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Development of miR-27a* for the Treatment of Head and Neck Squamous Cell Carcinoma

开发 miR-27a* 用于治疗头颈鳞状细胞癌

基本信息

批准号：
10752726
负责人：
STEPHEN Y LAI
金额：
$ 65.49万
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：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752726
关键词：
AKT1 gene Address Affect Apoptosis Biological Biological Assay Biological Process Cell Death Cell Line Cell Survival Cetuximab Cisplatin Clinical Combined Modality Therapy Contracts Critical Pathways Data Dental Development Disease Disease Progression EGFR Protein Overexpression Endocytosis Engineering Epidermal Growth Factor Receptor Evaluation FRAP1 gene Family Future Genes Goals Head and Neck Squamous Cell Carcinoma Health Histone Deacetylase In Vitro Intravenous Knowledge Malignant Neoplasms Mediating Mediator Methods MicroRNAs Microbubbles Mission Modeling Molecular Molecular Target Mus National Institute of Dental and Craniofacial Research Oligonucleotides Oncogenes Oncogenic Oral Outcome Pathogenesis Pathway interactions Patients Pre-Clinical Model Process Proteins Proto-Oncogene Proteins c-akt Publishing RNA RNA Degradation RNA delivery Radiation Regulation Repression Research Role Safety Sampling Signal Pathway Site Small Interfering RNA Specimen Survival Rate System Testing Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Intervention Therapeutic Uses Tissue Sample Tissues Tongue Neoplasms Toxic effect Translating Treatment Protocols Tumor Promotion Tumor Tissue Ultrasonic Therapy antitumor effect cancer cell cancer diagnosis chemotherapy clinical implementation clinical practice clinical translation combat combinatorial craniofacial drug use screening effective therapy image guided improved improved outcome in silico in vitro Assay in vivo inducible gene expression inhibitor innovation microRNA delivery mouse model multimodality neoplastic cell novel novel therapeutic intervention novel therapeutics overexpression prevent screening standard of care targeted agent targeted delivery targeted treatment theranostics therapeutic RNA treatment optimization tumor tumor growth tumor progression ultrasound

项目摘要

PROJECT SUMMARY Overexpression of epidermal growth factor receptor (EGFR), which frequently occurs in head and neck squamous cell carcinoma (HNSCC), correlates with poor patient survival. However, therapies targeting EGFR in multimodality therapy for HNSCC have not significantly improved outcomes for advanced stage disease. Therefore, alternative approaches targeting EGFR and associated critical pathways are needed to combat HNSCC, the sixth most diagnosed cancer worldwide. Our previous research identified microRNA-27a* (miR- 27a*; miR-27a-5p) as a regulator of EGFR, protein kinase B (AKT1), and mammalian target of rapamycin (mTOR). All these proteins are commonly upregulated in cancer cells, likely as a consequence of tumors repressing miR-27a* expression, and provide a cell survival advantage. Furthermore, re-introduction of miR- 27a* into tumor cells in vitro and in vivo causes apoptosis, raising the exciting prospect that by simultaneously targeting multiple oncogenic pathways, miR-27a* may be an effective therapy for HNSCC. Accordingly, our long-term clinical translational objective is to develop miR-27a* as an effective multimodality therapeutic option for HNSCC, which is directly relevant to the mission of the NIDCR “…to improve oral, dental, and craniofacial health through research...”. This requires us to understand the functional role of miR-27a* targets, to define novel therapeutic combinations that enhance the ability of miR-27a* to inhibit HNSCC progression, and to develop an approach to translate miR-27a* into the clinical arena. Currently, a knowledge gap exists regarding validated targets of miR-27a* and the pathways they influence in HNSCC progression, as well as combinatorial treatments that could augment miR-27a* anti-tumor effects. Moreover, methods for tumor-specific delivery of miRs are lacking. Accordingly, we will comprehensively test the potential of miR-27a* in conjunction with established and novel combinatorial agents for HNSCC treatment using in vitro and orthotopic in vivo tumor models. To overcome challenges in the delivery of miRs in vivo, we will use a novel ultrasound-targeted microbubble delivery platform to administer miR-27a* specifically to tumor. The overall objective of this proposal is to determine the role of miR-27a* in modulating biological processes through regulation of its target genes, while leveraging these and previous findings towards the therapeutic use of miR-27a* within the context of current standard of care and future combinatorial treatment regimens. Our central hypothesis is that re- introduction of miR-27a* in HNSCC negatively modulates critical oncogenic drivers to promote tumor apoptosis. We propose three Specific Aims: (1) To confirm direct molecular targets of miR-27a* that mediate HNSCC pathogenesis; (2) To define miR-27a*-combinatorial treatment regimens for HNSCC; and (3) To characterize the role of miR-27a* delivery in enhancing current and future multimodality treatment regimens for HNSCC. The findings will significantly impact our understanding of miR-27a* targets, the processes they regulate, their role in tumor progression, and ultimately inform clinical implementation of miR-27a* therapy.

