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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要作为一种缺乏 FDA 批准的靶向治疗的致命疾病，三阴性乳腺癌 (TNBC) 涉及一个复杂且纠缠的致癌过程网络，其中长非编码RNA （lncRNA）是一类新型的调节性 RNA 分子，这项研究可能会发挥重要作用。基因利用 TNBC 中 lncRNA 调节的细胞网络来确定改进的治疗策略。研究阐明了 lncRNA 参与 TNBC 转移和代谢重编程。 lncRNA（LINK-A）在 TNBC 中表达上调，与乳腺癌患者的预后呈负相关。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，与人类 TNBC 具有形态和转录相似性。此外，LINK- 的表达也相似。 A 营造免疫抑制环境，并通过 lncRNA- 深刻影响 CD9+ T 细胞浸润从机制上讲，LINK-A 同时激活多种致癌信号。途径并促进肽负载复合物的 TRIM71 依赖性降解，导致受损因此，LINK-A 转基因小鼠应该成为解剖抗原呈递的有力工具。 TNBC 的分子复杂性并评估针对 TNBC 的精确治疗配方。途径抑制剂在TNBC临床试验中一直不成功，一种lncRNA导向的治疗方法，免疫治疗的适当组合可能会优化 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损失和免疫抑制，以便可以制定改进的策略来降低 TNBC 发病率和我们的中心假设是 LINK-A 促进乳腺癌的发生和免疫抵抗，可以通过组合治疗方法在体内减弱我们的假设。以下几个方面：我们首先定义lncRNA依赖性抗原性的潜在分子机制然后，我们将通过靶向 lncRNA 和 lncRNA 相关信号事件来恢复抗原性。确定 lncRNA 在乳腺癌肿瘤发生中的功能重要性。 lncRNA 致癌作用及其在介导中的作用的新证据免疫监视和免疫抑制，需要进一步鉴定 TNBC 特异性 lncRNA 和未来的应用取决于它们的活动，我们的目标是证明 LINK-A 作为 TNBC 的标志，可以作为预测癌症对免疫治疗敏感性的诊断标记。结合免疫检查点阻断剂和基于 lncRNA 的治疗策略有可能显着从长远来看，这些研究结果将使癌症界受益。介绍靶向 lncRNA 的强大临床效果以及基于患者分层的明确方法关于这些致癌lncRNA。