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

项目摘要：抑制、预防复发或治疗癌症的精确方法仍然是一个挑战。 美国的首要任务。虽然不同的抑制剂已经为这些目的做出了显著的改进（例如， 免疫检查点抑制剂、生长因子受体抑制剂等），很明显， 由于癌症的异质性和以下事实，需要将联合收割机与这些现有疗法结合， 许多癌症对不同的抑制剂具有抗性。因此，描绘新的分子机制， 用于更精确地抑制和治疗癌症的组合方法具有很高的意义。的 过氧化物酶体增殖物激活受体-β/δ（peroxisome proliferator-activated receptor-β/δ，PPARβ/δ）是一种具有潜在应用价值的分子靶点， 预防和/或治疗结肠直肠癌（CRC）。PPARβ/δ的典型配体增加和减少靶点 基因表达。然而，最近已经开发了更具选择性的抑制性的PPARβ/δ配体， 仅抑制基因表达而不增加靶基因。这些选择性抑制性的PPARβ/δ配体 可以显著抑制与癌症抑制、进展和转移相关的细胞事件。没有 有争议的是，选择性的抑制性PPARβ/δ配体是有效的抗癌分子。这些事实和 初步数据为这一提议的中心假设提供了强有力的支持和严谨性， 通过选择性抑制性配体抑制PPARβ/δ靶基因可以调节CRC， 针对精确的方法来抑制/治疗CRC。这个假设将通过三个目标来检验。要求1 将包括组织浓度随时间变化的选择性、抑制性PPARβ/δ配体DG 172的PK分析， 以及选择性抑制性PPARβ/δ配体在组织、生物体液和组织中的I相和II相代谢， 肿瘤的目的2将确定选择性的、抑制性的PPARβ/δ配体DG 172对抑制 利用独特的基因型变异的人类肿瘤的新型原位肿瘤模型中的肿瘤发生和干性 具有对用于治疗CRC的标准抑制剂表现出抗性的基因型的癌细胞系， PPARβ/δ的功能丧失模型。PPARβ/δ调节干性的机制也将在 测定对于目标3，我们将整合基因组学和代谢组学生物信息学分析，以阐明 特异性代谢和肿瘤促进途径，可被选择性抑制性PPARβ/δ靶向 配体来抑制CRC进展和治疗CRC。Aim 3的数据将通过以下方式提供给科学家： 开发一个基于网络的平台，以允许系统分析抑制PPARβ/δ的特异性通路， 《儿童权利公约》。这些研究的结果将产生持续的影响，因为它们将提供新的PPARβ/δ依赖性 这些靶点可能与其他抑制剂联合使用，以开发更有效的治疗方法， 复发，CRC。

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.