Therapeutic Targeting of RNA Splicing in Triple-Negative Breast Cancer

RNA 剪接在三阴性乳腺癌中的治疗靶向

• 批准号: 10660649
• 负责人: Thomas Westbrook
• 金额: $ 71.73万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-05 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660649
• 关键词: Affect; Agonist; Antiviral Response; Automobile Driving; Biology; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; Cell Compartmentation; Cells; Chemicals; Clinical; Computational algorithm; Data; Double-Stranded RNA; Evaluation; FRAP1 gene; Funding; Genetic Screening; Genetic Transcription; Heterogeneity; Human; Hypersensitivity; Immune; Immune response; Immune signaling; Immune system; Immunocompetent; Immunologics; Immunomodulators; Impairment; Inflammation; Inflammatory; Interferons; Label; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Nature; Newly Diagnosed; Oncogenic; PIK3CA gene; Pathway interactions; Pattern; Process; Productivity; Prognosis; Proto-Oncogene Proteins c-myc; RNA; RNA Splicing; RNA-Binding Proteins; RNA-targeting therapy; Regimen; Regulation; Reporter; Resistance; Role; Signal Pathway; Signal Transduction; Spliceosomes; Structure; Therapeutic; Treatment Efficacy; Tumor Immunity; Viral; Work; anti-tumor immune response; cancer type; cell type; chemical genetics; clinical development; cohort; combat; combinatorial; efficacy testing; immune activation; immune cell infiltrate; immune modulating agents; immunogenic; in vivo; mRNA Precursor; malignant breast neoplasm; mimicry; molecular targeted therapies; neoplastic cell; novel; pre-clinical; preclinical development; programs; response; sensor; single-cell RNA sequencing; targeted treatment; therapy resistant; transcriptome; treatment response; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is recalcitrant to molecular targeted therapies and accounts for about 200,000 new diagnoses per year worldwide. Immunomodulators, therapies that harness the immune system against cancer, have revolutionized the treatment of some cancers and have recently been approved for treatment of TNBC. Disappointingly, TNBC patient response to these therapies has been heterogeneous and significantly lower than other types of cancers. TNBCs are notoriously immunologically cold, with relatively low levels of baseline immune infiltration limiting the efficacy of immunomodulators that amplify productive antitumor immune response. Therefore, a great deal of effort has been focused on promoting immune engagement in these tumors. We have previously shown that oncogenic aberrations common in TNBC result in hypersensitivity to perturbation of the RNA splicing machinery. Importantly, multiple studies, including our own (Bowling, Wang, et al. 2021), have revealed that therapeutic efficacy of spliceosome-targeted therapies (STTs) is in part due to engaging the host immune system. While these discoveries hold great promise for clinical deployment of STTs, especially in combination with immunomodulators, several aspects of their role in activation of antitumor immunity require further understanding. Herein, we propose to interrogate the species of mis-spliced RNA that trigger viral mimicry and trigger tumor inflammation and antitumor immunity. Aim 1. Investigate combinatorial therapy approaches based on STT-induced antitumor immune response. Our preliminary data indicate that activation of tumor-intrinsic antiviral signaling by STT treatment modifies interaction with the tumor microenvironment. By leveraging a diverse cohort of immune-competent syngeneic models of TNBC, we will elucidate the STT-induced change in immune infiltrate and evaluate treatment in combination with immunomodulators to enhance the efficacy of STTs. Aim 2: Define cellular modulators of endogenous dsRNA-mediated antiviral signaling. Prominent oncogenic aberrations have been shown to modulate baseline and agonist-induced inflammatory signaling in tumor cells. Indeed, we have observed heterogeneity in antiviral transcriptional response across a panel of TNBC cell lines with STT-induced dsRNA accumulation. Thus, we will leverage an interferon reporter-based genetic screen to identify novel regulators of cell-intrinsic immune response to endogenous dsRNA accumulation. Aim 3: Evaluate features of STT-induced mis-spliced RNA that stimulate antiviral signaling. Preliminary studies indicate that distinct chemotypes of STTs being investigated in the clinical setting result in differential antiviral immune signaling. Using chemical genetic perturbation and novel RNA labeling and sequencing methods, we will profile immunogenic misprocessed RNA generated by perturbation of distinct spliceosome components encompassing the entirety of the RNA splicing cycle.

三阴性乳腺癌(TNBC)是乳腺癌的一种侵袭性亚型，对 分子靶向治疗，每年全球约有20万例新诊断。 免疫调节剂，即利用免疫系统对抗癌症的疗法，已经彻底改变了 治疗一些癌症，最近已被批准用于治疗TNBC。令人失望的是，TNBC 患者对这些疗法的反应是不同的，而且明显低于其他类型的癌症。 TNBCs是出了名的免疫寒冷，基线免疫渗透水平相对较低 限制放大产生抗肿瘤免疫反应的免疫调节剂的有效性。因此，一个伟大的 许多努力一直集中在促进这些肿瘤的免疫参与上。我们之前已经展示了 在TNBC中常见的致癌异常导致对RNA剪接的干扰敏感 机械设备。重要的是，多项研究，包括我们自己的(鲍林，王等人)。2021年)，已经透露 剪接体靶向治疗(STT)的疗效部分归因于激发宿主免疫 系统。虽然这些发现为STT的临床应用带来了巨大的希望，特别是在联合 对于免疫调节剂，它们在激活抗肿瘤免疫中的几个方面的作用需要进一步 理解。在这里，我们建议询问错误拼接的RNA的物种，这些错误拼接的RNA会触发病毒模仿和 引发肿瘤炎症和抗肿瘤免疫。 目的1.探索基于STT诱导的抗肿瘤免疫的联合治疗途径 回应。我们的初步数据表明，STT治疗激活了肿瘤固有的抗病毒信号 改善与肿瘤微环境的相互作用。通过利用不同的免疫能力队列 同基因的TNBC模型，我们将阐明STT诱导的免疫浸润的变化，并评估 联合免疫调节剂治疗，以提高STTS的疗效。 目的2：确定内源性dsRNA介导的抗病毒信号的细胞调节剂。突出 致癌异常已被证明调节基线和激动剂诱导的炎症信号。 肿瘤细胞。事实上，我们已经观察到一组TNBC在抗病毒转录反应方面的异质性。 STT诱导dsRNA积聚的细胞系。因此，我们将利用干扰素报告基因 筛选内源性dsRNA积聚的细胞内源性免疫反应的新调节因子。 目的3：评估STT诱导的错误剪接RNA刺激抗病毒信号转导的特征。初步 研究表明，在临床环境中研究的不同的STT化学类型导致不同的 抗病毒免疫信号。利用化学遗传扰动和新的RNA标记和测序 方法，我们将分析由于不同剪接体的扰动而产生的免疫原性错误处理的RNA 包含整个RNA剪接周期的组件。