Development of Long non-coding RNA-directed Target Therapy for Triple-Negative Breast Cancer

长链非编码RNA靶向治疗三阴性乳腺癌的开发

• 批准号: 10092976
• 负责人: Chunru Lin
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092976
• 关键词: Acids; Address; Antibody Therapy; Antigen Presentation; Antigen-Presenting Cells; Attenuated; Binding; Biological Markers; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Treatment; Breast cancer metastasis; Cancer Patient; Combination immunotherapy; Communities; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Dependence; Development; Diagnosis; Disease; Down-Regulation; Duct (organ) structure; Effectiveness; Environment; Event; Exhibits; FDA approved; Formulation; Future; Genetic; Genetic Transcription; Goals; HIF1A gene; Human; Immune checkpoint inhibitor; Immunologic Surveillance; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Impairment; Infiltration; Kinetics; Knock-in; Major Histocompatibility Complex; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Metabolic; Metastatic Neoplasm to the Lung; Molecular; Morbidity - disease rate; Morphology; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Outcome; PD-1/PD-L1; PD-L1 blockade; Pathway interactions; Patient-Focused Outcomes; Patient-derived xenograft models of breast cancer; Patients; Peptides; Play; Process; Prognosis; Prognostic Marker; Proto-Oncogene Proteins c-akt; RNA; Research; Resistance; Role; Signal Pathway; Signal Transduction; Site; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Treatment Efficacy; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; Ubiquitination; Untranslated RNA; Work; anti-PD-1; anti-PD1 antibodies; anticancer research; base; cancer clinical trial; cancer initiation; cancer risk; clinical effect; combinatorial; cytotoxic CD8 T cells; diagnostic biomarker; immune checkpoint blockers; immune resistance; improved; in vivo; inhibitor/antagonist; innovation; malignant breast neoplasm; mortality; mouse genome; novel; patient stratification; predictive marker; prevent; programmed cell death ligand 1; protein degradation; response; restoration; targeted treatment; therapeutic target; tool; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis; ubiquitin-protein ligase

Project Summary As a deadly disease lacking an FDA-approved targeted therapy, triple-negative breast cancer (TNBC) involves a complicated and entangled network of oncogenic processes in which long non-coding RNAs (lncRNAs), a novel class of regulatory RNA molecules, may play important roles. The proposed study will genetically exploit lncRNA-regulated cellular networks in TNBC to identify an improved therapeutic strategy. Our research has illuminated lncRNA involvement in TNBC metastasis and metabolic reprogramming. One lncRNA, LINK-A, is upregulated in TNBC and is negatively correlated with breast cancer patient outcomes. Tissue-specific expression of LINK-A in mouse mammary glands drives tumor development and lung metastasis, which shares morphological and transcriptional similarity to human TNBC. Furthermore, the expression of LINK- A facilities an immunosuppressive environment and profoundly impacts CD9+ T-cell infiltration via lncRNA- mediated antigenicity loss. Mechanistically, LINK-A concurrently activates multiple oncogenic signaling pathways and promotes TRIM71-dependent degradation of the peptide-loading complex, leading to impaired antigen presentation. Therefore, LINK-A transgenic mice should serve as a powerful tool for dissecting the molecular complexity of TNBC and assessing precise therapeutic formulations against TNBC. Since most pathway inhibitors in TNBC clinical trials have been unsuccessful, a lncRNA-directed therapeutic approach, with the appropriate combination of immunotherapy, may optimize the efficacy of therapies for TNBC. The long-term goal of the proposal is to demonstrate the molecular mechanisms of lncRNA-mediated antigenicity loss and immunosuppression so that improved strategies can be developed to reduce TNBC morbidity and mortality. Our central hypothesis is that LINK-A promotes the initiation and immunoresistance of breast cancer, which can be attenuated in vivo by a combinatorial treatment approach. We will address our hypothesis from following aspects: we will first define the underlying molecular mechanism of lncRNA-dependent antigenicity loss. We will then restore antigenicity by targeting lncRNA and lncRNA-related signaling events. Finally, we will ascertain the functional importance of lncRNAs in breast cancer tumorigenesis. Emerging evidence of the oncogenic involvement of lncRNAs, as well as their implicated roles in mediating immunosurveillance and immunosuppression, warrants further characterization of TNBC-specific lncRNAs and future applications that hinge on their activity. Our goal is to demonstrate that LINK-A, as a hallmark of TNBC, may serve as a diagnostic marker that predicts a cancer’s sensitivity to immunotherapy. Thus, a strategy that combines immune checkpoint blockers and lncRNA-based therapeutic strategies has the potential to significantly advance TNBC treatment. In the long run, these research findings will benefit the cancer community by introducing the robust clinical effects of targeting lncRNAs and a well-defined means of stratifying patients based on these oncogenic lncRNAs.

项目摘要 作为一种缺乏FDA批准的靶向治疗的致命疾病，三阴性乳腺癌（TNBC） 涉及一个复杂的和纠缠的致癌过程网络，其中长的非编码RNA lncRNA作为一类新的调控RNA分子，可能发挥着重要的作用。拟定的研究将 在TNBC中遗传地利用lncRNA调节的细胞网络以鉴定改进的治疗策略。我们 研究已经阐明lncRNA参与TNBC转移和代谢重编程。一 lncRNA，LINK-A，在TNBC中上调，并与乳腺癌患者结果呈负相关。 小鼠乳腺中LINK-A的组织特异性表达驱动肿瘤发展和肺转移， 其与人TNBC具有形态和转录相似性。此外，LINK的表达- A促进免疫抑制环境，并通过lncRNA深刻影响CD 9 + T细胞浸润。 介导的抗原性丧失。从机制上讲，LINK-A同时激活多种致癌信号传导 途径，并促进TRIM 71依赖性的肽负载复合物的降解，导致受损的 抗原呈递因此，LINK-A转基因小鼠应作为解剖 TNBC分子复杂性和评估针对TNBC的精确治疗制剂。由于大多数 TNBC临床试验中的途径抑制剂一直不成功，这是一种lncRNA导向的治疗方法， 免疫疗法的适当组合可以优化TNBC疗法的功效。 该提案的长期目标是证明lncRNA介导的抗原性的分子机制 损失和免疫抑制，以便可以开发改进的策略来降低TNBC发病率， mortality.我们的中心假设是LINK-A促进乳腺癌的发生和免疫抵抗， 其可以通过组合治疗方法在体内减弱。我们将讨论我们的假设， 以下几个方面：我们将首先明确lncRNA依赖性抗原性的分子机制 损失然后，我们将通过靶向lncRNA和lncRNA相关的信号传导事件来恢复抗原性。最后我们将 确定lncRNA在乳腺癌肿瘤发生中的功能重要性。 新出现的证据表明lncRNA参与致癌，以及它们在介导肿瘤发生中的作用。 免疫监视和免疫抑制，保证了TNBC特异性lncRNA的进一步表征， 未来的应用取决于他们的活动。我们的目标是证明LINK-A作为TNBC的标志， 可以作为一种诊断标志物，预测癌症对免疫疗法的敏感性。因此，一项战略， 结合免疫检查点阻断剂和基于lncRNA的治疗策略， 先进的TNBC治疗。从长远来看，这些研究结果将使癌症社区受益， 介绍了靶向lncRNA的强大临床效果和基于患者的分层的明确方法， 这些致癌lncRNA上。