Therapeutic targeting of Wnt & Metabolism in Colon Cancer

Wnt 的治疗靶向

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要这个国家的大多数零星结肠癌源于激活规范的基因突变 Wnt/beta-catenin信号通路。然而，在诊所中，结肠癌患者的治疗方式相同已经存在数十年：一种化学疗法方案（例如，III阶段的FOLFOX）和附加抗抗抗素血管生成剂，例如贝伐单抗或阿avastin。附加治疗延长了约5个月的寿命，但他们几乎总是失败，因为肿瘤发育抗性。只有一个Wnt抑制剂已进入II期临床转移性结肠癌试验。显然，有必要增加治疗替代方案。我们最近的工作 Wnt信号已确定Wnt/β-catenin途径指导癌症代谢，促进有氧运动通过更新（包括丙酮酸）的糖酵解基因表达的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信号活动和糖酵解在Xenographictic和患者肿瘤中是异质的。肿瘤异质性是公认的标志癌症，被认为是源自代谢和信号网络的细胞内重编程，A 有助于癌细胞适应养分可利用性和压力环境的灵活性。 wnt 我们在异种移植结肠肿瘤中观察到的糖酵解异质性作为细胞簇的阵列（5-7 细胞，中心〜30µm）在肿瘤的增殖，非残疾周围的细胞。我们也观察到肿瘤使用单细胞测序分析，逐一基础上的异质性。常规阵列的出现异种移植肿瘤中的细胞簇表明异质性是图案化和调节的。因此，我们开发了一种数学模型，该模型在肿瘤和Wnt信号的前沿重新创建了这种模式是该模型的核心。我们已经测试了有关代谢图案和基因的几个模型预测表达和结果支持模型的有效性。但是，重要的预测不是经过测试 - 与开发癌症疗法的新思想最相关的一种。在肿瘤生长的硅硅建模中表明抗Wnt和抗PDK（糖酵解）药物的组合应协同作用于复制品肿瘤生长。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，这将指向靶向肿瘤的新致命高跟鞋。在目的中，我将测试是否反对 Wnt/抗PDK组合疗法将使用药物协同抑制结肠癌的Xenographic Entragy Growtings 目前正在临床试验中。在AIM II中，我们将评估肿瘤和小鼠基质如何对单一和单一的反应使用单细胞RNA测序（SCRNASEQ），BOLK 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步骤研究重点是人类PDX和原发性患者组织的癌症代谢。