Understanding and targeting mutant splicing factors in pancreatic cancer

了解和靶向胰腺癌中的突变剪接因子

基本信息

批准号：
10708159
负责人：
Luisa Escobar Hoyos
金额：
$ 39.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708159
关键词：
Animal Model Automobile Driving Biotechnology Cancer Patient Cell Line Cell Proliferation Cell Survival Cells Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Defect Development Disease Resistance Event Frequencies Future Genetic Genetic Transcription Genetically Engineered Mouse Genomics Genotype Goals Histologic In Vitro KRAS oncogenesis KRAS2 gene Knowledge Lead Link Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Messenger RNA Methods Mission Modality Modeling Molecular Monitor Mus Mutation Oligonucleotides Oncogenic Oncoproteins Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacogenomics Phenocopy Play Pre-Clinical Model Precision therapeutics Predisposition Protein Isoforms Public Health RNA Splicing Research Resistance Role Sampling Scientific Advances and Accomplishments Signal Transduction Spliceosomes Study models TP53 gene Testing Therapeutic Therapeutically Targetable Treatment Efficacy Tumorigenicity Work chemotherapeutic agent clinical investigation design driver mutation drug sensitivity gain of function gain of function mutation improved in vivo inhibitor innovation loss of function molecular subtypes mouse model mutant new therapeutic target novel novel therapeutics pancreatic cancer patients pancreatic ductal adenocarcinoma cell personalized medicine refractory cancer response screening small molecule small molecule inhibitor synergism targeted treatment therapeutic target therapy development therapy outcome therapy resistant transcriptome transcriptome sequencing treatment response tumor tumor growth tumorigenesis tumorigenic ultrasound

项目摘要

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal cancer that is resistant to currently available therapies. Notably, we discovered that PDACs are exquisitely susceptible to a range of therapies directed at RNA splicing. However, it is unknown how alterations in RNA splicing drive PDAC tumorigenesis or impact therapeutic responses. Thus, identification of the role of aberrant RNA splicing in PDAC tumorigenesis could reveal novel therapeutic targets for PDAC. Our long-term goal is to identify, design, and test novel mechanistic-based targeted therapies for highly aggressive tumors such as PDAC. The main objective of this proposal is to characterize the role of RNA splicing factor mutations in PDAC pathogenesis and treatment response. Recently, we identified that the most common gain-of-function driver mutations found in 50% of PDACs (mutant KRAS and p53) synergize and cooperate through altered RNA splicing. While >90% of PDAC cases harbor mutant KRAS, only 50% co-occur with mutant p53. We performed mutual exclusivity analysis among hundreds of annotated mutations in PDACs and identified two mutant splicing factors, SF3B1 and RBM10, that co-occur with mutant KRAS but do not co-occur with mutant p53 and are mutually exclusive between each other. Additionally, our proof-of-concept studies using newly generated genetically engineered mouse models, oligo-therapy and RNA splicing inhibitors demonstrated that RNA splicing is a therapeutic target. Our central hypothesis is that persistent RNA splicing defects, downstream of SF3B1 and RBM10 mutations, are a required adaptive mechanism for KRAS-mediated tumorigenicity and represent a therapeutic target for PDAC. We aim to 1) determine the role of aberrant RNA splicing in PDAC tumorigenesis, 2) identify the function and correct RNA splicing defects in pancreatic cancer, and 3) evaluate the impact of mutant RNA splicing factors on the therapeutic efficacy of spliceosome inhibitors and chemotherapeutic agents. Our expected outcomes include identification of 1) how aberrant RNA splicing underlies major cancer-driving events, 2) novel therapeutic targets for our newly generated oligo-therapy or small molecule inhibitors, and 3) a previously overlooked mechanism for how cancer can evolve through multiple mutations converging at a common mechanistic function. We will use innovative newly generated genetically engineered mouse models co-expressing KRAS and splicing-factor mutations in the pancreas leading to autochthonous PDAC resembling patient tumors, and we will employ novel computational and genetic biotechnologies to identify and correct RNA splicing defects. These results will uncover a fundamental, yet novel non-mutational mechanism required for PDAC pathogenesis: altered RNA splicing. This will provide a strong basis for future approaches to treat PDAC, which would significantly impact personalized therapies and patient outcomes. This research directly aligns with NCI’s mission to advance scientific knowledge of drivers and targets of cancer to improve patient’s lives.

胰腺导管腺癌 (PDAC) 是一种高度侵袭性和致命性的癌症，对值得注意的是，我们发现 PDAC 对一系列药物非常敏感。针对 RNA 剪接的疗法然而，RNA 剪接的改变如何驱动 PDAC 尚不清楚。肿瘤发生或影响治疗反应因此，鉴定异常RNA剪接在其中的作用。 PDAC 肿瘤发生可以揭示 PDAC 的新治疗靶点。设计和测试针对高度侵袭性肿瘤（例如 PDAC）的新型基于机制的靶向疗法。该提案的主要目的是表征 RNA 剪接因子突变在 PDAC 中的作用最近，我们发现了最常见的功能获得驱动因素。 50% 的 PDAC 中发现的突变（突变型 KRAS 和 p53）通过改变 RNA 协同作用虽然 >90% 的 PDAC 病例携带突变型 KRAS，但只有 50% 的病例与突变型 p53 共存。对 PDAC 中数百个带注释的突变进行相互排他性分析，并确定了两个突变剪接因子 SF3B1 和 RBM10，与突变 KRAS 共同出现，但不与突变突变同时出现 p53 和彼此之间是相互排斥的，我们使用新的概念验证研究。基因工程小鼠模型、寡核苷酸疗法和 RNA 剪接抑制剂表明 RNA 剪接是一个治疗靶标，我们的中心假设是持续的 RNA 剪接缺陷， SF3B1 和 RBM10 突变的下游，是 KRAS 介导的必需的适应机制致瘤性并代表 PDAC 的治疗靶点我们的目标是 1) 确定异常 RNA 的作用。 PDAC肿瘤发生中的剪接，2）鉴定胰腺中的功能并纠正RNA剪接缺陷癌症，3）评估突变RNA剪接因子对剪接体治疗效果的影响我们的预期结果包括确定 1) 异常程度。 RNA 剪接是主要癌症驱动事件的基础，2）我们新产生的治疗新靶标寡核苷酸疗法或小分子抑制剂，以及 3) 以前被忽视的癌症机制通过多种突变汇聚到一个共同的机械功能中来进化我们将使用创新。新生成的基因工程小鼠模型共表达 KRAS 和剪接因子突变胰腺导致类似于患者肿瘤的本土 PDAC，我们将采用新颖的计算和遗传生物技术来识别和纠正 RNA 剪接缺陷。揭示 PDAC 发病机制所需的一个基本但新颖的非突变机制：RNA 改变这将为未来治疗 PDAC 的方法提供坚实的基础，这将产生重大影响。这项研究与 NCI 推动进步的使命直接相关。关于癌症驱动因素和目标的科学知识，以改善患者的生活。