Inhibiting VHL-positive kidney cancer

抑制 VHL 阳性肾癌

基本信息

项目摘要

DESCRIPTION (provided by applicant): Patients with VHL-positive renal cell carcinoma (RCC) have very few treatment options. Indeed, these patients are most often told by their oncologists that experimental treatments are their best option, since there are no biologically rational treatments for them. The lack of therapeutic targets to treat VHL-positive RCC is a critical unmet need in cancer treatment. We recently demonstrated in human VHL-positive RCC cancer cells and patient tumors that the oncogenic Src kinase signaling pathway was elevated. Moreover, we found that the Src inhibitor, dasatinib reduced the proliferation of VHL-positive cells both in vitro and in mouse models. Together, our studies represent the first breakthrough for the molecularly targeted treatment of VHL-positive RCC. While dasatinib alone did slow cell proliferation, however, it failed to kill VHL-positive RCC in vitro and in vivo. We hypothesize tha the response observed with Src inhibition by dasatinib alone resulted from bypass pathways present in kidney cancer that override the therapeutic benefit of inhibiting a single target. Consistent with this possibility, VHL-positive RCC contains elevated levels of Signal Transducer and Activator of Transcription-3 (STAT3) and activated Src homology phosphotyrosine phosphatase (Shp2). Indeed, dasatinib alone failed to block oncogenic STAT3 activation. We further hypothesize that the STAT3 and Shp2 signaling pathways represent new therapeutic targets for treatment of VHL-positive RCC. This is because STAT3 plays a pivotal role in activating genes responsible for survival and chemoresistance, and Shp2 can activate downstream effectors of cell transformation in the face of Src inhibition. To address this hypothesis we will pursue the following: Aim 1: Determine the role of STAT3 in overriding Src inhibition; Aim 2: Determine the role and requirement of Shp2 signaling in VHL-positive RCC pathogenesis; and Aim 3: Identify kinase inhibitors that work synergistically with dasatinib to kil VHL-positive RCC cells. We will use human cancer cell lines and tumor specimens to establish the biological rationale for inhibiting survival and tumor-specific bypass pathways in VHL-Positive RCC and leverage this insight into novel drug combinations and biomarkers for a disease that is incurable. This proposed research, which builds on our published work, will comprehensively determine the role of transcription factors, tyrosine phosphatases and kinases in mediating resistance to Src inhibitors-and ultimately is expected to deliver more effective therapies. Importantly, this is not an incremental advance in treatment since it shifts from a reliance on monotherapy to evidence-based combination therapies that override resistance from the get-go, and thereby deliver sustained clinical responses.
描述(由申请人提供):VHL阳性肾细胞癌(RCC)患者的治疗选择非常少。事实上,这些患者最常被他们的肿瘤学家告知,实验性治疗是他们最好的选择,因为没有生物学上合理的治疗方法。缺乏治疗VHL阳性RCC的治疗靶标是癌症治疗中未满足的关键需求。我们最近在人VHL阳性RCC癌细胞和患者肿瘤中证实,致癌Src激酶信号通路升高。此外,我们发现Src抑制剂达沙替尼在体外和小鼠模型中均可减少VHL阳性细胞的增殖。总之,我们的研究代表了VHL阳性RCC分子靶向治疗的第一个突破。虽然单独的达沙替尼确实减缓了细胞增殖,但是,它在体外和体内都不能杀死VHL阳性的RCC。我们假设,单独使用达沙替尼抑制Src时观察到的反应是由肾癌中存在的旁路途径引起的,这些旁路途径覆盖了抑制单一靶点的治疗益处。与这种可能性一致,VHL阳性RCC含有升高水平的信号转导和转录激活因子-3(STAT 3)和激活的Src同源磷酸酪氨酸磷酸酶(Shp 2)。事实上,单独的达沙替尼未能阻断致癌性STAT 3激活。我们进一步假设STAT 3和Shp 2信号通路代表了VHL阳性RCC治疗的新靶点。这是因为STAT 3在激活负责存活和化学抗性的基因中起着关键作用,而Shp 2可以在Src抑制的情况下激活细胞转化的下游效应子。为了解决这一假设,我们将进行以下研究:目的1:确定STAT 3在压倒Src抑制中的作用;目的2:确定Shp 2信号传导在VHL阳性RCC发病机制中的作用和要求;目的3:鉴定与达沙替尼协同作用以抑制VHL阳性RCC细胞的激酶抑制剂。我们将使用人类癌细胞系和肿瘤标本来建立抑制VHL阳性RCC中的存活和肿瘤特异性旁路途径的生物学原理,并利用这种见解来开发新型药物组合和生物标志物,用于治疗不可治愈的疾病。这项拟议的研究建立在我们已发表的工作基础上,将全面确定转录因子,酪氨酸磷酸酶和激酶在介导Src受体抗性中的作用,并最终有望提供更有效的治疗方法。重要的是,这不是治疗的渐进式进步,因为它从依赖单一疗法转变为基于证据的联合疗法,从一开始就克服耐药性,从而提供持续的临床反应。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Combining trail with PI3 kinase or HSP90 inhibitors enhances apoptosis in colorectal cancer cells via suppression of survival signaling.
  • DOI:
    10.18632/oncotarget.1162
  • 发表时间:
    2013-08
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Saturno G;Valenti M;De Haven Brandon A;Thomas GV;Eccles S;Clarke PA;Workman P
  • 通讯作者:
    Workman P
Metastatic renal cell carcinoma without evidence of a renal primary.
无肾原发证据的转移性肾细胞癌。
  • DOI:
    10.1007/s11255-015-1145-3
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    2
  • 作者:
    Costantino,Corey;Thomas,GeorgeV;Ryan,Christopher;Coakley,FergusV;Troxell,MeganL
  • 通讯作者:
    Troxell,MeganL
{{ 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 }}

