Therapeutic targeting of RTK protein granules in cancer

RTK 蛋白颗粒在癌症中的治疗靶向

• 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
• 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

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 候选人：Asmin Tulpule，医学博士，博士，是一名儿科肿瘤学家和内科医生，其长期目标是 领导一个独立的基于实验室的研究项目，研究基础生物学和治疗 在癌症中靶向融合癌蛋白。他最近在Cell上发表的第一作者论文， 在《自然医学》、《自然遗传学》、《细胞报告》和第一作者论文中的作者身份 研究生工作在细胞干细胞和血液，证明了他作为一个癌症研究人员的潜力。K08 申请对他的持续职业发展至关重要，为他提供关键的指导和培训， 1)人类癌症的小鼠模型和临床前药物测试，2）研究的显微镜技术 生物分子浓缩物，以及3）RTK和RAS/RAF生物学培训。 研究：对标准治疗酪氨酸激酶抑制剂（TKI）治疗的耐药性对大多数人来说是不可避免的。 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。 博士Tulpule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，局部协调RAS激活，对肿瘤发生至关重要。这个目标 一项建议是开发针对独特致癌信号传导的机制性治疗方法， 这种癌症特异性生物分子凝聚物的性质。建议的具体目标如下：（1） 在异种移植模型中测试SHP 2抑制剂作为新的RTK蛋白颗粒导向的治疗策略，以及2） 确定无膜RTK蛋白颗粒如何激活RAF激酶。 导师和培训：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频繁会议。 Asmin的主要导师是Trever Bivona，MD，PhD，一位胸肿瘤学家，擅长分子靶向治疗。 治疗和RAS生物学。Bivona博士已经指导了四名博士后研究员在 在过去的五年里，并得到了NIH的广泛研究支持（4个由NCI-Funded R 01）。图普尔博士 为他的咨询委员会组建了一个由医生和科学家组成的庞大团队， Alejandro Sweet-Cordero，MD（儿科肿瘤学家和异种移植模型专家），Bo Huang，PhD（专家 Kevin Shannon，MD（RAS生物学和小鼠模型专家），以及 William韦斯，医学博士，哲学博士（癌症信号专家）。该咨询委员会在以下方面有着重要的业绩记录： 指导受训人员独立，并将提供必要的科学和指导支持。 环境图普尔博士的培训和研究将发生在加州大学弗朗西斯科分校，一个世界- 著名的生物医学研究中心，获得NIH近7亿美元的支持（排名第三）。 所有机构）。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， 这两个组织都有长期支持医学科学家调查的记录。