项目摘要表皮生长因子受体（EGFR）过度表达，常发生在头颈部鳞状细胞癌（HNSCC）与患者生存率差相关。然而，靶向EGFR的疗法在HNSCC的多模式治疗中，没有显著改善晚期疾病的结果。因此，需要靶向EGFR和相关关键途径的替代方法来对抗 HNSCC是全球第六大诊断癌症。我们之前的研究发现microRNA-27 a *（miR-27 a *）， 27 a *; miR-27 a-5 p）作为EGFR、蛋白激酶B（AKT 1）和雷帕霉素的哺乳动物靶点的调节剂（mTOR）。所有这些蛋白质通常在癌细胞中上调，可能是肿瘤的结果。抑制miR-27 a * 表达，并提供细胞存活优势。此外，重新引入miR- 27 a * 在体外和体内进入肿瘤细胞引起细胞凋亡，提出了令人兴奋的前景，同时通过 miR-27 a * 靶向多种致癌途径，可能是HNSCC的有效治疗方法。因此，委员会认为，我们的长期临床转化目标是将miR-27 a * 开发为有效的多模式治疗药物， HNSCC的选择，这与NIDCR的使命直接相关“. 通过研究促进颅面健康."。这需要我们了解miR-27 a * 靶点的功能作用，定义增强miR-27 a * 抑制HNSCC进展的能力的新型治疗组合，和开发一种将miR-27 a * 翻译到临床竞技场的方法。目前，在以下方面存在知识差距： miR-27 a * 的有效靶点及其在HNSCC进展中的影响途径，以及miR-27 a * 与HNSCC的联合作用。可以增强miR-27 a * 抗肿瘤作用的治疗。此外，用于肿瘤特异性递送药物组合物的方法也是可行的。缺少的是MIRs。因此，我们将全面测试miR-27 a * 与使用体外和原位体内肿瘤治疗HNSCC的已建立的和新的组合药剂模型为了克服体内递送miR的挑战，我们将使用一种新的超声靶向的在一些实施方案中，使用微泡递送平台将miR-27 a * 特异性地施用至肿瘤。本提案的总体目标是确定miR-27 a * 通过调节其靶基因在调节生物过程中的作用，同时利用这些和先前的发现在以下背景下对miR-27 a * 的治疗用途进行研究：目前的护理标准和未来的组合治疗方案。我们的核心假设是，重新- 在HNSCC中引入miR-27 a * 负调节关键致癌驱动因子以促进肿瘤凋亡我们提出了三个具体的目的：（1）确定miR-27 a * 介导的直接分子靶点， HNSCC发病机制;（2）定义用于HNSCC的miR-27 a *-组合治疗方案;和（3）表征miR-27 a * 递送在增强当前和未来的多模式治疗方案中的作用， HNSCC。这些发现将显著影响我们对miR-27 a * 靶点的理解，以及它们的作用过程。调节它们在肿瘤进展中的作用，并最终为miR-27 a * 治疗的临床实施提供信息。