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A novel regimen to target both pancreatic cancer K-ras and antiapoptotic proteins

一种针对胰腺癌 K-ras 和抗凋亡蛋白的新疗法

基本信息

批准号：
8786875
负责人：
Fengzhi Li
金额：
$ 8.49万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786875
关键词：
Animal Model Apoptosis Apoptosis Inhibitor Area BCL2 gene BIRC4 gene Cancer Cell Growth Cancer Patient Cancer cell line Cell Line Cell Survival Cells Chemicals Clinical Colon Comprehensive Cancer Center Development Disease Dose Early Diagnosis Ensure Epithelial Epithelial Cells Exhibits Family Future Genetic Goals Head and neck structure Health Human Induction of Apoptosis K-ras Gene K-ras Oncogene KRAS2 gene Lead Malignant Neoplasms Malignant neoplasm of pancreas Medicinal Plants Modeling Mus Mutate Mutation Nature Neoplasm Metastasis Normal Cell Oncogenic Ovarian Pancreatic duct Pathway interactions Patients Pilot Projects Proteins RNA Interference Regimen Relapse Reporting Research Personnel Severe Combined Immunodeficiency Side Signal Pathway Survival Rate System Testing Tissues Toxic effect Treatment Protocols Tumor Volume Xenograft Model Xenograft procedure cancer cell cancer type chemical reaction collaborative environment design effective therapy experience gain of function gain of function mutation gemcitabine gene product inhibitor/antagonist innovation killings leukemia mouse model mutant novel pancreatic cancer cells pancreatic neoplasm screening survivin targeted treatment therapy resistant treatment duration tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): The goal of this R03 pilot project is to demonstrate a proof of concept for an innovative combination treatment regimen designed to target pancreatic cancer with K-ras mutations and aberrant expression of one or more antiapoptotic proteins. K-ras oncogenic mutations and aberrant expression of major antiapoptotic proteins (e.g. survivin, Mcl-1, XIAP, cIAP2) in pancreatic cancer heavily contribute to pancreatic cancer development and aggressiveness (treatment resistance, metastasis, and relapse). Gain-of-K-ras-function mutations is observed in >90% of pancreatic cancer patients. Genetic silencing of mutated K-ras induces apoptosis and inhibits pancreatic cancer cell growth, invasiveness, malignant tumor formation, and xenograft tumor growth. However, there are no effective targeted therapies available for pancreatic cancer K-ras mutations. Using a novel screening approach with K-ras mutant cells versus normal cells, fifteen chemical constituents from the medicinal plant Amoora rohituka were identified, and over 50 derivatives were generated using semi-synthetic approaches from the 15 hits. These compounds were then rescreened using K-ras mutant cells versus normal cells. AMR-Me and AMR-MeOAc were identified as the most potent compounds selectively against the K-ras mutant cells. Our previous studies indicated that AMR-Me targets the K-ras pathway, and that 3 mg/kg daily for 28-day treatment of mice shows no clear toxicity, while it extends leukemia mouse survival. We plan to combine AMR-MeOAc (best selectivity) with our novel compound, FL118, which selectively inhibits survivin, Mcl-1, XIAP, and cIAP2, for testing this novel combinational-targeted treatment regimen. It has previously been shown that combination of K-ras silencing with gemcitabine dramatically reduces tumor volumes in mice compared with either single agent alone. Therefore, we hypothesize that inhibition of both mutated K-ras and the major antiapoptotic proteins with the novel agents AMR-MeOAc and FL118 would lead to a strikingly enhanced induction of apoptosis and inhibition of pancreatic cancer cell and tumor growth than the inhibition from either agent alone. The following three specific aims are proposed in this project. Aim 1: Determine the efficacy of AMR-MeOAc in the presence or absence of low dose FL118 on pancreatic cancer cell growth, apoptosis, and modulation of proteins in the relevant signaling pathways. Aim 2: Determine the efficacy of AMR-MeOAc in the presence or absence of low dose FL118 using human pancreatic cancer cell line-derived xenograft models. Aim 3: Determine the efficacy of AMR-MeOAc in the presence or absence of low dose FL118 against xenografts directly derived from patient pancreatic cancer tissues. Pancreatic cancer with K-ras gain-of-function mutations and aberrant expression of one or more antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) is hard to treat. This project may develop a novel and targeted combination strategy to effectively control this challenging and difficult-to-treat cancer.

描述(申请人提供)：这个R03试点项目的目标是证明一种创新的联合治疗方案的概念，该方案旨在针对K-ras突变和一种或多种抗凋亡蛋白异常表达的胰腺癌进行治疗。胰腺癌中K-ras癌基因突变和主要抗凋亡蛋白(如Survivin、Mcl-1、XIAP、cIAP2)的异常表达与胰腺癌的发展和侵袭性(治疗抵抗、转移和复发)密切相关。在90%的胰腺癌患者中观察到K-ras功能增强突变。突变的K-ras基因沉默可诱导细胞凋亡，抑制胰腺癌细胞生长、侵袭性、恶性肿瘤形成和异种移植瘤生长。然而，目前还没有针对胰腺癌K-ras突变的有效靶向治疗方法。采用K-ras突变细胞与正常细胞比较的新筛选方法，从药用植物羊肚菌中鉴定出15种化学成分，并利用半合成方法从这15种化合物中产生了50多种衍生物。然后使用K-ras突变细胞和正常细胞对这些化合物进行重新筛选。AMR-Me和AMR-MeOAc是选择性抑制K-ras突变细胞的最有效的化合物。我们以前的研究表明，AMR-Me针对K-ras途径，每天3 mg/kg治疗28天的小鼠没有明显的毒性，同时它延长了白血病小鼠的生存时间。我们计划将AMR-MeOAc(最佳选择性)与我们的新化合物FL118结合起来，用于测试这一新的联合靶向治疗方案。先前已经表明，与单独使用任何一种药物相比，K-ras沉默和吉西他滨联合使用显著减少了小鼠的肿瘤体积。因此，我们推测，用新型药物AMR-MeOAc和FL118同时抑制突变的K-ras和主要的抗凋亡蛋白，将比单独使用任何一种药物抑制胰腺癌细胞和肿瘤的生长、诱导细胞凋亡和抑制肿瘤生长都显著增强。本项目提出了以下三个具体目标。目的：研究AMR-MeOAc在有或无小剂量FL118作用下对胰腺癌细胞生长、凋亡及相关信号转导通路蛋白表达的影响。目的：利用人胰腺癌细胞系异种移植模型，研究AMR-MeOAc在低剂量FL118存在或不存在的情况下的疗效。目的：研究AMR-MeOAc在小剂量FL118存在或不存在的情况下对胰腺癌组织直接来源的异种移植瘤的抑制作用。具有K-ras功能增强突变和一种或多种抗凋亡蛋白(Survivin、Mcl-1、XIAP、cIAP2)异常表达的胰腺癌是一种难以治疗的肿瘤。该项目可能会开发一种新颖的、有针对性的组合策略，以有效控制这种具有挑战性和难以治疗的癌症。