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:8813063
- 负责人:
- 金额:$ 21.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-03-01 至 2021-02-28
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAffectCancer PatientCancerousCapsicumCell CycleCell DeathCell ProliferationCellsCenters of Research ExcellenceCombined Modality TherapyDNA DamageDataDevelopmentDiagnosticDietDiseaseEffectivenessFruitFutureGoalsHumanK-ras OncogeneK-ras mouse modelKRAS2 geneKnowledgeLiteratureMalignant NeoplasmsMalignant neoplasm of pancreasMeasuresMissionMolecularMutationNatural ProductsNeoplasm MetastasisNormal CellOutcomeOxidative StressPancreasPropertyRadiation therapyReactive Oxygen SpeciesResearchResearch Project GrantsResistanceRoleSamplingSignal TransductionTestingTherapeuticToxic effectTransgenic MiceTranslatingTreatment EfficacyWorkbasebiomarker identificationcancer biomarkerscancer cellcancer therapycell typechemosensitizing agentchemotherapyclinical practicedisease diagnosiseffective therapygemcitabineimprovedkillingsmortalitymouse modelmutantneoplastic cellnovelnovel strategiespancreatic cancer cellspreventprotein expressionsmall moleculetumortumor 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:使用 ROS 诱导剂和吉西他滨治疗胰腺癌(PI:
凯蒂·雷德尔博士)
项目概要
胰腺癌(PC)是一种极其致命的疾病,死亡率接近95%。目前的
PC 患者可用的治疗方案只能将他们的生命延长几个月。因此,有一个关键的
需要识别可以增强化疗效果的有效化合物,特别是 K-
ras 突变 PC 细胞通常对治疗有抵抗力。该研究项目的目标是评估一部小说
基于天然产物的药物与吉西他滨(GEM)联合用于胰腺癌治疗,最终
导致临床上有用的基于天然产物的药物的最终开发,用于治疗
癌症。该项目的目标是建立 Piperlongumine (PPLGM) 作为 PC 的化学增敏剂
确定其作用机制和治疗效果。我们的中心假设是 PPLGM,孤立的
来自长辣椒的果实,使肿瘤细胞(而非正常细胞)对化疗引起的细胞死亡敏感
通过诱导活性氧 (ROS) 和增强 DNA 损伤。我们制定了这个
基于现有文献和我们自己的初步发现的假设,表明 PPLGM 可以提高 ROS
癌细胞中的水平导致肿瘤细胞死亡增加。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水平并诱导细胞增殖的机制
PC细胞死亡; 2) 评估 PPLGM 对 PC 细胞(而非正常细胞)致敏的作用,以
化疗; 3) 评估单独使用 PPLGM 或与 GEM 联合使用的治疗效果
PC 鼠标型号。对于第一个目标,我们将治疗 K-ras 突变型和野生型的正常细胞和 PC 细胞
与 PPLGM 一起,我们将确定 PPLGM 引起 ROS 诱导细胞的分子机制
死亡。对于第二个目标,我们将使用相同的细胞来确定 PPLGM 和 GEM 的综合效果
PC细胞死亡的影响并研究它们诱导PC细胞死亡的协同机制。为了第三个目标,我们
将使用原位小鼠评估 PPLGM 单独使用或与 GEM 联合使用的治疗效果
K-ras突变型人类PC模型和转基因小鼠模型。该方法使用一种新型饮食剂
这表明在 PC 化疗背景下具有有效的抗癌作用。拟议的研究是
预计将垂直推进和扩展对 ROS 诱导剂如何用作
用于癌症治疗的化学增敏剂。最终,这些知识有可能改变这个领域
化疗可以为许多癌症提供更有效的治疗。
_________________________________________________________________________________________________
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Katie Reindl其他文献
Katie Reindl的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Katie Reindl', 18)}}的其他基金
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
- 批准号:
9230406 - 财政年份:
- 资助金额:
$ 21.75万 - 项目类别:
相似国自然基金
干旱内陆河高含沙河床对季节性河流入渗的影响机制
- 批准号:52379031
- 批准年份:2023
- 资助金额:51 万元
- 项目类别:面上项目
沿纬度梯度冠层结构多样性变化对森林生产力的影响
- 批准号:32371610
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
开放与二元结构下的中国工业化:对增长与分配的影响机制研究
- 批准号:72373005
- 批准年份:2023
- 资助金额:40 万元
- 项目类别:面上项目
基于MF和HPLC-ICP-MS监测蛋白冠形成与转化研究稀土掺杂上转换纳米颗粒对凝血平衡的影响机制
- 批准号:82360655
- 批准年份:2023
- 资助金额:32 万元
- 项目类别:地区科学基金项目
高寒草灌植被冠层与根系结构对三维土壤水分动态的影响研究
- 批准号:42301019
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Characterizing Entorhinal Cortex Circuit Dysfunction in an APOE Mouse Model of Chemotherapy-Induced Cognitive Impairment
化疗引起认知障碍的 APOE 小鼠模型中内嗅皮层回路功能障碍的特征
- 批准号:
10677984 - 财政年份:2023
- 资助金额:
$ 21.75万 - 项目类别:
Immunomodulatory biomaterial to enhancing T-cell responses to triple negative breast cancer
免疫调节生物材料可增强 T 细胞对三阴性乳腺癌的反应
- 批准号:
10699815 - 财政年份:2023
- 资助金额:
$ 21.75万 - 项目类别:
Targeting the HMGB1-TLR5 pathway to prevent senescence-induced metastasis in breast cancer.
靶向 HMGB1-TLR5 通路预防乳腺癌衰老诱导的转移。
- 批准号:
10599637 - 财政年份:2023
- 资助金额:
$ 21.75万 - 项目类别:
Elucidating a novel WNT4 regulatory axis as a driver of gynecologic cancer health disparities
阐明新的 WNT4 调节轴作为妇科癌症健康差异的驱动因素
- 批准号:
10773991 - 财政年份:2023
- 资助金额:
$ 21.75万 - 项目类别:
The Breast Cancer and the Workforce Communication App: A randomized controlled trial of an English/Spanish intervention to promote long-term job retention
乳腺癌和劳动力沟通应用程序:一项针对促进长期工作保留的英语/西班牙语干预措施的随机对照试验
- 批准号:
10443450 - 财政年份:2023
- 资助金额:
$ 21.75万 - 项目类别: