Decoding and Targeting the PI3K-mTOR Signaling Network in Cancer

解码和靶向癌症中的 PI3K-mTOR 信号网络

基本信息

批准号：
10674995
负责人：
BRENDAN D. MANNING
金额：
$ 93.2万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
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：
2022-08-01 至 2029-07-31
项目状态：
未结题

项目摘要

ABSTRACT The major growth factor signaling pathways in normal cells (e.g., PI3K and RAS) are also the ones that are most frequently genetically activated in cancer cells, leading to cell autonomous growth and proliferation. mTOR complex 1 (mTORC1) is a shared downstream effector of these pathways and a central driver of cell growth and is aberrantly activated in the majority of human cancers. This activation occurs through a network of upstream oncogenes and tumor suppressors that converge on a small G protein switch directly upstream of mTORC1. This switch involves the tuberous sclerosis complex (TSC) tumor suppressors, which form a protein complex (the TSC complex) that regulates a member of the Ras family of GTPases, called Rheb, an essential direct activator of mTORC1. Our previous studies have found that the TSC complex and Rheb serve as the key molecular link between the PI3K pathway and mTORC1 signaling and that this regulation promotes changes in key metabolic pathways underlying cell growth in both normal and cancer cells. Supported by the last 6 years of funding from this R35, we have greatly advanced and expanded this area of research, opening up several previously unforeseen new avenues of investigation through both published and ongoing work. Taking advantage of the long-term, stable funding afforded by this mechanism, we have also developed innovative new genetic mouse models and methodologies that set us up for new breakthrough discoveries over the next cycle of this grant, especially related to PI3K-mTOR signaling within the poorly understood nutrient and metabolic niche of the tumor microenvironment, which is a major focus of this renewal. Four major areas of research will include defining A) the biochemical and pathophysiological mechanisms underlying the regulation and function of the TSC complex, B) the capacity of mTORC1 to properly integrate oncogenic and nutrient signals within the tumor microenvironment, C) the metabolic consequences of PI3K- mTOR activation and inhibition in tumors of different origins, stages, and niches, and D) targetable metabolic vulnerabilities accompanying its aberrant regulation in tumors. While key mechanistic questions regarding this ubiquitous signaling network will continue to be answered through rigorous biochemical and cell biological studies, much of our efforts will combine novel genetic models with state-of-the-art analytical tools to define the salient in vivo features of the PI3K-mTOR network as they apply to tumor metabolism, growth, and progression. The overarching goals of our research are to define the precise roles of this signaling network in cancer and how best to therapeutically target the high percentage of tumors with uncontrolled mTORC1 signaling, beyond the single-agent use of mTOR inhibitors. I am confident that, if given the resources, we will continue to gain a deeper understanding of cancer cell biology, the tumor microenvironment, and therapeutic vulnerabilities, while also making leaps into new, currently unpredictable domains of cancer research.

抽象的正常细胞（例如PI3K和RAS）中的主要生长因子信号通路也是在癌细胞中最常被遗传激活，导致细胞自主生长和增殖。 MTOR复合物1（MTORC1）是这些途径的共享下游效应器，也是单元的中心驱动器在大多数人类癌症中生长，异常激活。这种激活通过网络发生直接在小G蛋白开关上收敛的上游癌基因和肿瘤抑制剂 mtorc1。该开关涉及结节性硬化症复合物（TSC）抑制剂，该肿瘤形成蛋白质调节GTPases Ras家族的成员的复合物（TSC复合物）称为Rheb，这是必不可少的 MTORC1的直接激活剂。我们以前的研究发现，TSC复合物和Rheb是 PI3K途径与MTORC1信号传导之间的关键分子链接，并且该调节促进正常细胞和癌细胞中细胞生长的关键代谢途径的变化。由这款R35的过去6年的资金，我们已经大大提高和扩展了这一研究领域，开放了通过出版和正在进行的工作，提高了一些以前无法预料的新调查途径。利用这种机制提供的长期，稳定的资金，我们也开发了创新的新遗传鼠标模型和方法，使我们为新的突破发现做好了准备在该赠款的下一个周期中，尤其是与知识渊博的PI3K-MTOR信号传导有关肿瘤微环境的营养和代谢细分市场，这是该更新的主要重点。四个研究的主要领域将包括定义a）生化和病理生理机制 TSC复合物的调节和功能的基础，b）MTORC1正确整合的能力肿瘤微环境内的致癌和营养信号，c）PI3K-的代谢后果 MTOR激活和抑制不同起源，阶段和壁ches的肿瘤，d）可靶向代谢伴随其在肿瘤中异常调节的脆弱性。而关键的机理问题普遍的信号网络将继续通过严格的生化和细胞生物学来回答研究，我们的大部分努力将将新颖的遗传模型与最先进的分析工具相结合以定义 PI3K-MTOR网络的体内特征的显着特征，它们适用于肿瘤代谢，生长和进展。我们研究的总体目标是定义此信号网络的确切作用癌症以及如何最好地靶向不受控制的MTORC1的肿瘤比例很高信号传导，超过单药物的MTOR抑制剂。我有信心，如果有资源，我们将继续对癌细胞生物学，肿瘤微环境和治疗性有更深入的了解脆弱性，同时也突飞猛进，目前无法预测的癌症研究领域。