Decoding and Targeting the PI3K-mTOR Signaling Network in Cancer

摘要 正常细胞中的主要生长因子信号传导途径（例如，PI 3 K和RAS）也是 在癌细胞中最常被基因激活，导致细胞自主生长和增殖。 mTOR复合物1（mTORC 1）是这些通路的共有下游效应物，并且是细胞增殖的中心驱动因子。 生长，并在大多数人类癌症中异常激活。这种激活通过网络发生 上游癌基因和肿瘤抑制基因的表达，这些基因聚集在一个小的G蛋白开关上， mTORC 1。这种转换涉及结节性硬化症复合体（TSC）肿瘤抑制因子， 一种调节GTP酶Ras家族成员Rheb的TSC复合物（TSC复合物）， mTORC 1的直接激活剂。我们以前的研究已经发现TSC复合物和Rheb作为 PI 3 K通路和mTORC 1信号传导之间的关键分子联系，这种调节促进 在正常细胞和癌细胞中细胞生长的关键代谢途径的变化。支持 过去6年的资金从这个R35，我们大大推进和扩大了这一领域的研究，开放 通过已发表的和正在进行的工作，开辟了几个以前没有预料到的新的调查途径。 利用这一机制提供的长期、稳定的资金，我们还开发了 创新的新遗传小鼠模型和方法，为我们带来新的突破性发现 在下一个周期的拨款，特别是有关PI 3 K-mTOR信号转导内知之甚少， 肿瘤微环境的营养和代谢生态位，这是这次更新的主要焦点。四 主要的研究领域将包括确定A）生物化学和病理生理机制 作为TSC复合物的调节和功能的基础，B）mTORC 1适当整合的能力 肿瘤微环境内的致癌和营养信号，C）PI 3 K的代谢结果， 不同起源、阶段和小生境的肿瘤中的mTOR活化和抑制，以及D）靶向代谢 在肿瘤中伴随其异常调节的脆弱性。虽然关于这一点的关键机制问题 无处不在的信号网络将继续通过严格的生物化学和细胞生物学来回答 我们的大部分努力将联合收割机与最先进的分析工具相结合， PI 3 K-mTOR网络的显著体内特征，因为它们适用于肿瘤代谢，生长， 进展我们研究的首要目标是定义这个信号网络在 癌症以及如何最好地治疗靶向高比例的mTORC 1不受控制的肿瘤 信号传导，超越了mTOR抑制剂的单药使用。我相信，如果有足够的资源， 继续深入了解癌细胞生物学，肿瘤微环境和治疗 脆弱性，同时也使跳跃到新的，目前不可预测的癌症研究领域。

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.