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

• 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
• 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

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 候选人：Ross Okimoto医学博士是一位医学肿瘤学家，他认为以疾病为重点的基础科学研究可以 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实验室， 转化研究计划旨在识别和靶向癌症转移的分子基础。 最近在Nature Genetics和PNAS上发表了两篇第一作者的论文，Okimoto博士已经证明了作为一个 转译癌症研究员K 08申请对他的职业发展至关重要， 在1）癌基因介导的正常和恶性肿瘤的转录调控方面有重要的指导和培训 进展; 2）先进的显微镜技术;和3）采用疾病特异性临床前工具，以增强 治疗建模并实现临床翻译。 研究：转移占癌症相关死亡的90%以上，但抑制癌症扩散的能力 由于缺乏促转移靶点和重现人类疾病的强大临床前模型而受阻。通过 Okimoto博士最近发现，在体内直视肺癌转移模型的开发中， 抑制子Capicua（CIC）抑制肺癌转移。由于候选人发现CIC表达是 他推测ERK抑制可以恢复CIC表达以阻断转移。 本研究的具体目的是：1）验证CIC是否是ERK信号转导的直接物理和功能底物; 2)以测试MEK-ERK抑制是否恢复CIC表达以在明确的原位小鼠模型中抑制转移。 指导和培训：Okimoto博士的培训将通过正式的课程和直接指导下完成。 指导世界领导人，包括Trever Bivona，医学博士，博士，胸部肿瘤学家与分子生物学专业知识 靶向治疗。Bivona博士得到了NIH的广泛研究支持（3个由NCI资助的R 01和DP 2主任 新创新者奖），并在过去五年内指导五名研究员独立。冲本医生将在 由Zena Werb博士共同指导，Zena Werb博士是转录转移调节专家。Werb博士是 2015年UCSF终身成就导师奖，表彰她对指导年轻医生的奉献精神- 科学家独立除了他的指导委员会，Okimoto博士还组建了一个单词班团队， 医生-科学家顾问，包括Kevin Shannon，MD（小鼠模型和MAPK信号传导专家），Andrei Goga， MD，PhD（致癌转录控制）和Neil Shah，MD，PhD（临床前/临床治疗学）提供 指导，并确保他成功地过渡到一个独立的医生，科学家。 环境：候选人的培训和研究将在加州大学弗朗西斯科分校进行， 世界著名的转化医学和研究卓越中心。冲本博士将被提供所有 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 和科学家。成功完成拟定研究将为临床使用提供临床前依据 已批准的MEK-ERK抑制剂在治疗选择很少的患者群体中阻断肺癌转移。

项目成果

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
• 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