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激活癌基因，但迄今为止，还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 癌基因通路来治疗人类。 在过去的 20 年里，我对 MYC 癌基因如何启动有了基本的新见解。 我的工作确立了这样的观点：MYC 是癌症的一个标志，也是许多癌症的标志。 癌症是“MYC癌基因成瘾的”，我已经确定了肿瘤内在的和宿主免疫依赖性的。 现在，我将利用实验室的这些见解和新方法来开发癌症 I 的新疗法。 是最早使用四环素调节系统（Tet系统）产生“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“致癌基因成瘾” （Felsher 和 Bishop，《分子细胞》，1999 年），我使用 Tet 系统制作了一个库。 癌基因驱动的T细胞急性淋巴瘤（T-ALL）、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 我使用条件转基因小鼠模型系统不仅是为了了解腺癌（RCC）。 MYC 和其他癌基因如何启动和维持肿瘤发生，同时还开发创新方法和 新技术为癌症研究做出了开创性贡献，展现出持续的生产力。 拟议的未来研究建立在最近结合使用 RNA、ChIP 和代谢组学的观察结果的基础上 分析以鉴定脂肪生成和 CRISPR 合成致死筛选以鉴定核运输为例 其他未知的 MYC 调节基因通路，当靶向时可以阻断和逆转 MYC- 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。 为了一般性地识别 MYC 癌基因途径中的靶向基因和途径，我将使用三个。 互补方法：RNAseq、ChIPseq 和 DESI-MSI，用于识别 MYC 驱动中的新漏洞 癌症；CRISPR 体外和体内合成致死筛选结合 CyTOF 和 CODEX 分析 识别 MYC 驱动的肿瘤模型中的靶标并了解它们在肿瘤发生中的机制作用； 功能报告系统能够筛选针对 MYC 驱动的癌症的基因和疗法。 拟议的研究计划得到了跨学科同事团队的广泛支持。 研究将收集有关 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。