Therapeutic targeting of RTK protein granules in cancer

RTK 蛋白颗粒在癌症中的治疗靶向

基本信息

批准号：
10591331
负责人：
Asmin Tulpule
金额：
$ 24.85万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591331
关键词：
Address Adult Advanced Malignant Neoplasm Advisory Committees Authorship Binding Biology Biomedical Research Blood CCDC6 gene California Cancer Center Cancer Etiology Cancer cell line Cell Line Cell Nucleus Cell Survival Cells Chest Clinical Complex Cytoplasmic Granules Cytoplasmic Protein Cytoplasmic Receptors Data Dimerization Disease Progression Doctor of Philosophy Environment Extracellular Domain Funding Fusion Oncogene Proteins Gene Rearrangement Genetic Goals Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Homodimerization Human Imaging Techniques Individual Institution Laboratories Lead Lung MEKs Malignant Childhood Neoplasm Malignant Neoplasms Mammalian Cell Mediating Medicine Membrane Membrane Lipids Mentors Mentorship Microscopy Mitogens Modeling Molecular Nature Nucleotides Oncogenes Oncogenic Oncologist Oncoproteins Output PTPN11 gene Paper Pathogenicity Patients Pediatric Oncologist Pediatric Oncology Phosphorylation Phosphotransferases Physical condensation Physicians Postdoctoral Fellow Proliferating Property Protein Isoforms Protein Kinase Proteins Publications Ras/Raf Receptor Protein-Tyrosine Kinases Reporting Research Research Personnel Research Support Resistance Role San Francisco Scientist Signal Transduction Specificity Structure Subcellular structure Techniques Testing Therapeutic Training Transfection Transmembrane Domain Tyrosine Kinase Inhibitor United States National Institutes of Health Universities Work Xenograft Model anaplastic lymphoma kinase cancer cell career development disorder control drug development drug testing growth factor receptor-bound protein 2 high resolution imaging human cancer mouse model inhibitor inhibitor therapy meetings membrane model molecular targeted therapies mortality mouse model mutant patient derived xenograft model pre-clinical programs raf Kinases recruit self assembly standard of care stem cells symposium targeted treatment teaching laboratory therapeutic evaluation therapeutic target tumor tumor xenograft tumorigenesis

项目摘要

Project Summary Abstract Candidate: Asmin Tulpule, MD, PhD, is a pediatric oncologist and physician-scientist whose long-term goal is to lead an independent laboratory-based research program studying the basic biology and therapeutic targeting of fusion oncoproteins in cancer. His recent first-author paper in Cell, as well as contributing authorship on publications in Nature Medicine, Nature Genetics, Cell Reports and first-author papers from his graduate work in Cell Stem Cell and Blood, demonstrate his potential as a cancer researcher. This K08 application is crucial for his ongoing career development by providing him with key mentorship and training in 1) Mouse modeling of human cancer and pre-clinical drug testing, 2) Microscopy techniques to study Biomolecular Condensates, and 3) Training in RTK and RAS/RAF biology. Research: Resistance to standard of care tyrosine kinase inhibitor (TKI) therapy is inevitable for the majority of patients with RTK fusion-driven lung and other advanced cancers and remains the major cause of mortality. Dr. Tulpule recently found that multiple RTK fusion oncoproteins self-assemble into membraneless cytoplasmic RTK protein granules that locally coordinate RAS activation and are critical for oncogenesis. The goal of this proposal is to develop mechanistically informed therapeutics that target the unique oncogenic signaling properties of this cancer-specific biomolecular condensate. The following specific aims are proposed: 1) To test SHP2 inhibitors in xenograft models as a new RTK protein granule-directed therapeutic strategy, and 2) To determine how membraneless RTK protein granules activate RAF kinases. Mentorship and Training: Dr. Tulpule’s training will be accomplished through direct teaching of laboratory techniques, formal coursework, academic conferences, and frequent meetings with his Advisory Committee. Asmin's primary mentor is Trever Bivona, MD, PhD, a thoracic oncologist with expertise in molecularly targeted therapies and RAS biology. Dr. Bivona has mentored four post-doctoral fellows to independence within the past five years and has extensive research support from the NIH (4 NCI-funded R01’s). Dr. Tulpule has assembled a tremendous team of physician-scientists for his Advisory Committee including co-mentor Alejandro Sweet-Cordero, MD (pediatric oncologist and expert in xenograft modeling), Bo Huang, PhD (expert in high-resolution imaging techniques), Kevin Shannon, MD (expert in RAS biology and mouse models), and William Weiss, MD, PhD (expert in cancer signaling). This Advisory committee has a significant track-record of mentoring trainees to independence and will provide the necessary scientific and mentoring support. Environment. Dr. Tulpule's training and research will occur at University of California, San Francisco, a world- renowned center of biomedical research with almost $700 million in support from the NIH (ranking 3rd among all institutions). He has the full support of the Division of Pediatric Oncology and the UCSF Cancer Center, both of which have a long-track record of supporting physician-scientist investigators.

