Combination Therapy: Targeting Pancreatic Cancer with a ROS Inducer and Gemcitabine

联合疗法：使用 ROS 诱导剂和吉西他滨治疗胰腺癌

基本信息

批准号：
9230406
负责人：
Katie Reindl
金额：
$ 21.28万
依托单位：
NORTH DAKOTA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9230406
关键词：
Adjuvant Affect Cancer Patient Cancerous Capsicum Cell Cycle Cell Death Cell Proliferation Cells Centers of Research Excellence Clinical Combined Modality Therapy DNA Damage Data Diagnostic Diet Disease Effectiveness Fruit Future Goals Human K-ras Oncogene K-ras mouse model KRAS2 gene Knowledge Literature Malignant Neoplasms Malignant neoplasm of pancreas Measures Mission Molecular Mutation Natural Products Neoplasm Metastasis Outcome Oxidative Stress Pancreas Property Radiation therapy Reactive Oxygen Species Research Research Project Grants Resistance Role Sampling Signal Transduction Testing Therapeutic Toxic effect Transgenic Mice Translating Treatment Efficacy United States National Institutes of Health Work base biomarker identification cancer cell cancer therapy cell type chemosensitizing agent chemotherapy clinical development clinical practice disease diagnosis effective therapy gemcitabine improved killings mortality mouse model mutant neoplastic cell novel novel strategies pancreatic cancer cells prevent protein expression small molecule targeted treatment tumor tumor progression

项目摘要

__________________________________________________________________________________________________ Project-3. Combination Therapy: Targeting Pancreatic Cancer with a ROS Inducer and Gemcitabine (PI: Dr. Katie Reindl) Project Summary Pancreatic Cancer (PC) is an extremely deadly disease with a mortality rate of nearly 95%. The current treatment options available for PC patients only extend their lives by a few months. Therefore, there is a critical need to identify potent compounds that could enhance the effectiveness of chemotherapies, especially for K- ras mutant PC cells that are often resistant to treatment. The goal of this research project is to evaluate a novel natural product-based agent in combination with gemcitabine (GEM) for pancreatic cancer therapy, eventually leading to the ultimate development of clinically-useful natural product-based agents for the treatment of cancer. The project objective is to establish piperlongumine (PPLGM) as a chemosensitizer for PC by determining its mechanisms of action and therapeutic efficacy. Our central hypothesis is that PPLGM, isolated from the fruits of long peppers, sensitizes tumor cells, but not normal cells, to chemotherapy-induced cell death through induction of reactive oxygen species (ROS) and enhanced DNA damage. We have formulated this hypothesis based on the existing literature and our own preliminary findings that show PPLGM elevates ROS levels in cancer cells leading to enhanced tumor cell death. To test our central hypothesis, we propose three Specific Aims: 1) To investigate the mechanisms by which PPLGM enhances ROS levels and induces cell death in PC cells; 2) To evaluate the effect of PPLGM on sensitizing PC cells, but not normal cells, to chemotherapy; and 3) To evaluate the therapeutic efficacy of PPLGM alone or in combination with GEM in mouse models of PC. For the first aim, we will treat normal and PC cells that are K-ras mutant and wildtype with PPLGM, and we will determine the molecular mechanisms by which PPLGM causes ROS-induced cell death. For the second aim, we will use the same cells to determine the combined effect of PPLGM and GEM on PC cell death and investigate their synergistic mechanisms for inducing PC cell death. For the third aim, we will evaluate the therapeutic efficacy of PPLGM alone or in combination with GEM using an orthotopic mouse model of K-ras mutant human PC and a transgenic mouse model. The approach uses a novel dietary agent that shows potent anti-cancer effects in the context of chemotherapy for PC. The proposed research is expected to vertically advance and expand understanding of how a ROS-inducing agent can be used as a chemosensitizer for cancer treatment. Ultimately such knowledge has the potential to change the field of chemotherapy and result in more effective treatment for many cancers. __________________________________________________________________________________________________

________________________________________________________________________________________________________________________ 项目3。联合疗法：用ROS诱导蛋白和吉西他滨（PI：）靶向胰腺癌（PI： Katie Reindl博士）项目摘要胰腺癌（PC）是一种非常致命的疾病，死亡率接近95％。电流 PC患者可用的治疗选择仅延长了几个月的寿命。因此，有一个关键需要鉴定有效的化合物，以提高化学疗法的有效性，尤其是对于K- RAS突变体PC细胞通常抗治疗。该研究项目的目的是评估小说基于天然产品的剂与胰腺癌治疗的吉西他滨（GEM）结合使用，最终导致最终开发临床可用性的基于天然产品的代理，以治疗癌症。该项目的目标是建立哌拉金（PPLGM）作为PC的化学敏表示确定其作用和治疗功效的机制。我们的中心假设是孤立的PPLGM 从长胡椒的果实中，将肿瘤细胞（而不是正常细胞）敏感到化学疗法诱导的细胞死亡通过诱导活性氧（ROS）和增强的DNA损伤。我们已经制定了这个基于现有文献和我们自己的初步发现，该假设显示PPLGM提升ROS 癌细胞的水平导致肿瘤细胞死亡增强。为了检验我们的中心假设，我们提出了三个具体目的：1）研究PPLGM增强ROS水平并诱导细胞的机制 PC细胞死亡； 2）评估PPLGM对敏化PC细胞而不是正常细胞的影响，化学疗法； 3）单独评估PPLGM的治疗功效或与GEM结合 PC的鼠标模型。为了第一个目标，我们将处理k-ras突变体和野生型的正常和PC细胞使用PPLGM，我们将确定PPLGM引起ROS诱导的细胞的分子机制死亡。对于第二个目标，我们将使用相同的单元格确定PPLGM和GEM的综合效果关于PC细胞死亡并研究其协同诱导PC细胞死亡的协同机制。对于第三个目标，我们将单独评估PPLGM的治疗功效或与GEM结合使用原位小鼠 K-RAS突变人类PC和转基因小鼠模型的模型。该方法使用一种新颖的饮食剂这显示了PC化学疗法的有效抗癌作用。拟议的研究是期望垂直提高并扩大对如何将ROS诱导剂用作的理解用于癌症治疗的化学敏化剂。最终，这种知识有可能改变领域化学疗法，并为许多癌症提供更有效的治疗方法。 ________________________________________________________________________________________________________________________