation. Dr. Werb was the recipient of the UCSF Lifetime Achievement in Mentoring Award in 2015, recognizing her devotion to mentoring young physician- scientist to independence. In addition to his mentorship committee, Dr. Okimoto has assembled a word class team of physician-scientist advisors including, Kevin Shannon, MD (expert in mouse models and MAPK signaling), Andrei Goga, MD, PhD (oncogenic transcriptional control), and Neil Shah, MD, PhD (preclinical/clinical therapeutics) to provide guidance and to ensure he succeeds in transitioning into an independent physician-scientist. Environment: The candidate's training and research will be performed at the University of California, San Francisco, a world-renowned center of excellence in translational medicine and research. Dr. Okimoto will be provided with all the institutional resources necessary to complete the proposed experiments in a well-integrated community of physicians and scientists. Successful completion of the proposed research will provide preclinical rationale to use clinically approved MEK-ERK inhibitors to block lung cancer metastasis in a patient population with few therapeutic options.