Therapeutic targeting of Wnt & Metabolism in Colon Cancer

Wnt 的治疗靶向

• 批准号: 9906187
• 负责人: Marian L Waterman
• 金额: $ 7.73万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-03 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906187
• 关键词: 3-Dimensional; Affect; Angiogenesis Inhibitors; Appearance; Avastin; Biochemical Pathway; Biological Assay; Biological Markers; Blood Vessels; Cancer Model; Cells; Chemotherapy-Oncologic Procedure; Chronic; Clinic; Clinical Trials; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Combined Modality Therapy; Complex; Country; DNA Sequence Alteration; Data; Development; Dichloroacetate; Diffusion; Drug resistance; Drug usage; Environment; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Glycolysis; Growth; Heterogeneity; Homeostasis; Human; Hypoxia; Immunohistochemistry; In Vitro; Knowledge; Life; Ligands; MCT-1 gene; Malignant Neoplasms; Measures; Mediator of activation protein; Metabolic; Metabolism; Modeling; Mus; Nature; Nuclear Translocation; Nutrient; Oxidative Phosphorylation; Oxygen; PDH kinase; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Phenotype; Population; Proliferating; Reaction; Regimen; Reporting; Research; Resistance development; S-Phase Fraction; Shapes; Signal Pathway; Signal Transduction; Spottings; Symbiosis; TCF Transcription Factor; Testing; Tissues; Up-Regulation; WNT Signaling Pathway; Work; Xenograft procedure; aerobic glycolysis; alternative treatment; angiogenesis; base; beta catenin; bevacizumab; cancer cell; cancer stem cell; cancer therapy; cell transformation; chemoradiation; colon cancer patients; density; enhancing factor; flexibility; in silico; in vivo evaluation; inhibitor/antagonist; mathematical model; metastatic colorectal; neoplastic cell; pre-clinical; preclinical study; predictive modeling; predictive test; recruit; single cell sequencing; single-cell RNA sequencing; stem-like cell; subcutaneous; therapeutic target; transcriptome; transcriptome sequencing; treatment arm; tumor; tumor growth; tumor heterogeneity; tumor metabolism; tumor xenograft

Project Summary/Abstract Most of the sporadic colon cancer in this country arises from genetic mutations that activate the canonical WNT/beta-catenin signaling pathway. Yet in the clinic, colon cancer patients are treated the same way they have been for decades: a chemotherapy regimen (e.g. FOLFOX for stages III, IV) and an add-on anti- angiogenic agent such as Bevacizumab or Avastin. Add-on treatments extend life for ~5 months, but they almost always fail because tumors develop resistance. Only one Wnt inhibitor has made it to a Phase II clinical trial for metastatic colon cancer. Clearly there is a need to increase treatment alternatives. Our recent work on WNT signaling has determined that the Wnt/β-catenin pathway directs cancer metabolism, promoting aerobic glycolysis and angiogenesis through upregulated expression of glycolysis genes including Pyruvate Dehydrogenase Kinase 1 (PDK1) and SLC16A1/MCT-1. We also discovered that Wnt signaling activity and glycolysis are heterogeneous in xenografts and patient tumors. Tumor heterogeneity is a recognized hallmark of cancer, and it is thought to derive from intracellular reprogramming of metabolic and signaling networks, a flexibility that helps cancer cells adapt to fluctuating nutrient availability and a stressful environment. The Wnt and glycolytic heterogeneity we observe in xenografted colon tumors presents as an array of cell clusters (5-7 cells, ~30µm center-to-center) at the proliferating, non-necrotic periphery of tumors. We also observe tumor heterogeneity on a cell-by-cell basis using single cell sequencing analysis. The emergence of a regular array of cell clusters in xenografted tumors suggests that the heterogeneity is patterned and regulated. We therefore developed a mathematical model that recreates this pattern at the leading edge of tumors and Wnt signaling lies at the core of this model. We have tested several model predictions about metabolic patterning and gene expression and the results support the validity of the model. However, an important prediction has not been tested - the one most relevant to developing new ideas for cancer therapy. In silico modeling of tumor growth suggests that a combination of anti-Wnt and anti-PDK (glycolysis) drugs should act synergistically to repress tumor growth. Therefore, the project proposed here is focused on testing this prediction. If this prediction is correct, it would point to a new Achilles Heel for targeting in tumors. In Aim I we will test whether anti- Wnt/anti-PDK combination therapy will synergistically suppress colon cancer xenograft growth using drugs that are currently in clinical trials. In Aim II we will assess how tumor and mouse stroma respond to the single and combination therapy regimen using single cell RNA sequencing (scRNAseq), bulk RNAseq and immunohistochemistry. This short-term, highly feasible project is a necessary step towards a larger scope study focused on cancer metabolism with human PDX and primary patient tissue.

项目概要/摘要 这个国家的大多数散发性结肠癌都是由基因突变引起的，这些突变激活了典型的结肠癌。 WNT/β-连环蛋白信号通路。然而在临床上，结肠癌患者的治疗方式与他们相同 几十年来一直如此：化疗方案（例如用于 III、IV 期的 FOLFOX）和附加抗- 血管生成剂，例如贝伐珠单抗或阿瓦斯汀。附加治疗可延长生命约 5 个月，但它们 几乎总是失败，因为肿瘤产生了耐药性。只有一种Wnt抑制剂进入II期临床 转移性结肠癌的试验。显然需要增加治疗替代方案。我们最近的工作 WNT 信号传导已确定 Wnt/β-catenin 通路指导癌症代谢，促进有氧运动 通过上调糖酵解基因（包括丙酮酸）的表达来促进糖酵解和血管生成 脱氢酶激酶 1 (PDK1) 和 SLC16A1/MCT-1。我们还发现 Wnt 信号传导活性和 糖酵解在异种移植物和患者肿瘤中是异质的。肿瘤异质性是公认的标志 它被认为源自代谢和信号网络的细胞内重编程， 灵活性有助于癌细胞适应波动的营养供应和压力环境。 Wnt 我们在异种移植结肠肿瘤中观察到的糖酵解异质性表现为一系列细胞簇（5-7 细胞（中心到中心~30μm）位于肿瘤增殖、非坏死的外围。我们还观察肿瘤 使用单细胞测序分析逐个细胞地分析异质性。正则数组的出现 异种移植肿瘤中的细胞簇表明异质性是有模式和调节的。我们因此 开发了一个数学模型，可以在肿瘤和 Wnt 信号传导的前沿重现这种模式 是这个模型的核心。我们测试了几种关于代谢模式和基因的模型预测 表达式和结果支持了模型的有效性。然而，重要的预测尚未出现 经过测试 - 与开发癌症治疗新想法最相关的一种。肿瘤生长的计算机模拟 表明抗 Wnt 和抗 PDK（糖酵解）药物的组合应协同作用以抑制 肿瘤生长。因此，这里提出的项目重点是测试这一预测。如果这个预测是 正确的，这将指出肿瘤靶向的新致命弱点。在目标 I 中，我们将测试是否反 Wnt/抗 PDK 联合疗法将使用以下药物协同抑制结肠癌异种移植物生长： 目前正在进行临床试验。在目标 II 中，我们将评估肿瘤和小鼠基质对单一和 使用单细胞 RNA 测序 (scRNAseq)、批量 RNAseq 和 免疫组织化学。这个短期、高度可行的项目是迈向更大范围的必要一步 研究重点是人类 PDX 和原发患者组织的癌症代谢。