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: 10582619
• 负责人: Chunru Lin
• 金额: $ 35.87万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582619
• 关键词: Acids; 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; Collaborations; 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; Link; 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; T cell infiltration; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Treatment Efficacy; Tumor Suppressor Proteins; Ubiquitination; Untranslated RNA; Work; anti-PD-1; anti-PD1 antibodies; anticancer research; 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; 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 RNA; 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) 涉及一个复杂而纠缠的致癌过程网络，在这个网络中，长的非编码RNA LncRNAs是一类新的调控RNA分子，可能发挥重要作用。拟议的研究将 从基因上利用TNBC中受lncRNA调控的细胞网络来确定改进的治疗策略。我们的 研究表明，LncRNA参与了TNBC转移和代谢重编程。一 LINK-A在TNBC中表达上调，与乳腺癌患者的预后呈负相关。 LINK-A在小鼠乳腺中的组织特异性表达推动肿瘤的发展和肺转移， 它在形态和转录上与人类TNBC相似。此外，链接-的表达- A建立了免疫抑制环境，并通过lncRNA-1深刻影响CD9+T细胞的渗透。 介导性抗原性丧失。机制上，LINK-A同时激活多个致癌信号 途径和促进依赖于TRIM71的多肽负载复合体的降解，导致受损 抗原呈递。因此，LINK-A转基因小鼠应该成为解剖卵巢癌的有力工具。 TNBC的分子复杂性和评估针对TNBC的精确治疗配方。因为大多数人 途径抑制剂在TNBC临床试验中未获成功，这是一种以lncRNA为导向的治疗方法， 适当的联合免疫治疗，可能会优化TNBC的治疗效果。 该提案的长期目标是证明lncRNA介导的抗原性的分子机制。 丢失和免疫抑制，以便制定改进的战略，以减少TNBC发病率和 死亡率。我们的中心假设是LINK-A促进乳腺癌的发生和免疫耐药， 它可以在体内通过组合治疗方法减弱。我们将从以下几个方面阐述我们的假设 以下方面：我们将首先定义lncRNA依赖抗原性的潜在分子机制 损失。然后我们将通过靶向lncRNA和与lncRNA相关的信号事件来恢复抗原性。最后，我们会 确定lncRNAs在乳腺癌发生中的功能重要性。 关于lncRNAs参与致癌的新证据，以及它们在调节中的作用 免疫监测和免疫抑制，需要进一步鉴定TNBC特异性的lncRNA和 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记物，预测癌症对免疫疗法的敏感性。因此，一种战略， 结合免疫检查点阻滞剂和基于lncRNA的治疗策略有可能显著 推进TNBC治疗。从长远来看，这些研究成果将使癌症社区受益 介绍靶向lncRNA的强大临床效果和一种明确的患者分层方法 在这些致癌的IncRNA上。