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.

项目摘要摘要候选人：医学博士Asmin Tulpule是一位儿科肿瘤学家和身体科学家，其长期目标是领导一个基于实验室的独立研究计划，研究基本生物学和治疗靶向癌症中的融合癌蛋白。他最近在牢房中的第一部作者和贡献关于自然医学出版物，自然遗传学，细胞报告和第一作者论文的作者细胞干细胞和血液中的研究生工作表明了他作为癌症研究人员的潜力。这个K08 申请对于他正在进行的职业发展至关重要。 1）人类癌症和临床前药物测试的小鼠建模，2）研究的显微镜技术生物分子冷凝物和3）在RTK和RAS/RAF生物学中进行培训。研究：对大多数人的抗药性酪氨酸激酶抑制剂（TKI）疗法是不可避免的 RTK融合驱动的肺和其他晚期癌症患者仍然是死亡率的主要原因。 Tulpulle博士最近发现，多种RTK融合癌蛋白会自组装到无膜细胞质中 RTK蛋白颗粒局部协调RAS激活，对肿瘤起源至关重要。目标的目标提案是开发机械知情的疗法，以靶向独特的致癌信号传导该癌症特异性生物分子冷凝物的特性。提出了以下特定目标：1）在Xenograpony模型中测试SHP2抑制剂作为一种新的RTK蛋白颗粒定向的治疗策略，而2）确定无膜RTK蛋白颗粒如何激活RAF激酶。指导和培训：Tulpule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咨询委员会的经常会议。 Asmin的主要心理是MD，PhD Trever Bivona，是一位具有分子靶向专业知识的胸部肿瘤学家疗法和RAS生物学。 Bivona博士已将四名博士后研究员介绍给独立过去五年，NIH获得了广泛的研究支持（NCI资助的R01）。 Tulpulle博士拥有为他的咨询委员会组成了一支巨大的身体科学家团队 Alejandro Sweet-Cordero，医学博士（儿科肿瘤学家和特征建模专家），博士（专家在高分辨率成像技术中），医学博士凯文·香农（RAS生物学和小鼠模型的专家），以及医学博士William Weiss（癌症信号专家）。该咨询委员会拥有大量的轨道记录指导学员独立，并将提供必要的科学和心理支持。环境。 Tulpule博士的培训和研究将在加利福尼亚大学，旧金山分校，世界 - 著名的生物医学研究中心，拥有近7亿美元的NIH支持（排名第三所有机构）。他得到了儿科肿瘤学和UCSF癌症中心的全部支持，两者都有支持身体科学研究者的长期记录。