Hypoxia and Anticancer Drug Action

缺氧与抗癌药物作用

基本信息

批准号：
8637740
负责人：
GARTH POWIS
金额：
$ 40万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-14 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8637740
关键词：
Adult Angiogenic Factor Antineoplastic Agents Apoptosis Binding Blood Vessels Cell Death Clinical Clinical Trials DNA Binding Development Drug Targeting Drug effect disorder Drug resistance Embryonic Development Endoplasmic Reticulum Environment FGF2 gene Genes Goals Grant Growth Health Heat shock proteins Human Hypoxia In Vitro Investigation Lead Ligase Maintenance Malignant Neoplasms Mediating Metabolism Molecular Neoplasm Metastasis Normal tissue morphology Nuclear Oxygen Pathway interactions Patients Perfusion Physiological Processes Protein Biosynthesis Protein Inhibition Proteins Radiation Regulation Resistance Role Small Interfering RNA Solid Neoplasm Staging Stress Therapeutic Therapeutic Intervention Tissues Translations Ubiquitination Up-Regulation analog angiogenesis base biological adaptation to stress cancer cell cancer therapy cell growth chemotherapy hypoxia inducible factor 1 in vivo inhibitor/antagonist neoplastic cell novel outcome forecast rapid growth response screening stress protein transcription factor tumor tumor growth ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Solid tumors exist in a stressed environment for cell growth. As even the smallest tumors grow they rapidly outstrip new blood vessel formation leading to poor perfusion and hypoxia. Genes induced by hypoxia allow the cancer cell to adapt to the hostile hypoxic environment by switching to anaerobic metabolism, decreasing overall protein synthesis, causing resistance to cell death, producing factors that increase the formation of new blood vessels from the existing vasculature (angiogenesis), and increased metastasis. Tumor cells also frequently develop constitutive upregulation of genes that regulate the hypoxic stress response. These constitutive and adaptive changes make tumors aggressive, resistant to radiation and chemotherapy, and lead to a poor patient prognosis. The hypoxic stress response is a normal physiological process employed in the early stages of embryogenesis but with a limited role in well perfused normal adult tissues. Although the changes result in aggressive, drug-resistant tumors they also provide an Achilles heel for selectively attacking the tumor, because without them the cancer cells will die. Thus, the hypothesis upon which our studies are based is that understanding the pathways that regulate the tumor's response to the stress of hypoxia and the consequences this has for tumor growth, will provide novel targets and the development of agents to selectively treat cancer. The most studied mechanism mediating the cancer cell's response to hypoxia is an increase in the levels of the hypoxia inducible factor-1 (HIF-11) transcription factor. We provide evidence for a new pathway of HIF-11 regulation by the endoplasmic reticulum (ER) unfolded protein response (UPR) that mediates the synthesis of HIF-11 and other stress proteins in hypoxia. We have also identified a novel oxygen independent pathway for HIF-11 degradation mediated by HAF/SART-1 which we have shown to be a novel E3 ubiquitin ligase for HIF-11. We will investigate the mechanisms and regulation of the HAF/SART-1-induced degradation of HIF-11 to provide novel targets for therapeutic intervention. There is ample clinical and experimental evidence for a HIF-11 independent mechanism for maintaining tumor growth in hypoxia. It is known that despite a general inhibition of protein translation during hypoxia the synthesis of HIF-11 and of other stress survival proteins is maintained or even increased. Understanding this mechanism could provide novel drug targets to inhibit the tumor's survival response to hypoxia. The overall goal of our studies is to understand mechanisms that contribute to the maintenance of tumor growth in hypoxia, involving both HIF-11 and other stress proteins that will provide new drug targets and therapeutic strategies for treating cancer.

描述（由申请人提供）：实体瘤存在于细胞生长的压力环境中。即使是最小的肿瘤，它们也会迅速超过新的血管形成，导致灌注和缺氧不良。缺氧诱导的基因使癌细胞通过切换到厌氧代谢，降低总体蛋白质合成，从而导致细胞死亡的耐药性，从而增加从现有的脉管造血（血管生成）增加新血管的形成，从而适应敌对的低氧环境。肿瘤细胞还经常出现调节低氧应激反应的基因的组成型上调。这些构成和适应性变化使肿瘤具有侵略性，对放射和化学疗法具有抗性，并导致患者的预后不佳。低氧应激反应是在胚胎发生的早期阶段采用的正常生理过程，但在灌注良好的正常成人组织中作用有限。尽管这些变化导致侵略性，耐药性肿瘤，但它们也提供了针刺的高跟鞋来有选择地攻击肿瘤，因为没有它们，癌细胞将死亡。因此，我们的研究基于的假设是了解调节肿瘤对缺氧应激的反应的途径以及对肿瘤生长的后果，将提供新颖的靶标和剂的发展，以选择性治疗癌症。介导癌细胞对缺氧反应的最多研究的机制是缺氧诱导因子-1（HIF-11）转录因子的水平增加。我们为内质网（ER）展开的蛋白质反应（UPR）调节HIF-11的新途径，该途径介导了缺氧中HIF-11的合成和其他应激蛋白的合成。我们还确定了HAF/SART-1介导的HIF-11降解的新型HIF-11降解途径，我们证明它是HIF-11的新型E3泛素连接酶。我们将研究HAF/SART-1诱导的HIF-11降解的机理和调节，以提供治疗干预的新靶标。有足够的临床和实验证据证明了HIF-11独立的机制可维持缺氧肿瘤的生长。众所周知，尽管缺氧期间对蛋白质翻译的一般抑制作用，但HIF-11和其他应力存活蛋白的合成仍然保持或增加。了解这种机制可以提供新的药物靶标，以抑制肿瘤对缺氧的生存反应。我们研究的总体目标是了解有助于维持缺氧肿瘤生长的机制，涉及HIF-11和其他应激蛋白，这些蛋白将提供新的药物靶标和治疗癌症的治疗策略。