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Modulation of sensitivity & imaging therapeutic response of hypoxic cancer cells

灵敏度调节

基本信息

批准号：
8627442
负责人：
WAFIK S. EL-DEIRY
金额：
$ 2.88万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-18 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627442
关键词：
Agonist Animals Antibodies Biological Response Modifier Therapy Cells Clinic Clinical Clinical Trials Colon Carcinoma Colonic Neoplasms Combined Modality Therapy Complex Development Failure Family Family member Fluorouracil HCT116 Cells Heterogeneity Human Hypoxia Image Immune system Immunologic Surveillance Investigation Lead Ligands Malignant Epithelial Cell Malignant Neoplasms Methods Neoplasm Metastasis Organ Phase Physiology Radiation therapy Resistance Signal Pathway System TNFSF10 gene Testing Therapeutic Translations Vascular blood supply Work c-myc Genes cancer cell cancer therapy chemotherapy conventional therapy cytotoxic efficacy testing in vivo interest irinotecan neoplastic cell novel novel therapeutic intervention novel therapeutics nucleoside analog optical imaging pressure receptor research study resistance mechanism response screening small molecule small molecule libraries therapeutic development tirapazamine tumor tumor microenvironment tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): One of the major obstacles to the efficacy of cancer therapy is the tumor microenvironment that often outgrows its blood supply and harbors hypoxic regions that are resistant to chemo- and radiotherapy. TRAIL is part of the host immune system that suppresses cancer and its metastases and both TRAIL as well as TRAIL receptor agonist antibodies are currently in early phase clinical trial testing. In preliminary studies we have uncovered evidence that certain tumor cells, including p53-null human HCT116 colon tumor cells that are sensitive to TRAIL under normoxic conditions, become significantly resistant to TRAIL under severely hypoxic conditions. Such tumor cells are not effectively sensitized to TRAIL under hypoxia by combination therapies that include TRAIL plus 5- Fluorouracil, TRAIL plus irinotecan, or TRAIL plus the hypoxia sensitizer Tirapazamine. This prompted us to develop and carry out a high throughput chemical library screen that has identified a number of small molecules, including a family of structurally-related nucleoside analogues we refer to as the SLMs. SLMs are potent sensitizers of TRAIL under hypoxia and some family members have cytotoxic effects as single agents under hypoxia. In vivo studies reveal anti-tumor effects of novel small molecules combined with TRAIL and novel non-invasive whole animal optical imaging reveals that such combinations are associated with reduced levels of hypoxia within treated tumors as well as reduced vascularity. These are exciting findings that merit further investigation through the following approaches: Specific Aim #1: Investigate mechanisms of resistance to TRAIL therapy under hypoxia with specific focus on c-Myc, Mcl-1, HIF and NFkB signaling pathways. Specific Aim #2: Investigate mechanisms of sensitization to TRAIL under hypoxia by novel small molecules, SLMs, isolated from high throughput chemical library screening. Specific Aim #3: Investigate the impact of the tumor microenvironment on TRAIL plus SLM sensitivity through non-invasive in vivo imaging of tumor hypoxia and anti-tumor effects. This proposal is highly relevant to the understanding of the barriers to effective anti-cancer therapy and has broad applicability to other systems and therapies as we gain this understanding. The proposal has high translational relevance as we are developing novel therapeutic combinations that may be tested in the clinic.

描述（由申请人提供）：癌症治疗功效的主要障碍之一是肿瘤微环境经常超出其血液供应，并且含有对化疗和放疗具有抵抗力的缺氧区域。 TRAIL 是抑制癌症及其转移的宿主免疫系统的一部分，TRAIL 以及 TRAIL 受体激动剂抗体目前正处于早期临床试验测试阶段。在初步研究中，我们发现了一些证据，表明某些肿瘤细胞，包括在常氧条件下对 TRAIL 敏感的 p53-null 人 HCT116 结肠肿瘤细胞，在严重缺氧条件下对 TRAIL 产生显着耐药。通过包括TRAIL加5-氟尿嘧啶、TRAIL加伊立替康或TRAIL加缺氧增敏剂替拉扎明的组合疗法，此类肿瘤细胞在缺氧下不能有效地对TRAIL敏感。这促使我们开发并进行了高通量化学库筛选，该筛选已鉴定出许多小分子，包括一系列结构相关的核苷类似物，我们称之为 SLM。 SLM 是缺氧条件下 TRAIL 的有效敏化剂，一些家族成员在缺氧条件下作为单一药物具有细胞毒性作用。体内研究揭示了新型小分子与 TRAIL 结合的抗肿瘤作用，而新型非侵入性整体动物光学成像表明，这种组合与治疗肿瘤内缺氧水平的降低以及血管分布的减少有关。这些令人兴奋的发现值得通过以下方法进一步研究：具体目标#1：研究缺氧条件下 TRAIL 疗法的耐药机制，特别关注 c-Myc、Mcl-1、HIF 和 NFkB 信号通路。具体目标#2：通过从高通量化学库筛选中分离出的新型小分子 SLM，研究缺氧条件下对 TRAIL 的敏感性机制。具体目标#3：通过肿瘤缺氧和抗肿瘤作用的非侵入性体内成像，研究肿瘤微环境对 TRAIL 加 SLM 敏感性的影响。该提案与理解有效抗癌治疗的障碍高度相关，并且随着我们获得这种理解，它对其他系统和疗法具有广泛的适用性。该提案具有很高的转化相关性，因为我们正在开发可以在临床上进行测试的新型治疗组合。