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：
8616128
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/8616128
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 Environment Epithelial Epithelial Cells Exhibits Family Future Genetic Goals Head and neck structure Human Induction of Apoptosis K-ras Gene K-ras Oncogene 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 Resistance 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 design effective therapy experience gain of function gain of function mutation gemcitabine inhibitor/antagonist innovation killings leukemia mouse model mutant novel pancreatic cancer cells pancreatic neoplasm public health relevance screening survivin treatment duration tumor tumor growth tumor xenograft

项目摘要

Abstract 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.

抽象的这个R03试点项目的目标是展示创新组合处理的概念证明旨在靶向胰腺癌的方案，具有K-RAS突变和一个或多个的异常表达抗凋亡蛋白。 K-Ras致癌突变和主要抗凋亡蛋白的异常表达（例如 Survivin，Mcl-1，XIAP，CIAP2）在胰腺癌中，大大促进了胰腺癌的发展和侵略性（耐药性，转移和复发）。观察到K-RAS功能突变在> 90％的胰腺癌患者中。突变的K-RAS的遗传沉默会诱导凋亡并抑制胰腺癌细胞的生长，侵袭性，恶性肿瘤形成和异种移植肿瘤生长。然而，没有有效的靶向疗法可用于胰腺癌K-RAS突变。使用小说用K-RAS突变细胞与正常细胞的筛选方法，来自15个化学成分鉴定了药用植物Amoora rohituka，并使用半合成产生了超过50个衍生物从15次命中开始。然后使用K-Ras突变细胞与正常细胞对这些化合物进行重新分组细胞。 AMR-ME和AMR-MEOAC被确定为针对K-RAS的最有效的化合物突变细胞。我们以前的研究表明，AMR-ME靶向K-RAS途径，每天3 mg/kg 小鼠的28天治疗没有明显的毒性，同时扩展了白血病小鼠的存活率。我们计划将AMR-MEOAC（最佳选择性）与我们的新型化合物FL118相结合，该化合物有选择地抑制Survivin， MCL-1，XIAP和CIAP2用于测试这种新型组合靶向治疗方案。它以前有已显示，K-RAS沉默与吉西他滨的组合大大减少了小鼠的肿瘤体积与单独的任何一个代理相比。因此，我们假设抑制两个突变的K-RAS 具有新型药物AMR-MEOAC和FL118的主要抗凋亡蛋白将导致明显增强了凋亡的诱导和胰腺癌细胞和肿瘤生长的抑制作用比单独的抑制作用。该项目提出了以下三个特定目标。 AIM 1：在胰腺上或不存在低剂量FL118的情况下确定AMR-MEOAC的功效相关信号通路中蛋白质蛋白的癌细胞生长，凋亡和调节。目标2：使用人类在存在或不存在低剂量FL118的情况下确定AMR-MEOAC的功效胰腺癌细胞系衍生的异种移植模型。目标3：在存在或不存在低剂量FL118的情况下，确定AMR-MEOAC的功效异种移植物直接源自患者胰腺癌组织。胰腺癌具有K-Ras功能获得突变和一个或多个抗凋亡的异常表达蛋白质（Survivin，Mcl-1，XIAP，CIAP2）很难治疗。这个项目可能会发展出小说并有针对性有效控制这种具有挑战性且难以治疗的癌症的组合策略。