UNFOLDED PROTEIN RESPONSE IN DRUG SENSITIVITY AND RESISTANCE

药物敏感性和耐药性中未折叠的蛋白质反应

基本信息

批准号：
7313997
负责人：
Linda M Hendershot
金额：
$ 27.01万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7313997
关键词：
Affect Aftercare Angiogenesis Inhibitors Angiogenic Factor Animal Model Animals Antineoplastic Agents Apoptotic Buffers Carmustine Cell Cycle Arrest Cell physiology Cells Characteristics Cisplatin Class Collaborations Coupled Cultured Cells DNA Damage Data Doctor of Philosophy Drug resistance Elements Embryo Engineering Fibroblasts Funding Gene Targeting Genetic Transcription Human Knock-out Malignant Childhood Neoplasm Mediating Molecular Chaperones Mus Numbers Pathway interactions Pediatric Neoplasm Personal Satisfaction Pharmaceutical Preparations Play Poison Process Proteins Range Regulatory Element Research Personnel Resistance Role Sampling Stress Testing Tissue Array Analysis Topoisomerase II Topotecan Toxic effect Transcription Process Transcriptional Activation Type I DNA Topoisomerases Up-Regulation Upper arm Vascular Endothelial Growth Factors Vascular blood supply Vascular remodeling Vascularization Xenograft Model Xenograft procedure antitumor agent cell killing chemotherapeutic agent clinically relevant drug efficacy drug sensitivity experience genetic analysis human TOP1 protein molecular pathology neoplastic cell programs promoter protein folding research study response temozolomide tumor tumor growth

项目摘要

Due to inadequate blood supply, tumor cells exist in a compromised microenvironment that impinges on normal protein folding and can activate the unfolded protein response (DPR). In addition to contributing to tumor growth and survival, data from cell culture studies demonstrate that pharmacological activation of the UPR can also alter the sensitivity of cells to chemotherapeutic agents, making them more sensitive in some cases and more resistant in others. In the previous cycle of funding, we showed that UPR activation is both necessary and sufficient to reduce the sensitivity to topoisomerase II targeted therapy and found that this is a result of PERK activation. We propose genetic analyses in the coming cycle to identify the responsible target(s) and determine to what extent the UPR affects drug sensitivity in xenograft studies. Conversely, UPR activation increases the sensitivity of cells to cisplatin, which damages both DMA and proteins. As a number of anti-cancer agents have similar characteristics, we propose to explore interactions between these agents and the UPR and to determine the mechanism or interaction where synergies exist. Given the broad affects of the UPR on cellular processes, it is likely that this pathway will interact with other chemotherapeutic agents. Indeed, our preliminary data demonstrate that activation of the UPR reduces the sensitivity of cells to the topoisomerase I poison, topotecan. Finally, anti-angiogenic agents are being used to inhibit tumor vascularization, which should contribute to UPR activation in the tumor. However, recent data demonstrate that they can also promoter vascular remodeling, making it unclear how this will affect UPR activation. Since the UPR leads to both increased transcription and processing of pro-angiogenic factors, it is essential to understand the affect of anti-angiogenic agents on the UPR and to determine if the UPR plays a role in resistance to these agents. In this proposal, we describe experiments to determine the mechanisms by which the UPR increases sensitivity to some agents while decreasing sensitivity to others, explore possible interactions with additional chemotherapeutic agents, and determine the affect of UPR activation on drug sensitivity in animal models. In addition, we will extend our initial examination of UPR activation in tumor samples to other UPR targets and multiple types of tumors to establish the scope of the significance of our findings to pediatric cancers.

由于血液供应不足，肿瘤细胞存在于受损的微环境中，影响正常的蛋白质折叠并可以激活未折叠蛋白质反应（DPR）。除了贡献肿瘤生长和存活，细胞培养研究的数据表明，药理学激活 UPR还可以改变细胞对化疗药物的敏感性，使它们在某些情况下更加敏感。病例中，而其他病例中则更具抵抗力。在上一个资助周期中，我们表明 UPR 激活既是降低对拓扑异构酶 II 靶向治疗的敏感性是必要且充分的，并发现这是一个 PERK 激活的结果。我们建议在下一个周期进行基因分析，以确定造成这种情况的原因目标并确定 UPR 对异种移植研究中药物敏感性的影响程度。反过来， UPR 激活会增加细胞对顺铂的敏感性，从而损害 DMA 和蛋白质。作为一个许多抗癌药物具有相似的特征，我们建议探索这些药物之间的相互作用剂和 UPR 并确定存在协同作用的机制或相互作用。鉴于广泛 UPR 对细胞过程的影响，该途径很可能会与其他途径相互作用化疗剂。事实上，我们的初步数据表明，UPR 的激活会降低细胞对拓扑异构酶 I 毒物拓扑替康的敏感性。最后，使用抗血管生成剂抑制肿瘤血管化，这应该有助于肿瘤中 UPR 的激活。然而，最近数据表明它们还可以促进血管重塑，但尚不清楚这将如何影响 UPR激活。由于 UPR 导致促血管生成的转录和加工增加因素，了解抗血管生成药物对 UPR 的影响并确定是否 UPR 在抵抗这些药物方面发挥着重要作用。在这个提案中，我们描述了实验以确定 UPR 增加对某些药物的敏感性同时降低对其他药物的敏感性的机制，探索与其他化疗药物可能的相互作用，并确定 UPR 的影响激活对动物模型药物敏感性的影响。此外，我们将延长对普遍定期审议的初步审查肿瘤样本中对其他 UPR 靶点和多种类型肿瘤的激活，以确定 UPR 的范围我们的研究结果对儿科癌症的意义。