A novel miR-198 replacement therapy for pancreatic cancer

一种治疗胰腺癌的新型 miR-198 替代疗法

• 批准号: 9004611
• 负责人: Qizhi C. Yao
• 金额: $ 47.39万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-03 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9004611
• 关键词: Animal Model; Autophagocytosis; Biodistribution; Cancer Patient; Cancer cell line; Cell Culture Techniques; Clinical; Clinical Data; DNA; Data; Data Analyses; Development; Disease; Drug Delivery Systems; Drug Kinetics; Early Diagnosis; Exhibits; Formulation; Health; Homeobox; Human; Immunodeficient Mouse; In Vitro; Link; Malignant neoplasm of pancreas; Mediating; MicroRNAs; NF-kappa B; Neoplasm Metastasis; Operative Surgical Procedures; POU2F2 gene; Pathogenesis; Patient-Focused Outcomes; Patients; Polymers; Pre-B-Cell Leukemia; Prognostic Marker; Recombinants; Replacement Therapy; Repression; Role; Sampling; Specimen; Statistical Data Interpretation; Testing; Tissue Sample; Toxic effect; Transfection; Translating; Treatment Efficacy; Tumor Suppression; Tumor Suppressor Proteins; Tumorigenicity; Up-Regulation; Xenograft Model; Xenograft procedure; anticancer research; base; clinical practice; clinically relevant; cohort; cytotoxicity; design; effective therapy; gemcitabine; human tissue; improved; innovation; intravenous administration; killings; mesothelin; molecular targeted therapies; mouse model; nanoparticle; novel; novel marker; novel therapeutics; outcome forecast; overexpression; pancreatic cancer cells; pre-clinical; prognostic significance; protein expression; reconstitution; self assembly; transcription factor; translational study; treatment strategy; tumor; tumor growth; tumor progression; tumorigenic; valosin-containing protein

DESCRIPTION (provided by applicant): We recently discovered a tumorigenic factor interactome connected through the tumor suppressor microRNA-198 in human pancreatic cancer (PC) patient samples and confirmed the tumor suppressive roles of miR-198 in PC animal models. We found that miR-198 is downregulated in PC and is involved in an intricate reciprocal regulatory loop with mesothelin (MSLN), which represses miR-198 through NF-kB-mediated homeobox transcription factor POU2F2 (OCT-2) induction. Furthermore, miR-198 repression leads to overexpression of pre-B-cell leukemia homeobox factor 1 (PBX-1) and valosin-containing protein (VCP). The dysregulated PBX-1/VCP axis leads to an increase in tumorigenicity. Reconstitution of miR-198 in PC cells results in reduced tumor growth, decreased metastasis, and increased survival through direct targeting of MSLN, PBX-1, and VCP. Our preliminary data strongly suggest the significant role of miR-198 and this interactome in PC pathogenesis. In addition, we found that miR-198 can sensitize PC cells for gemcitabine killing because miR-198 effectively downregulates VCP expression and inhibits autophagy maturation in PC cells. In this proposal, we hypothesize that miR-198 and this interactome could serve as a potential prognostic marker and the miR-198 replacement therapy could attack this tumorigenic network through a central vantage point and improve therapeutic efficacy in pre-clinical animal models. Three specific aims are proposed: 1). Demonstrate the significant role of miR-198 and the tumorigenic factor interactome in human PC clinical prognosis in a large cohort of PC patient samples; 2). Design and characterize MSLN-specific targeted miR-198 nanoparticles for specifically delivering miR-198 to PC cells; and 3). Demonstrate the therapeutic efficacy of MSLN-targeted miR-198 replacement in PC patient-derived xenograft (PDX) mouse models. The project will substantially contribute to PC research and will have an enormous impact on clinical practice for patients with PC.

描述（由申请人提供）：我们最近在人胰腺癌（PC）患者样本中发现了一个通过抑瘤因子microRNA-198连接的致瘤因子相互作用组，并在PC动物模型中证实了miR-198的抑瘤作用。我们发现miR-198在PC中下调，并参与了一个与间皮素（MSLN）复杂的相互调节回路，MSLN通过nf - kb介导的同源盒转录因子POU2F2 （OCT-2）诱导抑制miR-198。此外，miR-198抑制导致b细胞前白血病同源盒因子1 （PBX-1）和含缬素蛋白（VCP）的过表达。PBX-1/VCP轴失调导致致瘤性增加。通过直接靶向MSLN、PBX-1和VCP，在PC细胞中重组miR-198可降低肿瘤生长，减少转移，提高生存率。我们的初步数据强烈提示miR-198及其相互作用组在PC发病机制中的重要作用。此外，我们发现miR-198可以使PC细胞对吉西他滨杀伤敏感，因为miR-198可以有效下调VCP表达并抑制PC细胞的自噬成熟。在这项提议中，我们假设miR-198和这个相互作用组可以作为一个潜在的预后标志物，miR-198替代疗法可以通过中心优势点攻击这个致瘤网络，提高临床前动物模型的治疗效果。提出了三个具体目标：1)。在大量PC患者样本中证明miR-198和致瘤因子相互作用组在人类PC临床预后中的重要作用；2）. 设计和表征msln特异性靶向miR-198纳米颗粒，用于特异性地将miR-198递送到PC细胞；和3)。在PC患者来源的异种移植（PDX）小鼠模型中证明msln靶向miR-198替代的治疗效果。该项目将极大地促进PC研究，并将对PC患者的临床实践产生巨大影响。