Targeting GCNT3 for Pancreatic Cancer

靶向 GCNT3 治疗胰腺癌

基本信息

批准号：
10260098
负责人：
Chinthalapally V. Rao
金额：
--
依托单位：
OKLAHOMA CITY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-10-01 至 2025-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10260098
关键词：
Address Adenocarcinoma Anabolism Binding Carcinoma Cell physiology Chemoresistance Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Development Disease Docking Dose Drug Delivery Systems Duct (organ) structure Enzymes Family Female Future Genes Genetic Genetic Engineering Growth Health Human Impairment In Vitro Incidence Investigation KPC model Knock-out Lead Lesion Light MUC5AC gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Molecular Mucin 1 protein Mucin-2 Staining Method Mucins Mus N-Acetylglucosaminyltransferases Nature Neoplasm Metastasis Neoplasms Oncogenic Outcome Paclitaxel Pancreas Pancreatic Intraepithelial Neoplasia Pathogenesis Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Positron-Emission Tomography Production Property Research Resistance Role Signal Pathway Signal Transduction Site Slice Small Interfering RNA Source Survival Analysis Survival Rate Testing Therapeutic Therapeutic Effect Tissues Treatment Efficacy Tumor Tissue Tumor Weights Up-Regulation Veterans Xenograft procedure cancer therapy chemotherapy clinically relevant effective therapy efficacy evaluation gemcitabine gene synthesis human data improved in silico in vivo inhibitor knock-down male mortality neoplastic neoplastic cell next generation sequencing novel novel strategies novel therapeutic intervention novel therapeutics overexpression pancreatic cancer cells pancreatic cancer patients pancreatic neoplasm patient derived xenograft model preclinical study response simulation targeted treatment therapeutic target transcriptome sequencing translational approach treatment response treatment strategy tumor tumor growth tumor progression tumor xenograft tumorigenesis uptake whole genome

项目摘要

Summary Pancreatic cancer (PC) has the highest mortality of any cancer, with a 5-year survival rate of less than 10%. Despite progress in the development of targeted therapies, the survival rate is still unacceptably low. It is, therefore, important to identify novel therapeutic approaches that could lead to a more effective treatment for this malignant disease. This proposal explores the novel concept that a core 2 mucin synthesis gene, GCNT3, regulates PC growth and survival, ascribing a new and critical role to GCNT3. We have shown that GCNT3 is overexpressed in PC patients and contributes to PC pathogenesis, indicating that GCNT3 is a promising therapeutic target. However, how GCNT3 regulates PC is not clear. Using in silico small molecular docking simulation approaches, we discovered that talniflumate is a novel inhibitor that selectively binds to GCNT3. Examining the molecular mechanisms of GCNT3-mediated PC growth, we found that siRNA-mediated knockdown of GCNT3 or treatment with talniflumate, inhibited xenograft tumors. Talniflumate also reduced GCNT3 expression, leading to reduced production of mucins in vivo and in vitro, and improved cellular gemcitabine uptake. Taken together, our findings strongly suggest that targeting mucin biosynthesis through GCNT3 may improve responsiveness to drug treatment. We, therefore, hypothesize that aberrant expression of GCNT3 will lead to excessive mucin synthesis during PC development and cause chemoresistance. Hence, the inhibition of aberrant mucin synthesis is sufficient to disrupt the barrier properties of the mucin mesh to efficiently increase the access of chemotherapeutics to target sites. Three independent, yet interrelated, specific aims are proposed to address this hypothesis. Aim 1: Generate GCNT3-deficient KPC mice and determine whether targeting GCNT3 ablates the mucin barrier and inhibits PC progression/metastasis by increasing gemcitabine and nab-paclitaxel (NPT) efficacy. Aim 2: Determine whether combinational therapy of talniflumate plus NPT are effective in treating PC by a) evaluating the efficacy and dose-response effects of the combination administered in vivo in a clinically relevant KPC model of spontaneous PC and b) determining mucin disruption and gemcitabine or NPT uptake in combination-treated tumors. c) We will establish the GCNT3 and NPT levels in tumor tissue and their correlation with mucin subtypes (Mucs) and PC treatment efficacy via whole genome transcriptome sequencing and PET imaging. Aim 3: We will investigate the role of GCNT3 in gemcitabine resistance, mucin overexpression and PC growth. a) For clinical relevance, we will assess the inhibition of human patient- derived xenografts (PDX) and PC slice cultures by combinational therapy. b) Evaluate the efficacy of combination against GCNT3 overexpressing human PC PDX tumors in vivo. Veterans Health Relevance: Pancreatic cancer major health problem and many veterans and their families suffered from this neoplastic disease. The results obtained from this study will have high impact, since they will shed light on future development of novel therapeutic strategies for PC. Thus, this proposal is highly translational in nature

概括胰腺癌（PC）在任何癌症中的死亡率最高，5年生存率低于10％。尽管有针对性疗法的发展进展，但生存率仍然不可接受。这是，因此，重要的是确定新型的治疗方法，这可能会导致更有效的治疗方法这种恶性疾病。该建议探讨了一个新的概念，即核心2粘蛋白合成基因GCNT3，调节PC的生长和生存，将新的和关键作用归因于GCNT3。我们已经证明了GCNT3 PC患者过表达并导致PC发病机理，表明GCNT3是一个有前途的治疗靶标。但是，GCNT3如何调节PC尚不清楚。在硅小分子对接中模拟方法，我们发现塔尔尼氟酸酯是一种新型抑制剂，有选择地结合GCNT3。检查GCNT3介导的PC生长的分子机制，我们发现siRNA介导敲低gcnt3或用梯形抑制异种移植肿瘤的治疗。塔尔尼氟酸酯也减少了 GCNT3表达，导致粘蛋白在体内和体外的产生降低，并改善了细胞吉西他滨的吸收。综上所述，我们的发现强烈表明，通过 GCNT3可能会提高对药物治疗的反应。因此，我们假设GCNT3的异常表达会导致粘蛋白合成过多在PC开发过程中并引起化学抗性。因此，异常粘蛋白合成的抑制是足以破坏粘蛋白网格的屏障特性，以有效增加化学治疗剂针对靶位点。提出了三个独立但相互关联的特定目标来解决这个假设。 AIM 1：生成缺乏GCNT3的KPC小鼠并确定靶向GCNT3是否消融粘蛋白屏障并通过增加吉西他滨和NAB-甲氟甲酰胺（NPT）来抑制PC的进展/转移功效。 AIM 2：确定象talniflumate Plus NPT的组合治疗是否有效治疗PC 通过a）评估在临床上体内给药的组合的功效和剂量反应效应自发PC和B）确定粘蛋白破坏和吉西他滨或NPT摄取的相关KPC模型在结合处理的肿瘤中。 c）我们将在肿瘤组织及其中建立GCNT3和NPT水平通过整个基因组转录组与粘蛋白亚型（MUC）和PC治疗疗效的相关性测序和宠物成像。 AIM 3：我们将研究GCNT3在吉西他滨耐药性粘蛋白中的作用过表达和PC增长。 a）对于临床相关性，我们将评估人类患者的抑制作用 - 通过组合疗法衍生的异种移植物（PDX）和PC切片培养物。 b）评估的功效针对GCNT3过表达人体PC PDX肿瘤的组合。退伍军人健康相关性：胰腺癌主要健康问题及其许多退伍军人及其家庭患有这种肿瘤性疾病。从这项研究中获得的结果将产生很大的影响，因为他们将阐明PC的新型治疗策略的未来发展。因此，该提议很高本质上的翻译