George Victor Thomas其他文献

George Victor Thomas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('George Victor Thomas', 18)}}的其他基金

Novel Treatment Strategies for Cancer
癌症新治疗策略
  • 批准号:
    10193053
  • 财政年份:
    2021
  • 资助金额:
    $ 31.96万
  • 项目类别:
Developing novel polytherapies for Non-Clear Cell Renal Cell Carcinoma
开发非透明细胞肾细胞癌的新型多疗法
  • 批准号:
    10555185
  • 财政年份:
    2021
  • 资助金额:
    $ 31.96万
  • 项目类别:
Developing novel polytherapies for Non-Clear Cell Renal Cell Carcinoma
开发非透明细胞肾细胞癌的新型多疗法
  • 批准号:
    10308505
  • 财政年份:
    2021
  • 资助金额:
    $ 31.96万
  • 项目类别:
Biospecimen Acquisition, Processing and Classification Unit
生物样本采集、处理和分类装置
  • 批准号:
    10005914
  • 财政年份:
    2018
  • 资助金额:
    $ 31.96万
  • 项目类别:
Biospecimen Acquisition, Processing and Classification Unit
生物样本采集、处理和分类装置
  • 批准号:
    10471934
  • 财政年份:
    2018
  • 资助金额:
    $ 31.96万
  • 项目类别:
Biospecimen Acquisition, Processing and Classification Unit
生物样本采集、处理和分类装置
  • 批准号:
    10246895
  • 财政年份:
    2018
  • 资助金额:
    $ 31.96万
  • 项目类别:
Inhibiting VHL-positive kidney cancer
抑制 VHL 阳性肾癌
  • 批准号:
    8503820
  • 财政年份:
    2013
  • 资助金额:
    $ 31.96万
  • 项目类别:
Inhibiting VHL-positive kidney cancer
抑制 VHL 阳性肾癌
  • 批准号:
    8634752
  • 财政年份:
    2013
  • 资助金额:
    $ 31.96万
  • 项目类别:
Inhibiting VHL-positive kidney cancer
抑制 VHL 阳性肾癌
  • 批准号:
    9038327
  • 财政年份:
    2013
  • 资助金额:
    $ 31.96万
  • 项目类别:
Biolibrary and Pathology
生物图书馆和病理学
  • 批准号:
    10205354
  • 财政年份:
    1997
  • 资助金额:
    $ 31.96万
  • 项目类别:

