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

转录抑制因子 Capicua 抑制肺癌转移的治疗拯救

基本信息

批准号：
10328925
负责人：
Ross Okimoto
金额：
$ 17.74万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328925
关键词：
Achievement Award Basic Science Binding California Cancer Etiology Cancer Patient Cessation of life Chest Clinical Clinical Trials Co-Immunoprecipitations Community Physician Data Development Disease Doctor of Philosophy ETV4 gene Ensure Environment Funding Genetic Genetic Transcription Genomics Goals Human Hyperactivity Laboratories Lead Lung Adenocarcinoma MAP Kinase Gene MEKs Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mammalian Cell Mediating Medical Oncologist Mentors Mentorship Microscopy Modeling Molecular Molecular Target Nature Neoplasm Metastasis Nuclear Export Oncogenes Oncogenic Oncologist Operative Surgical Procedures Output Pathway interactions Patient-Focused Outcomes Patients Phosphorylation Phosphorylation Site Physicians Pre-Clinical Model Publications Recurrence Regulation Repression Research Research Personnel Research Support Resources San Francisco Scientist Signal Transduction Site-Directed Mutagenesis Substrate Specificity Techniques Testing Therapeutic Training Transcription Repressor Transcriptional Regulation Translational Research United States National Institutes of Health Universities base cancer cell career development clinical translation efficacy testing experimental study human disease improved outcome in vivo in vivo Model inhibitor innovation loss of function mutation lung cancer cell molecular targeted therapies mouse model novel patient population patient subsets phosphoproteomics pre-clinical preclinical trial prevent protein degradation protein expression small molecule inhibitor targeted treatment tool translational medicine translational research program tumor

项目摘要

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.

项目摘要摘要候选人：医学博士Ross Okimoto是一名医学肿瘤学家，他认为疾病以疾病为基础科学研究可以改善癌症患者的预后。 Okimoto博士的长期目标是领导一个独立的基于实验室的转化研究计划旨在识别和靶向癌症转移的分子基础。凭借自然遗传学和PNA的两份最新作者出版物，Okimoto博士表现出潜力转化癌研究员。该K08应用程序对于他正在进行的职业发展至关重要，为他提供通过关键指导和培训1）癌基因介导的正常和恶性转录调节进展； 2）高级显微镜技术； 3）使用疾病特定的临床前工具来增强治疗建模并实现临床翻译。研究：转移占癌症相关死亡的90％，但抑制癌症传播的能力为由于缺乏概括人类疾病的促临界靶标和鲁棒的临床前模型而受到阻碍。通过 Yokimoto博士的开发是体内矫形肺癌转移模型，最近发现转录 Capicua（CIC）阻遏物抑制肺癌转移。由于候选人发现CIC表达是 ERK激活后减少，他假设ERK抑制可以恢复CIC表达以阻断转移。提出了以下特定目的：1）测试CIC是否是ERK信号的直接物理和功能底物； 2）测试MEK-ERK是否抑制恢复CIC表达以抑制明确定义的原位小鼠模型中的转移。指导和培训：Okimoto博士的培训将通过正式课程和直接完成世界领导人的指导，包括Trever Bivona，医学博士，博士学位，一位具有分子专业知识的胸部肿瘤学家靶向疗法。 Bivona博士获得了NIH的广泛研究支持（NCI资助的R01和DP2董事新的创新者奖），并在过去五年中指导了五名研究员到独立。 Okimoto博士将由转录转移性调节专家Zena Werb，博士学位。 Werb博士是 UCSF终生成就在2015年获得指导奖，认识到她致力于指导年轻的医生 - 科学家独立。除了他的指导委员会外，Okimoto博士还组建了一个单词班团队医师科学家顾问，包括凯文·香农（Kevin Shannon），医学博士（鼠标模型和MAPK信号的专家），安德烈·戈加（Andrei Goga），医学博士，博士（致癌转录控制）和医学博士Neil Shah（临床前/临床治疗）提供指导并确保他成功地过渡到独立的医师科学家。环境：候选人的培训和研究将在加利福尼亚大学旧金山分校进行世界知名的转化医学与研究卓越中心。 Okimoto博士将提供所有在良好的医师社区中完成拟议的实验所需的机构资源和科学家。成功完成拟议的研究将为临床上的使用提供临床前的理由批准的MEK-ERK抑制剂可阻止患者人群中的肺癌转移，而治疗选择很少。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Capicua in Human Cancer.

DOI：
10.1016/j.trecan.2020.08.010
发表时间：
2021-01
期刊：
Trends in cancer
影响因子：
18.4
作者：
Kim JW;Ponce RK;Okimoto RA
通讯作者：
Okimoto RA

Tumor morphology and location associate with immune cell composition in pleomorphic sarcoma.

DOI：
10.1007/s00262-021-02935-2
发表时间：
2021-10
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
0
作者：
Wustrack RL;Shao E;Sheridan J;Zimel M;Cho SJ;Horvai AE;Luong D;Kwek SS;Fong L;Okimoto RA
通讯作者：
Okimoto RA