Targeting Aldehyde Dehydrogenase for Cancer Prevention

以醛脱氢酶为靶点预防癌症

基本信息

  • 批准号:
    10327368
  • 负责人:
  • 金额:
    $ 12.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-04-15 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY: This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 21-009 to establish a collaboration between the parent 1 R01 CA241148-01A1 and the NCI-supported PDX Development and Trial Centers Research Network (PDXNet)-Wistar Institute site. The project focuses on a unique form of cancer cell drug resistance identified in the parent R01 mediated by the Aldehyde Dehydrogenase (ALDH) expressing cellular subpopulations present in tumors. The ALDH family of enzymes convert toxic aldehydes generated during cellular metabolism into corresponding less toxic carboxylic acids that can be excreted and removed. ALDH expression and activity increases during tumor progression with a corresponding higher positive (ALDH+) subpopulation. In the parent R01, we have found that changing the size of the ALDH+ and negative (ALDH-) cell subpopulations, which occurs during drug treatment and resistance development, performs an important role in maintaining tumor ROS levels in an optimal range needed for the development of this novel type of drug resistance. This supplement proposes a collaboration to use melanoma PDXs developed by Dr. Meenhard Herlyn at the Wistar Institute to identify the most effective approach to prevent this novel form of cancer cell resistance. The goal will be to target the ALDH+ cells using DIMATE (under clinical evaluation for leukemia) in combination with a clinically used BRAF and MEK inhibitor combination targeting the ALDH- subpopulation. The evaluation would be undertaken in PDX models naïve or resistant to the BRAF/MEK drug combination. In the parent R01, we have discovered that ALDH+ and ALDH- cell subpopulations, cooperate to promote survival and achieve drug resistance. Furthermore, we have discovered in cultured cell line-based models that this cooperation can best be prevented by therapeutically targeting both populations. The ALDH cell number and/or the related ROS pathway signaling can be used as biomarkers to assess treatment efficacy in the PDX models. Therefore, we have formulated a novel central hypothesis that drug resistance can be prevented in cancer by targeting the ALDH positive cell population with DIMATE and the negative population by targeting the MAP kinase pathways through BRAF and MEK inhibition in PDX tumors resistant to MAP kinase inhibition. To test this hypothesis, we will determine the most effective consecutive or simultaneous targeting approach to prevent resistance in PDX melanoma models naïve or resistant to BRAF/MEK inhibition using DIMATE. PDX models used would have developed resistant to MAP kinase pathway inhibition through different mechanisms. The effectiveness of DIMATE will be compared to nanoKS100 (a preclinical agent developed in the Parent R01 Award), which we have found is effective at preventing resistance when combined with MAP kinase pathway targeting. The clinical significance of this project is that if successful, these discoveries could provide a solid rationale for testing this approach in the clinic.
项目总结: 本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的 21-009在父1 R01 CA241148-01A1和NCI支持的PDX之间建立协作 开发和试验中心研究网络(PDXNet)-Wistar研究所网站。该项目的重点是 亲本R01中由乙醛脱氢酶介导的独特形式的癌细胞耐药性 (ALDH)表达肿瘤中存在的细胞亚群。ALDH家族的酶可将有毒物质 细胞代谢过程中产生的醛转化为相应的毒性较低的羧酸,这些羧酸可以 排泄物和排泄物。ALDH的表达和活性在肿瘤进展过程中增加,相应的 较高的阳性(ALDH+)亚群。在亲本R01中,我们发现改变ALDH+的大小 和阴性(ALDH-)细胞亚群,在药物治疗和耐药性形成过程中发生, 在将肿瘤ROS水平维持在发展所需的最佳范围方面发挥重要作用 这种新型的抗药性。本增刊建议合作使用开发的黑色素瘤PDX 由Wistar研究所的Meenhard Herlyn博士提出,以确定防止这种新形式的最有效方法 癌细胞的抗药性。目标将是使用DIMATE(正在进行临床评估)靶向ALDH+细胞 白血病)与临床使用的靶向ALDH的BRAF和MEK抑制剂组合相结合。 亚群。评估将在对BRAF/MEK药物天真或耐药的PDX模型中进行 组合。在亲本R01中,我们发现ALDH+和ALDH-细胞亚群,协同作用 促进生存,实现抗药性。此外,我们还发现在培养的细胞系中 模型表明,通过针对这两个人群进行治疗,这种合作可以得到最好的预防。ALDH 细胞数量和/或相关的ROS通路信号转导可作为评估疗效的生物标志物 在PDX型号中。因此,我们提出了一个新的中心假设,即耐药性可能是 通过用DIMATE靶向ALDH阳性细胞群和通过靶向ALDH阴性细胞群来预防癌症 通过抑制BRAF和MEK靶向MAP激酶通路在耐药的PDX肿瘤中的作用 抑制力。为了验证这一假设,我们将确定最有效的连续或同时目标 预防PDX黑色素瘤模型对BRAF/MEK抑制耐药的方法 DIMATE。使用的PDX模型将通过不同的方式产生对MAPK途径抑制的抗性 机制。DIMATE的有效性将与NanKS100(一种临床前药物,在 父母R01奖),我们发现当与MAP结合时,它在预防耐药性方面是有效的 以激酶通路为靶点。该项目的临床意义在于,如果成功,这些发现可能会 为在临床上测试这种方法提供了坚实的理由。

