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.

摘要 MYC是人类癌症中最常被激活的癌基因。然而，到目前为止，没有现有的治疗方法， 直接靶向MYC或MYC通路。我现在的目标是靶向MYC癌基因通路， 癌在过去的20年里，我对MYC癌基因如何启动 并维持肿瘤发生。我的工作已经确立了MYC是癌症的标志的观点， 癌症是“MYC癌基因成瘾”。我已经确定了肿瘤的内在和宿主免疫依赖性 机制等现在，我将利用这些来自实验室和新方法的见解来开发癌症的新疗法。我 是最早使用四环素调节系统（泰特系统）生成“条件”的研究者之一 转基因小鼠模型，以证明MYC诱导的癌症是“可逆的”或“癌基因成瘾” （Felsher和Bishop，Molecular Cell，1999）。从那时起，我就用泰特系统建立了一个图书馆， 癌基因驱动的T细胞急性淋巴瘤（T-ALL）、白血病和白血病转基因小鼠模型（MYC、RAS、BCR-ABL） (AML)、骨肉瘤（OS）、肝细胞癌（HCC）、肺腺癌（LAC）和肾细胞癌 腺癌（RCC）。我用我的条件性转基因小鼠模型系统， MYC和其他癌基因如何启动和维持肿瘤发生，而且还开发了创新方法， 在癌症研究中做出开创性贡献的新技术，表现出持续的生产力。我 建议未来的研究是建立在最近的观察，使用组合RNA，ChIP和代谢组学 以鉴定脂肪生成分析和鉴定核转运的CRISPR合成致死筛选为例 未知的MYC调节基因途径，当靶向时可以阻断和逆转MYC- 被逼癌症现在，我建议使用我的条件转基因小鼠模型和人类PDX模型库， 一般鉴定MYC致癌基因途径中的靶向基因和途径。我用三个 互补方法：RNAseq，ChIPseq和MMS-MSI，以确定MYC驱动的新漏洞 癌症; CRISPR体外和体内合成致死筛选结合CyTOF和CODEX分析， 在我的MYC驱动的肿瘤模型中确定靶点，并了解它们在肿瘤发生中的机制作用; MYC 功能报告系统能够筛选靶向MYC驱动的癌症的基因和疗法。我 拟议的研究计划得到了同事的跨学科团队的广泛支持。我建议的 研究将收集关于MYC如何驱动肿瘤发生的新机制见解，并利用这些见解来开发 新的治疗靶点。