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：
Andrew Patterson
金额：
$ 64.15万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
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

来源：
https://reporter.nih.gov/project-details/10539245
关键词：
APC gene Acute Antineoplastic Agents Bioinformatics Biological Markers Breast Cancer Model Cancer Model Cancer cell line Cells Colon Colon Carcinoma Colorectal Cancer Complex Coupled Data Databases Disease Disputes Dose Down-Regulation Drug Kinetics Drug Targeting Drug resistance Epithelium Evaluation Event Exhibits Feces Gene Expression Genes Genetic Genetic Transcription Genomics Genotype Goals Growth Factor Receptors Histology Human Immune checkpoint inhibitor Invaded KRAS2 gene Ligands Link Malignant Neoplasms Metabolic Metabolic Pathway Metabolism Methodology Modeling Molecular Molecular Target Morbidity - disease rate Mutation Mutation Spectra NU/NU Mouse Neoplasm Metastasis Nodal Nuclear Receptors PPAR-beta Pathway interactions Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phase Pre-Clinical Model Prevention Proto-Oncogenes Recurrence Recurrent disease Regulation Repression Research Resistance Role Scientist Study models Systems Analysis TP53 gene Testing Therapeutic Time Tissues Toxic effect Translational Research Tumor Promotion Tumor Suppressor Proteins United States Variant anti-cancer cancer cell cancer heterogeneity cancer prevention cancer therapy cancer type colon cancer patients colon cancer prevention colorectal cancer prevention colorectal cancer progression colorectal cancer treatment combinatorial constitutive expression dosimetry drug efficacy effective therapy efficacy evaluation fighting gain of function gene repression genetic corepressor improved inhibitor innovation insight loss of function metabolomics migration novel novel marker novel strategies overexpression personalized approach prevent receptor recruit refractory cancer stemness transcription factor translational impact tumor tumor progression tumorigenesis web platform

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.

项目摘要：抑制、预防复发或治疗癌症的精确方法仍然是一个难题尽管不同的抑制剂已针对这些目的做出了重大改进（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以及以下事实，需要与这些现有疗法相结合许多癌症对不同的抑制剂具有耐药性，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。过氧化物酶体增殖物激活受体-β/δ (PPARβ/δ) 作为分子靶点具有巨大潜力预防和/或治疗结直肠癌 (CRC) 的典型配体 PPARβ/δ 增加和减少靶点。然而，最近开发了更具选择性、抑制性的 PPARβ/δ 配体。这些选择性抑制 PPARβ/δ 配体仅抑制基因表达而不增加靶基因。可以显着抑制与癌症抑制、进展和转移相关的细胞事件。对于选择性、抑制性 PPARβ/δ 配体是有效的抗癌分子这一说法存在争议。初步数据为本提案的中心假设提供了强有力的支持和严格性：通过选择性抑制性配体抑制 PPARβ/δ 靶基因可以调节 CRC，并且可能针对抑制/治疗 CRC 的精确方法，该假设将通过 3 个目标 1 进行检验。将包括随时间推移对组织浓度的选择性抑制性 PPARβ/δ 配体 DG172 进行 PK 分析，组织、生物体液和组织中选择性抑制性 PPARβ/δ 配体的 I 期和 II 期代谢目标 2 将确定选择性抑制性 PPARβ/δ 配体 DG172 抑制肿瘤的功效。利用独特的基因型变异人类的新型原位肿瘤模型中的肿瘤发生和干细胞性具有对用于治疗 CRC 的标准抑制剂表现出抗性的基因型的癌细胞系，并且获得和 PPARβ/δ 的功能丧失模型也将是 PPARβ/δ 调节干性的机制。对于目标 3，我们将整合基因组和代谢组生物信息学分析来阐明如何实现。选择性抑制 PPARβ/δ 可以靶向的特定代谢和肿瘤促进途径抑制 CRC 进展和治疗 CRC 的配体将由 Aim 3 向科学家提供。开发一个基于网络的平台，以允许对抑制 PPARβ/δ 特异性途径进行系统分析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。可能与其他抑制剂联合开发更有效的疗法的目标，并预防复发，用于 CRC。