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（由申请人提供）：该 R03 试点项目的目标是证明创新联合治疗方案的概念证明，该方案旨在针对具有 K-ras 突变和一种或多种抗凋亡蛋白异常表达的胰腺癌。胰腺癌中 K-ras 致癌突变和主要抗凋亡蛋白（例如生存素、Mcl-1、XIAP、cIAP2）的异常表达在很大程度上促进了胰腺癌的发展和侵袭性（治疗耐药、转移和复发）。在 >90% 的胰腺癌患者中观察到 K-ras 功能获得突变。突变 K-ras 的基因沉默可诱导细胞凋亡并抑制胰腺癌细胞生长、侵袭、恶性肿瘤形成和异种移植肿瘤生长。然而，目前尚无针对胰腺癌 K-ras 突变的有效靶向疗法。使用 K-ras 突变细胞与正常细胞的新型筛选方法，从药用植物 Amoora rohituka 中鉴定出 15 种化学成分，并使用半合成方法从 15 种命中中产生了 50 多种衍生物。然后使用 K-ras 突变细胞与正常细胞重新筛选这些化合物。 AMR-Me 和 AMR-MeOAc 被确定为选择性对抗 K-ras 突变细胞的最有效化合物。我们之前的研究表明，AMR-Me 靶向 K-ras 通路，每天 3 mg/kg 对小鼠进行 28 天治疗，没有显示出明显的毒性，同时延长了白血病小鼠的生存期。我们计划将 AMR-MeOAc（最佳选择性）与我们的新型化合物 FL118（选择性抑制生存素、Mcl-1、XIAP 和 cIAP2）结合起来，以测试这种新型组合靶向治疗方案。先前的研究表明，与单独使用任一药物相比，K-ras 沉默与吉西他滨的组合可显着减少小鼠的肿瘤体积。因此，我们假设用新型药物 AMR-MeOAc 和 FL118 抑制突变的 K-ras 和主要抗凋亡蛋白，与任一药物的抑制相比，会显着增强细胞凋亡的诱导以及对胰腺癌细胞和肿瘤生长的抑制。独自的。本项目提出以下三个具体目标。目标 1：确定在存在或不存在低剂量 FL118 的情况下 AMR-MeOAc 对胰腺癌细胞生长、凋亡以及相关信号传导通路中蛋白质调节的功效。目标 2：使用源自人胰腺癌细胞系的异种移植模型确定 AMR-MeOAc 在存在或不存在低剂量 FL118 的情况下的功效。目标 3：确定 AMR-MeOAc 在存在或不存在低剂量 FL118 的情况下对直接源自患者胰腺癌组织的异种移植物的功效。具有 K-ras 功能获得性突变和一种或多种抗凋亡蛋白（生存素、Mcl-1、XIAP、cIAP2）异常表达的胰腺癌很难治疗。该项目可能会开发一种新颖的、有针对性的组合策略来有效控制这种具有挑战性且难以治疗的癌症。