Tumor-cell-specific targets for combined hyperthermia and radiation effects

结合热疗和放射效应的肿瘤细胞特异性靶标

基本信息

批准号：
8134902
负责人：
Tej K Pandita
金额：
$ 31.9万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134902
关键词：
Address Appearance Applications Grants Ataxia-Telangiectasia-Mutated protein kinase Biological Models Cell Cycle Kinetics Cell Line Cell Survival Cells Chromatin Chromatin Structure Chromosomes Clinical Clinical Trials Complex DNA DNA Damage DNA Double Strand Break DNA Repair Data Detection Development Enzymes Failure Fever GRN163 Glioblastoma Goals Heat-Shock Proteins 70 Heat-Shock Response Heating Hela Cells Human In Vitro Ionizing radiation Kinetics LNCaP Lipids MCF7 cell Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of prostate Mediating Metabolism Mus NBS1 gene Normal tissue morphology Pharmaceutical Preparations Phosphorylation Play Proteins Radiation Radiation Induced DNA Damage Radiation therapy Radiosensitization Reporting Research Ribonucleoproteins Role SS DNA BP Signal Pathway Site Somatic Cell Structure Telomerase Telomerase Inhibitor Telomerase RNA Component Telomerase inhibition Testing Tissues Toxic effect Treatment Protocols Tumor Cell Line Tumor Tissue Xenograft Model Xenograft procedure analog ataxia telangiectasia mutated protein base cell growth cell killing combinatorial design improved inhibitor/antagonist knock-down malignant breast neoplasm neoplastic cell novel public health relevance radiation effect repaired research study response synthetic construct telomere treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Tumor-cell-specific targets for combined hyperthermia and radiation effects. The inability of radiotherapy to control tumor growth is still a daunting clinical problem that leads to the failure of many treatment regimens. The fundamental question is: can tumor cells be specifically sensitized to ionizing radiations (IR) by heat by targeting essential molecules or structures exclusively expressed (present) in tumor cells? One such factor, expressed in most tumors and silent in somatic cells, is telomerase. Moreover, differences in telomerase activity and cell kinetics between normal and tumor tissues suggest that targeting telomerase would be relatively safe. In this grant application we propose to understanding how inactivation of ataxia-telangiectasia mutated (ATM) and telomerase could enhance heat mediated and IR-induced tumor cell killing. Our preliminary data suggest that: (1) Heat shock activates ATM signaling pathways that overlap with those activated by IR; (2) Hyperthermia transiently enhanced telomerase activity and; (3) The specific inhibition of telomerase activity by GRN163L (a lipid conjugated synthetic DNA analogue complementary to the template region of telomerase RNA "hTR") increased hyperthermia-mediated IR-induced cell killing. The latter result suggests that telomerase inactivation with GRN163L prior to combined hyperthermia and radiotherapy could improve tumor cell killing, specifically inhibiting tumor growth. Clinical trials are ongoing with telomerase inhibitor (GRN163L), the prospect of adding telomerase-based therapies to the growing list of target-specific radiosensitizing products is therefore promising, but the advantages or limitations of combining telomerase inhibition with altered DNA damage sensing needs to be determined. Therefore, we will determine the mechanistic basis of enhancing heat-mediated radiosensitization (HIR) by inhibiting telomerase and radiation signaling pathways, which result in the tumor growth control. Specifically, we propose to ask the following questions: (1) Does telomerase inhibition by GRN163L enhance heat-mediated IR-induced tumor control with little toxicity to normal tissue? (2) Does simultaneous inactivation of telomerase and ATM, or its recently identified effector hSSB1 (a single-strand DNA binding protein essential for DNA damage detection and repair), synergize heat-mediated IR-induced tumor control? (3) Does heat influence DNA damage sensing and the recruitment of repair proteins to DNA double strand break sites in the presence and absence of telomerase activity? Thus, determining the influence of heat and/or IR on ATM function and telomere metabolism will not only add to our understanding of the mechanisms of HIR but will aid in the development of new tumor treatment strategies. PUBLIC HEALTH RELEVANCE: We propose to investigate the mechanistic basis of enhancing cell killing by inhibiting telomerase prior heat and radiation treatment that could result in the suppression of tumor growth. Our preliminary studies suggest that hyperthermia activates ATM signaling pathways and enhances telomerase activity, thus inactivating telomerase prior heat and radiation treatment would result in increased cell killing. If the proposed research is successfully carried out, the novel information generated from the proposed studies will be useful in designing tumor specific therapies.

描述（由申请人提供）：用于组合热疗和辐射效应的肿瘤细胞特异性靶标。放疗无法控制肿瘤生长仍然是一个令人畏惧的临床问题，导致许多治疗方案失败。根本问题是：通过靶向肿瘤细胞中专门表达（存在）的必需分子或结构，肿瘤细胞是否可以通过热对电离辐射（IR）特异性敏感？端粒酶就是这样一种因子，它在大多数肿瘤中表达，但在体细胞中沉默。此外，正常组织和肿瘤组织之间端粒酶活性和细胞动力学的差异表明，靶向端粒酶相对安全。在这项拨款申请中，我们建议了解共济失调毛细血管扩张突变 (ATM) 和端粒酶的失活如何增强热介导和红外线诱导的肿瘤细胞杀伤作用。我们的初步数据表明：（1）热休克激活的 ATM 信号通路与 IR 激活的信号通路重叠； (2) 高温短暂增强端粒酶活性； (3) GRN163L（一种与端粒酶 RNA“hTR”模板区域互补的脂质缀合合成 DNA 类似物）对端粒酶活性的特异性抑制增加了热疗介导的红外线诱导的细胞杀伤。后一个结果表明，在联合热疗和放疗之前用 GRN163L 灭活端粒酶可以改善肿瘤细胞杀伤，特别是抑制肿瘤生长。端粒酶抑制剂 (GRN163L) 的临床试验正在进行中，因此，将基于端粒酶的疗法添加到不断增长的目标特异性放射增敏产品列表中的前景是有希望的，但将端粒酶抑制与改变 DNA 损伤传感相结合的优点或局限性需要了解决定。因此，我们将确定通过抑制端粒酶和辐射信号通路增强热介导放射增敏（HIR）从而控制肿瘤生长的机制基础。具体来说，我们建议提出以下问题：（1）GRN163L 抑制端粒酶是否会增强热介导的 IR 诱导的肿瘤控制，而对正常组织的毒性很小？ (2) 端粒酶和 ATM 或其最近发现的效应子 hSSB1（一种对 DNA 损伤检测和修复至关重要的单链 DNA 结合蛋白）的同时失活是否可以协同热介导的 IR 诱导的肿瘤控制？ (3) 在端粒酶活性存在和不存在的情况下，热是否会影响 DNA 损伤感知以及修复蛋白向 DNA 双链断裂位点的募集？因此，确定热和/或红外线对 ATM 功能和端粒代谢的影响不仅将增加我们对 HIR 机制的理解，而且将有助于开发新的肿瘤治疗策略。公共健康相关性：我们建议研究通过在热和放射治疗之前抑制端粒酶来增强细胞杀伤的机制基础，从而抑制肿瘤生长。我们的初步研究表明，高温会激活 ATM 信号通路并增强端粒酶活性，因此在热和放射治疗之前灭活端粒酶将导致细胞杀伤增加。如果拟议的研究成功进行，拟议研究产生的新信息将有助于设计肿瘤特异性疗法。