Targeting Endoplasmic Reticulum Stress Response for Cancer Therapy

靶向内质网应激反应进行癌症治疗

基本信息

批准号：
8320152
负责人：
BERTAL H. AKTAS
金额：
$ 36.81万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320152
关键词：
Acute Affect Animals Bilateral Binding Proteins Biogenesis Blood Blood Chemical Analysis Blood Vessels Boxing Cancer cell line Carrier Proteins Cell Line Cell Proliferation Cells Cellular Stress Chemical Agents Chemicals Chemistry Code Computer software Cytostatics Dose Drug Kinetics Endoplasmic Reticulum Eukaryotic Initiation Factors Failure Funding Genes Genetic Transcription Goals Histopathology Homeostasis Human Engineering Hypoxia In Vitro Injection of therapeutic agent Inositol Introns Lead Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Measures Messenger RNA Metabolism Molecular Chaperones Molecular Weight Mus Neoplasm Metastasis Nutrient Open Reading Frames Oxygen Pharmaceutical Preparations Phosphorylation Phosphotransferases Plasma Positioning Attribute Prokaryotic Initiation Factor-2 Protein Biosynthesis Protein S Proteins RNA Splicing Recombinants Recruitment Activity Resistance Side Solid Neoplasm Specificity Surface Testing Thiourea Time Toxic effect Transgenic Organisms Translation Initiation Work activating transcription factor arm base biological adaptation to stress cancer cell cancer therapy chemical genetics cytotoxic drug development efficacy testing endoplasmic reticulum stress food consumption indexing inhibitor/antagonist killings malignant breast neoplasm mutant neoplastic cell novel oxindole programs protein degradation protein kinase R protein transport tool transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to test the hypothesis that IERSR can be pharmacologically targeted for cancer therapy. Solid tumors are poorly vascularized and therefore cannot receive sufficient oxygen and nutrients particularly in the least vascularized regions. This causes accumulation of unfolded proteins in endoplasmic reticulum (ER), termed ER-stress. Activation of integrated ER-stress response (IERSR) critically contributes to tumor growth and survival. The IERSR involves inhibiting translation initiation to reduce the demand on the folding capacity of the ER and activating a transcription program to enlarge the size and the folding capacity of the ER. Translation initiation is inhibited through activation of protein kinase R (PKR)-like ER resident kinase PERK and phosphorylation of eukaryotic translation initiation factor 2 aplha (eIF2a). The transcription program to increase the size and the folding capacity of the ER is accomplished by activating key transcription factors such as X box binding protein-1 Xbp-1 that control expression of ER-chaperons, ER biogenesis and ER-associated retrograde protein transport and degradation genes. However, IERSR must be regulated in a spatial and temporal manner because either the failure to activate IERSR or sustained activation of IERSR will reduce survival of stressed cells. We hypothesize that tumor cells utilize IERSR in a spatially and temporally regulated manner to survive ER-stress or avoid the cytostatic and cytotoxic effects of prolonged IERSR. We further hypothesize that limiting the ability of tumors to activate IERSR or causing sustained and exaggerated IERSR will cause selective demise of tumors. We have developed chemical modulators of the IERSR and genetically engineered human cancer cells lines resistant to these agents. If this proposal is funded, we will utilize our transgenic cell lines and chemical modulators of IERSR to test our hypothesis and to determine conclusively if the IERSR can be pharmacologically targeted for cancer therapy. 1) We will test the hypothesis that N,N'-diarylurea induced sustained eIF2a phosphorylation will inhibit tumor growth. We will study the pharmacokinetic profile and acute toxicity of selected/optimized N,N'-diarylureas. We will determine their efficacy and mechanism specificity by treating mice carrying bilateral tumors expressing eIF2a-WT on one side and non-phosphorylatable mutant, eIF2a-S51A on the other side (Specific Aim 1). 2) We will test the hypothesis that inhibition of Xbp-1 splicing by diaryl-oxindoles inhibit tumor growth by studying the pharmacokinetic profile and acute toxicity of selected/optimized diaryl-oxindole. We will determine their efficacy and mechanism specificity by treating mice carrying bilateral tumors expressing only endogenous Xbp-1 on one side and already spliced Xbp-1 on the other side (Specific Aim 2), and 3) We will test the hypothesis that inhibition of Xbp-1 splicing and induction of eIF2a phosphorylation will synergistically inhibit tumor growth and metastasis (Specific Aim 3).

描述（由申请人提供）：该提案的总体目标是检验以下假设：IERSR可以针对癌症治疗。实体瘤的血管化较差，因此无法接受足够的氧气和营养，尤其是在最少的血管化区域。这会导致内质网中展开的蛋白质的积累，称为ER压力。综合ER应力反应（IERSR）的激活对肿瘤的生长和生存有效。 IERSR涉及抑制翻译起始，以减少ER折叠能力的需求，并激活转录程序以扩大ER的大小和折叠能力。翻译起始是通过激活蛋白激酶R（PKR）类似ER常驻激酶PERK和真核翻译起始因子2 APLHA（EIF2A）的磷酸化来抑制的。通过激活关键转录因子（例如X盒结合蛋白-1 XBP-1）来控制ER-CHAPERON，ER生物发生和与ER相关的逆行蛋白转运和降解基因来实现转录程序，以增加ER的大小和折叠能力。但是，必须以空间和时间方式调节IERSR，因为未能激活IERSR或IERSR的持续激活将减少应力细胞的存活。我们假设肿瘤细胞以空间和时间调节的方式利用IERSR来生存ER压力或避免长期IERSR的细胞抑制和细胞毒性作用。我们进一步假设，限制肿瘤激活IERSR或引起持续和夸张的IERSR的能力会导致肿瘤的选择性灭亡。我们已经开发了IERSR的化学调节剂和基因设计的人类癌细胞对这些药物的抗性。如果资助该提案，我们将利用IERSR的转基因细胞系和化学调节剂来检验我们的假设，并最终确定IERSR是否可以针对癌症治疗的药理目标。 1）我们将检验以下假设：N，N'diarelurea诱导的持续EIF2A磷酸化将抑制肿瘤的生长。我们将研究选定/优化的N，N'diarylureas的药代动力学特征和急性毒性。我们将通过处理一侧表达EIF2A-WT的双侧肿瘤的小鼠和不可磷酸磷酸的突变体，EIF2A-S51A在另一侧（特定AIM 1）来确定它们的功效和机理特异性。 2）我们将通过研究选定/优化的日二种氧烷的药代动力学特征和急性毒性来检验二二烷基氧冬糖对XBP-1剪接抑制肿瘤生长的假设。 We will determine their efficacy and mechanism specificity by treating mice carrying bilateral tumors expressing only endogenous Xbp-1 on one side and already spliced Xbp-1 on the other side (Specific Aim 2), and 3) We will test the hypothesis that inhibition of Xbp-1 splicing and induction of eIF2a phosphorylation will synergistically inhibit tumor growth and metastasis (Specific Aim 3).