Targeting the MYC Pathway for the Treatment of Cancer

摘要 MYC是人类癌症中最常见的激活癌基因。然而，到目前为止，还没有现有的治疗方法 直接靶向MYC或MYC途径。我现在的目标是以myc癌基因通路为靶点治疗人类 癌症。在过去的20年里，我对MYC癌基因是如何启动的有了根本性的新见解 并维持肿瘤的形成。我的工作确立了这样的观点，即MYC是癌症的标志，许多 巨蟹座是“MYC癌基因成瘾症”。我已经确定了肿瘤固有的和宿主免疫依赖的 机械装置。现在，我将利用这些来自实验室的见解和新的方法来开发癌症的新疗法。我 是最早使用四环素调控系统(TET系统)产生条件的调查人员之一 转基因小鼠模型证明MYC诱导的癌症是“可逆的”或“癌基因成瘾的” (Felsher和Bishop，分子细胞，1999)。从那时起，我使用TET系统制作了一个图书馆 癌基因驱动的T细胞急性淋巴瘤、白血病转基因小鼠模型(MYC、RAS、BCR-ABL) 急性髓细胞白血病、骨肉瘤、肝细胞癌、肺腺癌和肾细胞癌 腺癌(RCC)。我使用我的条件转基因小鼠模型系统不仅可以理解 MYC和其他癌基因如何启动和维持肿瘤发生，以及开发创新的方法和 在癌症研究中做出开创性贡献的新技术，显示出持续的生产力。我的 拟议的未来研究建立在最近的观察结果的基础上，这些观察使用了组合的RNA、芯片和代谢组学 以鉴定脂肪生成分析和CRISPR合成致死筛选鉴定核运输为例 其他未知的是MYC调控的基因通路，当靶向时，可以阻断和逆转MYC- 导致癌症。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癌基因通路中的靶向基因和通路。我要用三个 免费方法：RNAseq、ChIPseq和DESI-MSI，以识别MYC驱动的新漏洞 癌症；体外和体内合成致死筛选结合细胞飞行时间和食典分析 在我的MYC驱动的肿瘤模型中识别靶点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治疗方法。我的 拟议的研究计划得到了同事们跨学科团队的广泛支持。我的建议 研究将收集关于MYC如何驱动肿瘤发生的新的机制见解，并利用这些见解来开发 新的治疗靶点。

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.