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WDR5 WIN Site Inhibition in Colorectal Cancer

结直肠癌中的 WDR5 WIN 位点抑制

基本信息

批准号：
10538160
负责人：
Brian C Grieb
金额：
$ 8万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10538160
关键词：
2 year old ANXA5 gene Adherence Americas Antineoplastic Agents Apoptosis Binding Biological Markers Biological Models Biomass Breast Bromodeoxyuridine Burkitt Lymphoma CRISPR interference CRISPR screen CRISPR-mediated transcriptional activation Cancer Biology Cancer Cell Growth Cancer Etiology Cancer Model Cell Culture Techniques Cell Cycle Cell Survival Cells Cessation of life ChIP-seq Chromatin Clinical Clinical Trials Collaborations Colon Carcinoma Colorectal Cancer Communities Consensus Data Data Analyses Dependence Development Drug Combinations Drug Synergism Family Flow Cytometry Foundations Future Gene Expression Genes Genetic Transcription Genomic Instability Genomics Hematology Human Incidence Investigation Investigational Therapies Label Leukemic Cell Lung MYC Family Protein Malignant Neoplasms Mass Spectrum Analysis Metabolism Methods Molecular Mutation Oncogenes Oncogenic Organoids Pathway interactions Patient Selection Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Phase I Clinical Trials Physicians Population Pre-Clinical Model Production Protein Biosynthesis Protein Subunits Proteins Proteomics Proto-Oncogene Proteins c-myc Regulatory Element Research Resistance Ribosomal Proteins Ribosomes Scientist Selection Criteria Site Structure Technology Testing Therapeutic Therapeutic Agents Training Translations United States anticancer research base biological adaptation to stress cancer cell cancer therapy candidate selection career cofactor colon cancer cell line colon cancer patients colorectal cancer treatment combinatorial drug development drug discovery drug sensitivity effectiveness testing experimental study genome-wide improved in vivo inhibitor malignant state molecular marker mortality mouse model neuroblastoma cell novel novel therapeutic intervention novel therapeutics overexpression patient subsets pharmacodynamic biomarker pre-clinical programs recruit resistance mechanism response screening small molecular inhibitor small molecule inhibitor synergism transcription factor transcriptome sequencing transcriptomics tumor tumorigenesis

项目摘要

PROJECT SUMMARY Colorectal cancer is the third most common cancer in the United States. It accounts for over 50,000 deaths annually, the third highest cause of cancer related mortality in America. While improved screening methods and adherence have reduced the overall incidence of colon cancer in the US population as a whole, the incidence has increased in patients less than 50 years of age by 2% annually since the mid-1990s. Thus, new drug development is needed. This project investigates the mechanism and therapeutic potential of an indirect method of targeting MYC in colon cancer using small molecule inhibitors directed against MYC’s newly discovered cofactor WDR5. MYC is an oncogenic transcription factor overexpressed in the majority of human cancers, including colon cancer. As a transcription factor, MYC controls the expression of genes important for cancer cell growth and survival, but no pharmacologic method to inhibit MYC has been developed. WDR5 recruits MYC to a subset of its target genes. Recently developed WDR5 inhibitors block the ability of WDR5 to recruit MYC to its target genes. In so doing, WDR5 inhibitors serve as a novel means to inhibit a fundamental portion of oncogenic MYC transcriptional activity. Preliminary data reveal WDR5 inhibitors may represent a novel therapeutic strategy in colon cancer, yet little is known about the activity of these drugs in colon cancer cells. The proposed research includes a detailed mechanistic study of WDR5 inhibition in colon cancer, establishes molecular markers of sensitivity and resistance, and examines the breadth of WDR5 inhibitor activity as well as novel drug-drug combinatorial therapies in pre-clinical colon cancer models. Aim 1 of this project uses a combination of genomic, transcriptional, and proteomic approaches to fully characterize the molecular mechanism of WDR5 inhibitors in colon cancer cells and identify candidate pharmacodynamic biomarkers. Aim 2 will identify factors that govern sensitivity and resistance to WDR5 inhibitors, helping to forecast mechanisms of resistance as well as detect molecular pathways that can be targeted pharmacologically to improve response to WDR5 inhibition. Novel drug- drug combinations will be tested in cultured colon cancer cells and in a molecularly diverse panel of patient derived organoids, known for accurately predicting in vivo drug sensitivity. Results from these experiments may identify a subset of patients that could benefit from treatment with WDR5 inhibitors. Collectively these studies will lead to a robust understanding of the mechanism of WDR5 inhibitors and their utility as therapeutic agents in colon cancer. The results will provide practical pre-clinical evidence for possible patient selection criteria, pharmacodynamic biomarkers and novel combinatorial therapies that will be foundational to any future clinical trials of WDR5 inhibitors in colon cancer.

项目摘要结直肠癌是美国第三大常见癌症。它导致了超过五万人的死亡每年，癌症是美国癌症相关死亡率的第三大原因。虽然改进了筛选方法，坚持治疗降低了美国人群中结肠癌的总体发病率，自20世纪90年代中期以来，50岁以下的患者每年增加2%。因此，新药需要发展。本项目研究间接方法的机制和治疗潜力使用针对MYC新发现的小分子抑制剂靶向结肠癌中的MYC，辅助因子WDR 5。MYC是在大多数人类癌症中过表达的致癌转录因子，包括结肠癌作为一种转录因子，MYC控制着癌细胞重要基因的表达生长和存活，但还没有开发出抑制MYC的药理学方法。WDR 5招募MYC 它的靶基因的子集。最近开发的WDR 5抑制剂阻断WDR 5招募MYC至其细胞的能力。靶基因在这样做时，WDR 5抑制剂作为一种新的手段来抑制致癌基因的基本部分， MYC转录活性。初步数据显示WDR 5抑制剂可能代表一种新的治疗策略然而，关于这些药物在结肠癌细胞中的活性知之甚少。拟议研究包括结肠癌中WDR 5抑制的详细机制研究，建立了敏感性和耐药性，并检查WDR 5抑制剂活性的广度以及新的药物-药物临床前结肠癌模型中的组合疗法。该项目的目标1使用基因组，转录和蛋白质组学方法，以充分表征WDR 5抑制剂的分子机制，结肠癌细胞并鉴定候选药效学生物标志物。目标2将确定对WDR 5抑制剂的敏感性和耐药性，有助于预测耐药机制以及检测可以靶向的分子途径，以改善对WDR 5抑制的反应。新药- 药物组合将在培养的结肠癌细胞和一组分子多样性的患者中进行测试。衍生的类器官，以准确预测体内药物敏感性而闻名。这些实验的结果可能确定可以从WDR 5抑制剂治疗中获益的患者子集。总体而言，将导致对WDR 5抑制剂的机制及其作为治疗剂的效用的强大理解在结肠癌中。结果将为可能的患者选择标准提供实际的临床前证据，药效学生物标志物和新的组合疗法，这将是未来任何临床 WDR 5抑制剂在结肠癌中的试验。