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）是一种高度侵略性和致命的癌症，对目前可用的疗法。值得注意的是，我们发现PDAC完全容易受到一系列针对RNA剪接的疗法。但是，尚不清楚RNA剪接驱动器PDAC的变化如何肿瘤发生或影响治疗反应。那就是鉴定异常RNA剪接在中的作用 PDAC肿瘤发生可以揭示PDAC的新型治疗靶标。我们的长期目标是确定，设计，并测试了高度侵略性肿瘤（例如PDAC）的新型基于机械的靶向疗法。该建议的主要目的是表征RNA剪接因子突变在PDAC中的作用发病机理和治疗反应。最近，我们确定了最常见的功能驱动器在50％的PDAC（突变KRAS和p53）中发现的突变通过改变的RNA协同和协调剪接。 > 90％的PDAC病例具有突变体KRAS，而突变体p53仅50％。我们在PDAC中进行了数百个带注释的突变之间进行相互排他性分析，并确定了两个突变剪接因子SF3B1和RBM10，与突变的KRAS共发生，但不与突变体共同发生 p53，彼此之间相互排斥。此外，我们使用新的概念验证研究产生的一般工程的小鼠模型，寡疗法和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介导的自适应机制肿瘤性，代表PDAC的治疗靶标。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）确定胰腺中的功能并纠正RNA剪接缺陷癌症和3）评估突变RNA剪接因子对剪接体治疗效率的影响抑制剂和化学治疗剂。我们的预期结果包括识别1） RNA剪接是主要的癌症驾驶事件的基础，2）我们新生成的新型治疗靶标寡疗法或小分子抑制剂，以及3）先前被忽视的癌症的机制通过在共同的机械函数上收敛的多个突变演变。我们将使用创新新生成的一般工程的鼠标模型共表达KRAS和剪接因子突变胰腺导致自动PDAC重新组合患者肿瘤，我们将采用新颖计算和遗传生物技术以识别和纠正RNA剪接缺陷。这些结果将会揭示PDAC发病机理所需的基本但新颖的非突出机制：RNA改变剪接。这将为未来治疗PDAC的方法提供强大的基础，这将极大地影响个性化疗法和患者结果。这项研究与NCI的使命直接保持一致癌症驱动因素的科学知识，以改善患者的生活。