Targeting the MYC Pathway for the Treatment of Cancer

靶向 MYC 通路治疗癌症

• 批准号: 10256047
• 负责人: DEAN W FELSHER
• 金额: $ 96.33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10256047
• 关键词: Acute; Adenocarcinoma Cell; Biological Models; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Exhibits; Genes; Glean; Goals; Human; Immune; In Vitro; Libraries; Lung Adenocarcinoma; Lymphoma; MYC gene; Malignant Neoplasms; Methods; Modeling; Molecular; Oncogenes; Pathway interactions; Primary carcinoma of the liver cells; Productivity; RNA; Renal Cell Carcinoma; Reporter; Research; Research Personnel; Research Proposals; Role; Seminal; System; T-Lymphocyte; Tetracyclines; Transgenic Mice; Work; anticancer research; bcr-abl Fusion Proteins; cancer therapy; gene therapy; in vivo; innovation; insight; leukemia; lipid biosynthesis; metabolomics; mouse model; new technology; new therapeutic target; novel; novel therapeutics; nucleocytoplasmic transport; osteosarcoma; patient derived xenograft model; programs; transcriptome sequencing; tumor; tumorigenesis

Abstract MYC is the most commonly activated oncogene in human cancer. However, to date, no existing therapies directly target MYC or the MYC pathway. My goal is now to target the MYC oncogene pathway to treat human cancer. Over the last 20 years, I have gained fundamental new insights into how the MYC oncogene initiates and maintains tumorigenesis. My work has established the idea that MYC is a hallmark of cancer and that many cancers are “MYC oncogene addicted”. I have identified both tumor intrinsic and host-immune dependent mechanisms. Now, I will use these insights from lab and novel methods to develop new therapies for cancer. I was one of the first investigators to use the Tetracycline regulatory system (Tet system) to generate “conditional” transgenic mouse models to demonstrate that MYC-induced cancer is “reversible” or “oncogene addicted” (Felsher and Bishop, Molecular Cell, 1999). Since then, I have used the Tet system to make a library of oncogene driven transgenic mouse models (MYC, RAS, BCR-ABL) of T-cell acute lymphoma (T-ALL), leukemia (AML), osteosarcoma (OS), hepatocellular carcinoma (HCC), lung adenocarcinoma (LAC) and renal cell adenocarcinoma (RCC). I have used my conditional transgenic mouse model systems to not only understand how MYC and other oncogenes initiate and maintain tumorigenesis but also develop innovative methods and novel technologies to make seminal contributions in cancer research, exhibiting sustained productivity. My proposed future research is built on recent observations that have used combined RNA, ChIP and metabolomic analysis to identify that lipogenesis and CRISPR synthetic lethal screen to identify nuclear transport as examples of otherwise not known to be MYC-regulated gene pathways that when targeted can block and reverse MYC- driven cancer. Now, I propose to use my library of conditional transgenic mouse models and human PDX models to generally identify targetable genes and pathways in the MYC oncogene pathway. I will use three complimentary approaches: RNAseq, ChIPseq and DESI-MSI to identify novel vulnerabilities in MYC-driven cancers; CRISPR in vitro and in vivo synthetic lethal screens combined with CyTOF and CODEX analysis to identify targets in my MYC-driven tumor models and understand their mechanistic role in tumorigenesis; MYC function reporter systems to be able to screen for genes and therapies to target MYC-driven cancers. My proposed research program has extensive support from an interdisciplinary team of colleagues. My proposed studies will glean novel mechanistic insights for how MYC drives tumorigenesis and use these insights to develop new therapeutic targets.

抽象的 MYC是人类癌症中最常见的癌基因。但是，迄今为止，尚无现有疗法 直接针对MYC或MYC途径。我的目标是针对MYC癌基途径来治疗人类 癌症。在过去的20年中，我对Myc Oncogene如何启动了基本的新见解 并保持肿瘤发生。我的工作已经确定了MYC是癌症的标志的想法 癌症是“ Myc Oncogene上瘾”。我已经确定了肿瘤的固有和宿主免疫依赖性 机制。现在，我将使用实验室和新方法的这些见解来开发新的癌症疗法。 是最早使用四环素调节系统（TET系统）生成“条件”的研究者之一 转基因小鼠模型证明MYC诱导的癌症是“可逆的”或“癌基因上瘾” （Felsher和Bishop，分子细胞，1999）。从那以后，我使用TET系统制作了一个库 T细胞急性淋巴瘤（T-ALL），白血病的癌基因驱动的转基因小鼠模型（MYC，RAS，BCR-ABL） （AML），骨肉瘤（OS），肝细胞癌（HCC），肺腺癌（LAC）和肾细胞 腺癌（RCC）。我已经使用了有条件的转基因鼠标模型系统来理解 MYC和其他癌基因如何启动和维持肿瘤发生，还开发了创新的方法和 在癌症研究中做出第二贡献的新技术，表现出持续的生产力。我的 拟议的未来研究建立在最近使用RNA，芯片和代谢组合的最新观察基础上 分析以确定脂肪生成和CRISPR合成致命筛查以识别核转运为例子 否则不知道是Myc调节的基因途径 驱动的癌症。现在，我建议使用有条件的转基因鼠标模型和人类PDX模型的库 通常鉴定Myc致癌基因途径中的靶向基因和途径。我将使用三个 免费方法：RNASEQ，CHIPSEQ和DESI-MSI确定MYC驱动的新漏洞 癌症； CRISPR在体外和体内合成致死筛查以及cytof和codex分析的结合 在我的MYC驱动的肿瘤模型中识别靶标，并了解其在肿瘤发生中的机械作用；妈妈 功能记者系统能够筛选基因和疗法以靶向MYC驱动的癌症。我的 拟议的研究计划得到了跨学科的同事团队的广泛支持。我提出的 研究将了解MYC如何驱动肿瘤发生并利用这些见解来发展的新型机理见解 新的治疗靶标。