Unique targeting of PPARβ/δ regulation for cancer prevention and therapy

癌症预防和治疗中 PPARβ/β 调节的独特靶向

基本信息

  • 批准号:
    10539245
  • 负责人:
  • 金额:
    $ 64.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-12-06 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

Project Summary: Precision approaches for inhibiting, preventing recurrence, or treating cancers remains a top priority in the US. While different inhibitors have made significant improvements for these purposes (e.g. immune checkpoint inhibitors, growth factor receptor inhibitors, etc.), it is clear that additional molecular targets are needed to combine with these existing therapies due to the heterogeneity of cancers and the fact that many cancers are resistant to different inhibitors. Thus, delineating new molecular mechanisms for combinatorial approaches for more precision inhibition and therapy of cancer is of high significance. The peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) has great potential as a molecular target for preventing and/or treating colorectal cancer (CRC). Typical ligands for PPARβ/δ increase and decrease target gene expression. However, more selective, repressive PPARβ/δ ligands have recently been developed that only repress gene expression rather than increase target genes. These selective repressive PPARβ/δ ligands can markedly inhibit cellular events associated with cancer inhibition, progression and metastasis. There is no dispute that selective, repressive PPARβ/δ ligands are effective anti-cancer molecules. These facts and preliminary data provide strong support and rigor of the central hypothesis of this proposal that repressing PPARβ/δ target genes by a selective, repressive ligand can modulate CRC and may be targeted for precision approaches to inhibit/treat CRC. This hypothesis will be examined by 3 Aims. Aim 1 will include PK analysis of the selective, repressive PPARβ/δ ligand DG172 of tissue concentrations over time, and phase I and phase II metabolism of the selective, repressive PPARβ/δ ligand in tissues, biofluids and tumors. Aim 2 will determine the efficacy of the selective, repressive PPARβ/δ ligand DG172 to inhibit tumorigenesis and stemness in novel orthotopic tumors models that utilize unique, genotypically variant human cancer cell lines with genotypes that exhibit resistance to standard inhibitors used to treat CRC, and gain- and loss-of-function models for PPARβ/δ. The mechanisms by which PPARβ/δ regulates stemness will also be determined. For Aim 3, we will integrate genomic and metabolomic bioinformatic analyses to elucidate how specific metabolic and tumor-promoting pathways that can be targeted by selective repressive PPARβ/δ ligands to inhibit CRC progression and treat CRC. Data from Aim 3 will be made available to scientists by developing a web-based platform to allow for systems analyses of PPARβ/δ-specific pathways that inhibit CRC. Results from these studies will have a sustained impact as they will provide new PPARβ/δ-dependent targets that might be combined with other inhibitors to develop more effective therapies, and prevent recurrence, for CRC.
项目总结:精确的方法来抑制,预防复发,或治疗癌症仍然是一个

项目成果

期刊论文数量(0)
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Andrew Patterson其他文献

Andrew Patterson的其他文献

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{{ truncateString('Andrew Patterson', 18)}}的其他基金

Environmental Chemical Impact on the Host-Microbiome Interaction
环境化学对宿主-微生物组相互作用的影响
  • 批准号:
    10641509
  • 财政年份:
    2023
  • 资助金额:
    $ 64.15万
  • 项目类别:
Integrative Analysis of Metabolic Phenotypes (IAMP) Predoctoral Training Program
代谢表型综合分析(IAMP)博士前培训项目
  • 批准号:
    10417044
  • 财政年份:
    2020
  • 资助金额:
    $ 64.15万
  • 项目类别:
Integrative Analysis of Metabolic Phenotypes (IAMP) Predoctoral Training Program
代谢表型综合分析(IAMP)博士前培训项目
  • 批准号:
    10626745
  • 财政年份:
    2020
  • 资助金额:
    $ 64.15万
  • 项目类别:
Unique targeting of PPARβ/δ regulation for cancer prevention and therapy
癌症预防和治疗中 PPARβ/β 调节的独特靶向
  • 批准号:
    10066327
  • 财政年份:
    2019
  • 资助金额:
    $ 64.15万
  • 项目类别:
Unique targeting of PPARβ/δ regulation for cancer prevention and therapy
癌症预防和治疗中 PPARβ/β 调节的独特靶向
  • 批准号:
    10311068
  • 财政年份:
    2019
  • 资助金额:
    $ 64.15万
  • 项目类别:
R01: FXR and the Gut Microbiome as Modulators of Non-Alcoholic Fatty Liver Disease
R01:FXR 和肠道微生物组作为非酒精性脂肪肝的调节剂
  • 批准号:
    10228735
  • 财政年份:
    2019
  • 资助金额:
    $ 64.15万
  • 项目类别:
Unique targeting of PPARβ/δ regulation for cancer prevention and therapy
癌症预防和治疗中 PPARβ/β 调节的独特靶向
  • 批准号:
    9906573
  • 财政年份:
    2019
  • 资助金额:
    $ 64.15万
  • 项目类别:
R01: FXR and the Gut Microbiome as Modulators of Non-Alcoholic Fatty Liver Disease
R01:FXR 和肠道微生物组作为非酒精性脂肪肝的调节剂
  • 批准号:
    10488612
  • 财政年份:
    2019
  • 资助金额:
    $ 64.15万
  • 项目类别:
R01: FXR and the Gut Microbiome as Modulators of Non-Alcoholic Fatty Liver Disease
R01:FXR 和肠道微生物组作为非酒精性脂肪肝的调节剂
  • 批准号:
    10671560
  • 财政年份:
    2019
  • 资助金额:
    $ 64.15万
  • 项目类别:
R01: FXR and the Gut Microbiome as Modulators of Non-Alcoholic Fatty Liver Disease
R01:FXR 和肠道微生物组作为非酒精性脂肪肝的调节剂
  • 批准号:
    10022323
  • 财政年份:
    2019
  • 资助金额:
    $ 64.15万
  • 项目类别:

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