The targeting of the HIF switch in kidney cancer

HIF 开关在肾癌中的靶向作用

基本信息

批准号：
8611248
负责人：
Mei Yee Koh
金额：
$ 52.11万
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：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8611248
关键词：
Address Automobile Driving Binding Clear Cell Clinical Conventional (Clear Cell) Renal Cell Carcinoma Cystic kidney Development Diagnostic Neoplasm Staging Disease Progression Dysplasia Etiology Event Genetic Transcription Goals Hereditary Renal Cell Carcinoma Hydroxylation Hypoxia Hypoxia Inducible Factor In Vitro Lead Lesion Link Mediating Mediator of activation protein Metastatic Renal Cell Cancer Molecular Neoplasm Metastasis Oncogenic Patients Peptides Play Progression-Free Survivals Proline Radiation Refractory Renal Cell Carcinoma Renal carcinoma Role Sampling Testing Therapeutic Tissues Transactivation Translating Tumor Suppressor Genes Tumor Suppressor Proteins Tumor stage Von Hippel-Lindau Syndrome advanced disease base chemotherapy clinical application improved in vivo in vivo Model inhibitor/antagonist loss of function mimetics mouse model novel novel strategies outcome forecast pre-clinical public health relevance response small molecule therapy resistant tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Clear cell renal carcinoma (CRCC) is the most common and aggressive form of kidney cancer, and is inherently resistant to therapy. CRCC is typically initiated by inactivation of the von Hippel Lindau (VHL) tumor suppressor gene, resulting in the constitutive activation of the hypoxia inducible factors, HIF-1 and HIF-2. CRCC lesions show evidence of a shift from high HIF-1¿ expression in early lesions, to high HIF-2¿ expression in advanced disease. The mechanism for this 'HIF switch' is unknown. However, high HIF-2¿ is associated with increased dysplasia and advanced disease, whereas HIF-1¿ is frequently lost in advanced CRCC. Hence the targeting of the HIF switch that leads to HIF-2 specific activation may be of therapeutic benefit. We have identified the hypoxia associated factor (HAF), as a mediator of the switch from HIF-1¿ to HIF-2¿ by selectively degrading HIF-1¿, and promoting HIF-2¿ transactivation. We show that HAF promotes HIF-2 specific activation in CRCC cells, and that high HAF expression predicts for significantly decreased progression-free survival in patients with metastatic CRCC. Hence, our hypothesis is that CRCC is initiated by pVHL loss-of-function, resulting in the 'HIF switch' from HIF-1 to HIF-2 specific transcription mediated by HAF, which drives CRCC progression. Hence, the targeting of the HAF/HIF-2 axis may be of therapeutic benefit for the treatment of CRCC. The overall goal of our studies is to identify the mechanisms driving the HIF switch, which may lead to new strategies for more effectively treating CRCC, and to determine whether specific inhibition of HIF-2 will yield increased therapeutic benefit. Hence, our first aim is to elucidate the molecular mechanisms regulating the switch to HIF-2, which include HAF SUMOylation and hydroxylation of unique poly-proline motifs within HIF-2¿. Our second aim is to investigate the contribution of the HAF/HIF-2 axis in promoting CRCC progression and resistance to therapy using in vitro and in vivo models, and clinical CRCC samples. Here, we will address the impact of HAF on the anti-tumor response of CRCC cells in vitro and in vivo, and on tumor growth/metastasis in orthotopic mouse models. We will also investigate the relationship between HAF and HIF levels to tumor stage and patient survival, in samples from patients with VHL disease, and within a multistage CRCC tumor microarray. Our third aim is to develop peptide-mimetic inhibitors of HAF/HIF-2¿ binding as a novel way to specifically inhibit HIF-2. Our lead 7 residue peptide specifically inhibits HIF-2 activity in CRCC cells. This peptide will form the basis for a small molecule peptide-mimetic, which we will use as a pharmacological probe to investigate the potential anti-tumor activity of HIF-2 inhibition.

描述：清晰的细胞肾癌（CRCC）是肾癌蚂蚁最常见和侵略性的CRCC。 -1和HIF-2。在早期病变中的表达，高HIF-2。在晚期疾病中的表达是未知的。与发育不良和晚期疾病有关，Hif-1。经常在高级CRCC中丢失。到hif-2？通过有选择地降解HIF-1¿并促进hif-2。瞬变。我们表明，HAF促进了CRCC细胞中的HIF-2特异性激活，高HAF表达可预测转移性CRCC患者的无进度生存率。，HIF开关从HAF从HIF-1转到HIF-2特异性，HAF的靶向HAF/HIF-2轴的靶向可能是CRCC污染的治疗益处。我们研究的总体目标是HIF开关的机制，这可能会导致更多的策略，以更加珍视CRCC，以确定对HIF-2的特定吸收是否会产生不良的治疗益处，我们的目标是阐明转向HIF-2的转换hif-2中的脯氨酸FS我们的第二个目标是研究HAF/HIF -2 O模型，以及在这里临床CRCC样本。在多阶段的CRCC肿瘤微阵列中，HAF和HIF水平之间的转移模型。 AS AS AS AS抑制HIF-2 HIF-2抑制作用的潜在抗肿瘤活性。