项目成果

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SHANTU G AMIN其他文献

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{{ truncateString('SHANTU G AMIN', 18)}}的其他基金

Targeting Aldehyde Dehydrogenase for Cancer Prevention
以醛脱氢酶为靶点预防癌症
  • 批准号:
    10369718
  • 财政年份:
    2020
  • 资助金额:
    $ 12.5万
  • 项目类别:
Targeting Aldehyde Dehydrogenase for Cancer Prevention
以醛脱氢酶为靶点预防癌症
  • 批准号:
    9973328
  • 财政年份:
    2020
  • 资助金额:
    $ 12.5万
  • 项目类别:
Synthesis and Nanoformulation Core
合成和纳米制剂核心
  • 批准号:
    8554598
  • 财政年份:
    2013
  • 资助金额:
    $ 12.5万
  • 项目类别:
CORE--ORGANIC SYNTHESIS FACILITY
核心——有机合成装置
  • 批准号:
    6605471
  • 财政年份:
    2002
  • 资助金额:
    $ 12.5万
  • 项目类别:
CORE--ORGANIC SYNTHESIS FACILITY
核心——有机合成装置
  • 批准号:
    6413601
  • 财政年份:
    2001
  • 资助金额:
    $ 12.5万
  • 项目类别:
CORE--ORGANIC SYNTHESIS FACILITY
核心——有机合成装置
  • 批准号:
    6300127
  • 财政年份:
    1999
  • 资助金额:
    $ 12.5万
  • 项目类别:
CORE--ORGANIC SYNTHESIS FACILITY
核心——有机合成装置
  • 批准号:
    6101853
  • 财政年份:
    1998
  • 资助金额:
    $ 12.5万
  • 项目类别:
SYNTHESIS OF SELECTED CHEMICAL CARCINOGENS
选定化学致癌物的合成
  • 批准号:
    2764133
  • 财政年份:
    1997
  • 资助金额:
    $ 12.5万
  • 项目类别:
SYNTHESIS OF SELECTED CHEMICAL CARCINOGENS
选定化学致癌物的合成
  • 批准号:
    6286378
  • 财政年份:
    1997
  • 资助金额:
    $ 12.5万
  • 项目类别:
SYNTHESIS OF SELECTED CHEMICAL CARCINOGENS
选定化学致癌物的合成
  • 批准号:
    2556677
  • 财政年份:
    1997
  • 资助金额:
    $ 12.5万
  • 项目类别:

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