Targeting the Unfolded Protein Response in PanNETs

未折叠蛋白反应（Unfolded protein response，UPR）是一条由两个内质网（ER）共同调控的细胞内信号转导途径 跨膜激酶-IRE 1 β和PERK-与内质网的蛋白质折叠状态有关， 内质网（ER）的细胞核，以维持内稳态，这个细胞器。缺氧，营养 剥夺，蛋白酶体功能障碍，或对分泌途径的持续需求-条件往往 实体瘤细胞遇到的错误折叠--导致错误折叠的蛋白质在内质网中积累并引起“内质网应激”。 在可补救的ER应激水平下，UPR激活转录和翻译变化， 适应（稳态普遍定期审议）。但是，当面对无法补救的ER压力水平时，这些适应性 措施失败，UPR转而切换策略以触发细胞死亡（终端UPR）。 神经内分泌肿瘤（例如类癌）是一类可能对蛋白质特别敏感的实体瘤。 由于它们的高蛋白质分泌活性而引起的折叠应力。源自专职分泌细胞， 神经内分泌肿瘤可以发生在许多部位（例如胃肠道，肺），但这些肿瘤普遍存在于 过度分泌一种或多种肽激素。对于近12，000名被诊断患有 神经内分泌肿瘤每年，手术是唯一潜在的治愈性治疗。不幸的是，这五年 对于约25%发展为转移性疾病的患者，存活率极低。 我们有证据表明UPR是上调的，并且是胰腺神经内分泌肿瘤生长所必需的 （PanNET），这类分泌性实体瘤的代表性模型。根据初步数据，我们 假设PanNET依赖于水平升高的稳态UPR信号传导来避免毒性作用 蛋白质折叠压力，并有针对性的干预措施，以减少稳态UPR输出或 或者触发末端UPR将具有强效的抗肿瘤作用。我们将使用各种基因， 化学遗传学和药理学工具，在我们的实验室开发的选择性激活或禁用 UPR主调节器（IRE 1和PERK），以实现两个特定目标。(1)：定义激活 原代人UPR调节因子IRE 1 β和PERK的状态、信号输出和细胞生长效应 样本和PanNET的鼠异种移植模型。(2)：确定药理学抑制的作用， 在PanNET的鼠异种移植和遗传模型中，IRE 1 β和/或PERK对PanNET生长的影响。 我们的研究项目将为普遍定期审议对泛网络增长的作用提供强有力的机制性见解， 使用小分子来操纵这一途径以控制细胞命运。如果成功，我们的工作将 验证药物靶点，以改变PanNET和其他神经内分泌肿瘤的进展。

The unfolded protein response (UPR) is an intracellular signaling pathway largely controlled by two ER transmembrane kinases—IRE1 and PERK—that communicate the protein folding status of the endoplasmic reticulum (ER) to the nucleus in order to maintain homeostasis within this organelle. Hypoxia, nutrient deprivation, proteasome dysfunction, or sustained demands on the secretory pathway--conditions often encountered by solid tumor cells--lead to the accumulation of misfolded proteins in the ER and cause “ER stress.” Under remediable levels of ER stress, the UPR activates transcriptional and translational changes that promote adaptation (Homeostatic UPR). But when confronted with irremediable levels of ER stress, these adaptive measures fail, and the UPR instead switches strategies to trigger cell death (Terminal UPR). Neuroendocrine tumors (e.g. carcinoids) are one class of solid tumor that may be particularly sensitive to protein folding stress due to their high protein secretory activity. Derived from professional secretory cells, neuroendocrine tumors can arise in many sites (e.g. gastrointestinal tract, lung), but these tumors universally hypersecrete one or more peptide hormone(s). For the nearly 12,000 Americans diagnosed with a neuroendocrine tumor each year, surgery is the only potentially curative treatment. Unfortunately, the five year survival is extremely low for the ~25% of patients who develop metastatic disease. We have evidence that the UPR is upregulated and required for the growth of pancreatic neuroendocrine tumors (PanNETs), a representative model for this class of secretory solid tumors. Based on our preliminary data, we hypothesize that PanNETs are reliant on elevated levels of Homeostatic UPR signaling to avoid the toxic effects of protein folding stress, and that targeted interventions to either reduce Homeostatic UPR outputs or alternatively trigger the Terminal UPR will have potent antitumor effects. We will use a variety of genetic, chemical-genetic, and pharmacological tools developed in our laboratory to selectively activate or disable the UPR master regulators (IRE1 and PERK) in order to accomplish two specific aims. (1): Define the activation status, signaling outputs, and cell growth effects of the UPR regulators IRE1 and PERK in primary human samples and murine xenograft models of PanNETs. (2): Determine the effects of pharmacologic inhibition of IRE1 and/or PERK on the growth of PanNETs in murine xenograft and genetic models of PanNETs. Our research project will provide powerful mechanistic insights into the role of the UPR on PanNET growth and the use of small molecules to manipulate this pathway to control cell fate. If successful, our work promises to validate drug targets to modify progression of PanNET and other neuroendocrine tumors.