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:
  • 金额:
    $ 3.29万
  • 依托单位:
  • 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 每年。SF3B1的突变导致一种新形态蛋白质,该蛋白质引起数百个 转录本,包括已知的癌症相关基因。虽然这些改变促进 肿瘤发生还不完全清楚,我们的实验室以前已经表明SF3B1突变是有吸引力的 治疗目标SF3B1突变在许多癌症(乳腺癌、黑色素瘤、膀胱癌、胰腺癌、 因此,提高我们针对这些突变的能力可能会对公共卫生产生重大影响。做 因此,有必要更好地了解SF3B1突变如何驱动肿瘤发生。最近的工作 在急性髓系白血病中,不同类型的白血病在错误剪接、致癌效应和预后方面存在差异。 SF3B1热点突变,但迄今为止还没有研究调查这些实体恶性肿瘤。以确定 潜在的治疗策略,需要新的模型系统。一种创新的基因组编辑方法将 使我们能够研究乳腺癌和黑色素瘤、K700和 R625,分别在几个代表性的细胞系模型。转录组和表型的变化 增殖、迁移和侵袭的差异将决定是否有特定的改变, SF3B1导致不同的致癌表型。此外,初步系统分析了在线 癌症数据库显示SF3B1突变和TP53改变在癌症中是相互排斥的。这往往 提示由于在肿瘤发生中的共同作用,合成致死性或缺乏对共现的选择。 成功产生双SF 3B1突变体和TP 53突变体或TP 53敲除细胞系证明, 这些突变不太可能是合成致死的。相反,这种关系可能表明, 并将使我们能够确定SF3B1介导的肿瘤发生的新机制。以前的研究结果 SF3B1突变体由于UQCC 1的错误剪接和降解而表现出功能失调的细胞呼吸, 线粒体复合体III的一种成分。结果是葡萄糖增加,类似于众所周知的p53 在促进瓦尔堡效应中的作用。进一步研究突变型SF 3B1与TP 53的关系, 确定治疗弱点,可以额外利用对癌症的大子集, TP53突变。申办方利用基因组编辑策略研究个体突变的强大历史 在乳腺癌方面的研究,再加上范德比尔特大学丰富的资源和核心设施, 这些目标可以实现。这些目标的实现为癌症分子遗传学的研究奠定了良好的基础。 这将使PI获得技术技能,以建立独立的研究职业生涯, 肿瘤学,特别是研究癌症的新病理特征,这些特征导致独特的靶向治疗, 漏洞

项目成果

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