Targeting intracellular trafficking for cancer therapy

靶向细胞内运输用于癌症治疗

• 批准号: 10305190
• 负责人: Brendan Tyler Finicle
• 金额: $ 4.24万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305190
• 关键词: Address; Antigen Presentation; Antigen-Presenting Cells; Antisense Oligonucleotides; Base Pairing; Cancer Patient; Cell physiology; Cellular biology; Clinical; Communities; Cytoplasm; Data; Diagnosis; Disease; Drug Delivery Systems; Drug Targeting; Drug resistance; Fellowship; Future; Goals; Grant; Health; Human; Image; Immune checkpoint inhibitor; Immunology; In Vitro; Institution; Knowledge; Lead; Life; Malignant Neoplasms; Manuscripts; Mediating; Mission; Normal Cell; Normal tissue morphology; Nucleotides; Oligonucleotides; Oncogenes; Paper; Patients; Phase; Phosphoric Monoester Hydrolases; Positioning Attribute; Preparation; Proteins; Public Health; Publishing; RNA; RNA Splicing; Reaction; Recycling; Research; Research Personnel; Research Project Grants; Resistance; Resources; Signal Transduction; System; T cell response; T-Lymphocyte; Technical Expertise; Technology; Therapeutic; Therapeutic Uses; Training; Transformed Cell Line; Tumor Immunity; Tumor Tissue; United States National Institutes of Health; Work; Writing; anticancer research; base; cancer immunotherapy; cancer therapy; career; expectation; experience; genetic manipulation; immune checkpoint blockade; in vivo; innovation; intravital imaging; intravital microscopy; neoplastic cell; novel; novel strategies; novel therapeutics; nuclease; patient subsets; pre-doctoral; resistance mechanism; skills; small molecule; trafficking; translational cancer research; tumor; tumor immunology; tumor metabolism; tumor microenvironment; uptake

PROJECT SUMMARY/ABSTRACT My long-term goal is to lead a translational cancer research lab at a major research institution. Throughout my predoctoral work, I have cultivated expertise in studying intracellular trafficking in multiple contexts including cancer metabolism, phosphatase signaling, and nucleotide-based drug delivery. My overall objective in this application is to complete my ongoing studies and then leverage my experience studying endolysosomal trafficking to address critical open questions in cancer immunology during my postdoctoral work. For the F99 phase, I will complete studies evaluating small molecules that target intracellular trafficking as antisense oligonucleotide (ASO) potentiating agents in tumors and normal tissues. ASO are 16-20 bp nuclease-resistant oligonucleotides that base pair with a target RNA and can elicit its degradation or alter its splicing. Therefore, ASO are the ultimate platform technology that could cripple lethal, drug-resistant tumors by targeting “undruggable” oncogenes. Poor uptake into tumor cells currently limits the clinical use of ASO in cancer patients. By bringing a cell biology background to this field, which is populated primarily by biochemists, I have identified 4 novel proteins that when targeted increase ASO activity by an unprecedented 100-fold. For the K00 phase, I will continue to study endolysosomal trafficking, but shift my focus from ASO delivery to resistance mechanisms to cancer immunotherapies. The rationale underlying the proposed training plan is that the critical trafficking steps necessary to deliver ASO to the cytoplasm of tumor cells have also been implicated in anti- tumor immunity. Combining my expertise in intracellular trafficking and technical skills in advanced imaging with deep knowledge gained from working in a cancer immunology lab is likely to produce significant advances in this field. Completing these studies will also allow for me to develop a niche in this highly competitive field that I could expand upon in my own independent research lab. The overall training objective in this application is to develop and cultivate the management, networking, immunology expertise, and writing skills that are necessary to be successful in a postdoctoral fellowship and as an academic PI at a major research institution. The Training Plan addresses these training goals by taking advantage of critical resources provided by UCI and its vibrant, collaborative cancer research community.

项目总结/摘要 我的长期目标是在一家大型研究机构领导一个转化癌症研究实验室。在我的整个 博士前的工作，我培养了在多种情况下研究细胞内贩运的专业知识，包括 癌症代谢、磷酸酶信号传导和基于核苷酸的药物递送。我的总体目标是 申请是为了完成我正在进行的研究，然后利用我的经验研究内溶酶体 在我的博士后工作中，我致力于解决癌症免疫学中的关键开放问题。对于F99 阶段，我将完成评估靶向细胞内转运的小分子作为反义核酸的研究。 在肿瘤和正常组织中的寡核苷酸（阿索）增效剂。阿索对16-20 bp的核酸酶具有抗性 寡核苷酸与靶RNA碱基配对并可引发其降解或改变其剪接。因此，我们认为， 阿索是一种终极平台技术，可以通过靶向治疗致命的耐药肿瘤， “不可治愈的”致癌基因。目前，肿瘤细胞摄取不良限制了阿索在癌症中的临床应用 患者通过将细胞生物学背景引入这个主要由生物化学家组成的领域， 鉴定了4种新的蛋白质，当靶向时，阿索活性增加了前所未有的100倍。对于K 00 阶段，我将继续研究内溶酶体运输，但将重点从阿索递送转移到耐药性 癌症免疫疗法的机制。拟议培训计划的基本理由是， 将阿索递送至肿瘤细胞的细胞质所必需的运输步骤也与抗肿瘤作用有关。 肿瘤免疫结合我在细胞内运输方面的专业知识和先进成像技术 通过在癌症免疫学实验室工作获得的深入知识， 在该领域完成这些研究也将使我在这个竞争激烈的领域发展利基 我可以在我自己的独立研究实验室里进行扩展。 本应用程序的总体培训目标是开发和培养管理，网络， 免疫学专业知识和写作技能是必要的，以成功的博士后奖学金，并作为 一家大型研究机构的学术私家侦探培训计划通过以下方式实现这些培训目标： UCI及其充满活力的合作癌症研究社区提供的关键资源优势。