相似海外基金

A study for cross borders Indonesian nurses and care workers: Case of Japan-Indonesia Economic Partnership Agreement
针对跨境印度尼西亚护士和护理人员的研究:日本-印度尼西亚经济伙伴关系协定的案例
  • 批准号:
    22KJ0334
  • 财政年份:
    2023
  • 资助金额:
    $ 31.96万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
NSF-NOAA Interagency Agreement (IAA) for the Global Oscillations Network Group (GONG)
NSF-NOAA 全球振荡网络组 (GONG) 机构间协议 (IAA)
  • 批准号:
    2410236
  • 财政年份:
    2023
  • 资助金额:
    $ 31.96万
  • 项目类别:
    Cooperative Agreement
Conditions for U.S. Agreement on the Closure of Contested Overseas Bases: Relations of Threat, Alliance and Base Alternatives
美国关于关闭有争议的海外基地协议的条件:威胁、联盟和基地替代方案的关系
  • 批准号:
    23K18762
  • 财政年份:
    2023
  • 资助金额:
    $ 31.96万
  • 项目类别:
    Grant-in-Aid for Research Activity Start-up
MSI Smart Manufacturing Data Hub – Open Calls Grant Funding Agreement
MSI 智能制造数据中心 – 公开征集赠款资助协议
  • 批准号:
    900240
  • 财政年份:
    2023
  • 资助金额:
    $ 31.96万
  • 项目类别:
    Collaborative R&D
Challenges of the Paris Agreement Exposed by the Energy Shift by External Factors: The Case of Renewable Energy Policies in Japan, the U.S., and the EU
外部因素导致的能源转移对《巴黎协定》的挑战:以日本、美国和欧盟的可再生能源政策为例
  • 批准号:
    23H00770
  • 财政年份:
    2023
  • 资助金额:
    $ 31.96万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Continuation of Cooperative Agreement between U.S. Food and Drug Administration and S.C. Department of Health and Environmental Control (DHEC) for MFRPS Maintenance.
美国食品和药物管理局与南卡罗来纳州健康与环境控制部 (DHEC) 继续签订 MFRPS 维护合作协议。
  • 批准号:
    10829529
  • 财政年份:
    2023
  • 资助金额:
    $ 31.96万
  • 项目类别:
National Ecological Observatory Network Governing Cooperative Agreement
国家生态观测站网络治理合作协议
  • 批准号:
    2346114
  • 财政年份:
    2023
  • 资助金额:
    $ 31.96万
  • 项目类别:
    Cooperative Agreement
The Kansas Department of Agriculture's Flexible Funding Model Cooperative Agreement for MFRPS Maintenance, FPTF, and Special Project.
堪萨斯州农业部针对 MFRPS 维护、FPTF 和特别项目的灵活资助模式合作协议。
  • 批准号:
    10828588
  • 财政年份:
    2023
  • 资助金额:
    $ 31.96万
  • 项目类别:
Robust approaches for the analysis of agreement between clinical measurements: development of guidance and software tools for researchers
分析临床测量之间一致性的稳健方法:为研究人员开发指南和软件工具
  • 批准号:
    MR/X029301/1
  • 财政年份:
    2023
  • 资助金额:
    $ 31.96万
  • 项目类别:
    Research Grant
FER (H&L) AMR PACE (A-0438) grant funding agreement
费率(H
  • 批准号:
    107541
  • 财政年份:
    2023
  • 资助金额:
    $ 31.96万
  • 项目类别:
    Collaborative R&D
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了