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

项目摘要：抑制、预防或治疗癌症的精确方法仍然是一个 这是美国的首要任务。虽然不同的抑制剂已经在这些目的上取得了显著的改进(例如， 免疫检查点抑制剂、生长因子受体抑制剂等)，很明显，额外的分子靶点 由于癌症的异质性和事实，需要与这些现有的治疗方法相结合 许多癌症对不同的抑制剂具有抗药性。因此，描绘了新的分子机制 组合方法对于更精确地抑制和治疗癌症具有重要意义。这个 过氧化物酶体增殖物激活受体β/δ(PPARβ/δ)是一种很有潜力的分子靶标。 预防和/或治疗结直肠癌。PPARβ/δ增减靶标的典型配体 基因表达。然而，最近开发出了更具选择性、抑制性的PPARβ/δ配体 只抑制基因表达，而不是增加靶基因。这些选择性抑制的PPARβ/δ配体 能显著抑制与癌症抑制、进展和转移相关的细胞事件。没有 质疑选择性的、抑制性的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 通过选择性抑制配体抑制PPARβ/δ靶基因可以调节结直肠癌，并可能是 针对抑制/治疗CRC的精确方法。这一假设将由三个目标来检验。目标1 将包括对选择性、抑制性PPARβ/δ配体DG172随时间组织浓度的PK分析， 以及选择性的、抑制性的PPARβ/δ配体在组织、生物液和 肿瘤。目的2将确定选择性、抑制性PPARβ/δ配体DG172的抑制效果 利用独特的、基因变异的人类的新型原位肿瘤模型的肿瘤发生和干性 对用于治疗结直肠癌的标准抑制剂表现出抗药性的基因的癌细胞株，以及Gain-And PPARβ/δ的功能损失模型。PPARβ/δ调节茎干的机制也将是 下定决心。对于目标3，我们将整合基因组和代谢生物信息学分析，以阐明如何 选择性抑制性PPARβ/δ靶向的特定代谢和促肿瘤通路 用来抑制CRC进展和治疗CRC的配体。来自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，以允许对抑制PPARβ/δ的特定途径进行系统分析 CRC。这些研究的结果将产生持续的影响，因为它们将提供新的依赖于β/δ的PPAR 靶点，可能与其他抑制剂结合，以开发更有效的治疗方法，并防止 复发，用于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.