Harnessing hotspot specific differences among SF3B1 mutations to define novel mechanisms of tumorigenicity and targetability in solid malignancies

利用 SF3B1 突变之间的热点特异性差异来定义实体恶性肿瘤的致瘤性和靶向性的新机制

基本信息

批准号：
10747548
负责人：
Riley Bergman
金额：
$ 3.29万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

项目摘要

PROJECT SUMMARY SF3B1 is the most commonly mutated splicing factor in cancer, occurring in thousands of cancer patients annually. Mutations in SF3B1 result in a neomorphic protein that causes aberrant splicing of hundreds of transcripts, including known cancer associated genes. While the mechanisms by which these alterations promote tumorigenesis are incompletely understood, our lab has previously shown SF3B1 mutations are attractive therapeutic targets. SF3B1 mutations are prevalent in many cancers (breast, melanoma, bladder, pancreatic, leukemias), so improving our ability to target these mutations could have major public health implications. To do this, there is a fundamental need to better understand how SF3B1 mutations drive tumorigenesis. Recent work in acute myeloid leukemia shows differences in missplicing, oncogenic effects and prognosis among various SF3B1 hotspot mutations, yet there are no studies to date investigating these in solid malignancies. To determine potential therapeutic strategies, novel model systems are required. An innovative genome editing approach will allow us to study the mutations at the most common hotspots from breast cancer and melanoma, K700 and R625, respectively in several representative cell line models. Changes in the transcriptome and phenotypic differences in proliferation, migration, and invasion will determine whether there are specific alterations in SF3B1 that lead to distinct oncogenic phenotypes. Additionally, preliminary systematic analysis of online cancer databases shows SF3B1 mutations and TP53 alterations are mutually exclusive in cancer. This often suggests either synthetic lethality or a lack of selection for co-occurrence due to shared roles in tumorigenesis. Successful generation of dual SF3B1 mutant and TP53 mutant or TP53 knock out cell lines demonstrates that the mutations are unlikely to be synthetic lethal. Instead, this relationship likely demonstrates a shared role and will allow us to determine novel mechanisms of SF3B1-mediated tumorigenesis. Previous findings in SF3B1 mutants demonstrate dysfunctional cellular respiration due to missplicing and degradation of a UQCC1, a component of mitochondrial complex III. There is a resultant increase in glucose, similar to p53’s well known role in promoting the Warburg effect. Further studying the relationship between mutant SF3B1 and TP53 may identify therapeutic vulnerabilities that can be additionally leveraged against the large subset of cancers with TP53 mutations. The sponsor’s robust history of utilizing genome editing strategies to study individual mutations in breast cancer in conjunction with the abundant resources and core facilities at Vanderbilt University make these Aims achievable. Completion of these aims provide an excellent foundation in cancer molecular genetics. This will allow the PI to acquire the technical skills to build toward an independent investigational career in oncology, specifically studying novel pathologic features of cancers that lead to uniquely targetable vulnerabilities.

项目摘要 SF3B1是癌症中最常见的突变剪接因子，发生在数千名癌症患者中 SF3B1中的突变导致新形态蛋白，导致数百个拼接转录本，包括已知的癌症相关基因。而这些改变促进的机制肿瘤发生尚不完全了解，我们的实验室以前已经表明SF3B1突变很有吸引力治疗靶标。 SF3B1突变在许多癌症中普遍存在（乳腺癌，黑色素瘤，膀胱，胰腺，白血病），因此提高我们瞄准这些突变的能力可能会产生重大的公共卫生影响。做这是一种基本需求，以更好地了解SF3B1突变如何驱动肿瘤发生。最近的工作在急性髓样白血病中，各种失误，致癌作用和预后差异 SF3B1热点突变，但迄今为止尚无研究在固体恶性肿瘤中研究这些突变。确定需要潜在的治疗策略，需要新颖的模型系统。创新的基因组编辑方法将允许我们研究乳腺癌和黑色素瘤，K700和 R625分别在几种代表性的细胞系模型中。转录组和表型的变化增殖，迁移和入侵的差异将决定是否存在特定的改变 SF3B1导致不同的致癌表型。此外，在线的初步系统分析癌症数据库显示了SF3B1突变，TP53在癌症中互斥。这经常提示合成致死性或由于在肿瘤发生中共同作用而缺乏共同出现的选择。成功生成双SF3B1突变体和TP53突变体或TP53敲除细胞系表明突变不太可能是合成的致命。相反，这种关系可能表明了共同的角色并将使我们能够确定SF3B1介导的肿瘤发生的新型机制。以前的发现 SF3B1突变体表现出由于UQCC1的错失和降解而导致的功能失调的细胞呼吸，线粒体复合物III的组成部分。葡萄糖产生的增加，类似于p53的知名在促进沃堡效应中的作用。进一步研究突变体SF3B1和TP53之间的关系确定理论脆弱性，这些脆弱性可用于与大量癌症子集一起使用 TP53突变。赞助商使用基因组编辑策略研究个体突变的稳健历史乳腺癌与范德比尔特大学的丰富资源和核心设施合作。这些目标是可以实现的。这些目标的完成为癌症分子遗传学提供了良好的基础。这将使PI能够获得技术技能，从而朝着独立的研究职业发展肿瘤学，专门研究癌症的新型病理特征，这些特征导致独特的目标漏洞。