项目概要摘要候选人：Asmin Tulpule，医学博士、哲学博士，是一名儿科肿瘤学家和医师科学家，其长期目标是领导一个基于实验室的独立研究项目，研究基础生物学和治疗学他最近在《细胞》杂志上发表了一篇第一作者论文，并做出了贡献。在《自然医学》、《自然遗传学》、《细胞报告》等杂志上发表的论文以及他的第一作者论文细胞干细胞和血液领域的研究生工作，展示了他作为癌症研究员的潜力。应用程序为他提供了关键的指导和培训，这对他持续的职业发展至关重要 1) 人类癌症的小鼠模型和临床前药物测试，2) 用于研究的显微镜技术生物分子凝聚体，以及 3) RTK 和 RAS/RAF 生物学培训。研究：对大多数患者来说，对标准护理酪氨酸激酶抑制剂 (TKI) 治疗产生耐药性是不可避免的 RTK 融合驱动的肺癌和其他晚期癌症患者仍然是死亡的主要原因。 Tulpule博士最近发现多种RTK融合癌蛋白自组装成无膜细胞质 RTK 蛋白颗粒可局部协调 RAS 激活，对肿瘤发生至关重要。建议开发针对独特致癌信号的机械通知疗法这种癌症特异性生物分子凝聚物的特性提出了以下具体目标：1）在异种移植模型中测试 SHP2 抑制剂作为新的 RTK 蛋白颗粒定向治疗策略，以及 2) 确定无膜 RTK 蛋白颗粒如何激活 RAF 激酶。指导和培训：Tupule 博士的培训将通过实验室的直接教学来完成技术、正式课程、学术会议以及与他的顾问委员会的频繁会议。 Asmin 的主要导师是 Trever Bivona，医学博士、哲学博士，他是一位胸腔肿瘤学家，在分子靶向治疗方面拥有专业知识 Bivona 博士指导了四名博士后研究员在该领域取得独立。 Tupule 博士在过去五年中获得了 NIH 的广泛研究支持（4 项 NCI 资助的 R01）。为他的咨询委员会组建了一支由医师科学家组成的庞大团队，其中包括共同导师 Alejandro Sweet-Cordero，医学博士（儿科肿瘤学家和异种移植建模专家），Bo Huang，博士（专家高分辨率成像技术），Kevin Shannon，医学博士（RAS 生物学和小鼠模型专家），以及 William Weiss，医学博士、博士（癌症信号传导专家）。指导学员独立，并将提供必要的科学和指导支持。 Tupule 博士的培训和研究将在旧金山加利福尼亚大学进行，这是一所世界级的大学。著名的生物医学研究中心，获得 NIH 近 7 亿美元的支持（在美国排名第三）他得到了儿科肿瘤科和加州大学旧金山分校癌症中心的全力支持，两者都有支持医师科学家研究人员的长期记录。