Therapeutic targeting of RTK protein granules in cancer

项目摘要摘要 候选人：Asmin TulPule，医学博士，儿科肿瘤学家和内科科学家，其长期目标是 领导一个独立的实验室研究项目，研究基础生物学和治疗学 肿瘤中融合癌蛋白的靶向性研究。他最近在《细胞》杂志上发表了第一作者论文，并贡献了 发表于《自然医学》、《自然遗传学》、《细胞报告》及第一作者论文 在细胞、干细胞和血液方面的研究生工作证明了他作为癌症研究人员的潜力。这个K08 应用程序对他持续的职业发展至关重要，因为它为他提供了关键的指导和培训 1)人类癌症的小鼠模型和临床前药物试验；2)显微技术研究 生物分子缩合物，以及3)RTK和RAS/RAF生物学方面的培训。 研究：对标准护理酪氨酸激酶抑制剂(TKI)治疗的抵抗对大多数人来说是不可避免的 患有RTK融合驱动的肺癌和其他晚期癌症的患者，仍然是死亡的主要原因。 TulPule博士最近发现，多个RTK融合癌蛋白可以自我组装成无膜细胞质 局部协调RAS激活的RTK蛋白颗粒，对肿瘤的发生至关重要。这样做的目的是 建议开发针对独特致癌信号的机械信息疗法 这种癌症特异性生物分子凝聚物的性质。提出了以下具体目标：1) 在异种移植模型中测试SHP2抑制剂作为一种新的RTK蛋白颗粒导向治疗策略，以及2) 确定无膜RTK蛋白颗粒如何激活RAF激酶。 指导和培训：TulPule博士的培训将通过直接教授实验室来完成 技术，正式的课程，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医学博士，他是一位在分子靶向方面有专长的胸部肿瘤学家 疗法和RAS生物学。比沃纳博士已经指导了四名博士后研究员在 在过去的五年里，他得到了美国国立卫生研究院的广泛研究支持(4名美国国立卫生研究院资助的R01‘S)。塔普雷博士已经 为他的咨询委员会组建了一个庞大的内科科学家团队，包括共同导师 Alejandro Sweet-Cordero医学博士(儿科肿瘤学家和异种移植模型专家)，黄波博士(专家 高分辨率成像技术)、医学博士Kevin Shannon(RAS生物学和小鼠模型专家)以及 William Weiss，医学博士，博士(癌症信号专家)。这个咨询委员会有一个重要的记录， 指导受训人员走向独立，并将提供必要的科学和指导支持。 环境TulPule博士的培训和研究将在加州大学旧金山分校进行，这是一个- 著名的生物医学研究中心，得到了美国国立卫生研究院近7亿美元的支持(在 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， 这两家公司都有支持医生-科学家调查人员的长期记录。

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.