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（由申请人提供）：透明细胞肾癌（CRCC）是肾癌最常见且最具侵袭性的形式，并且CRCC通常是由冯希佩尔林道（VHL）肿瘤抑制基因失活引发的。导致缺氧诱导因子 HIF-1 和 HIF-2 的组成性激活，CRCC 病变显示出高 HIF-1 转变的证据。在早期病变中表达至高 HIF-2¿然而，高 HIF-2 的这种“HIF 开关”的机制尚不清楚。与不典型增生和晚期疾病的增加有关，而 HIF-1¿因此，导致 HIF-2 特异性激活的 HIF 开关的靶向可能具有治疗益处，我们已经确定缺氧相关因子 (HAF) 作为 HIF-1 开关的介体。至 HIF-2¿通过选择性降解 HIF-1¿ ，并推广 HIF-2¿我们发现 HAF 促进 CRCC 细胞中 HIF-2 的特异性激活，并且 HAF 的高表达预示着转移性 CRCC 患者的无进展生存期显着降低。因此，我们的假设是，CRCC 是由 pVHL 缺失引发的。功能，导致 HAF 介导的从 HIF-1 到 HIF-2 特异性转录的“HIF 转换”，从而驱动 CRCC 进展。因此，HAF/HIF-2 轴的靶向可能对治疗有益。我们研究的总体目标是确定驱动 HIF 转换的机制，这可能会产生更有效治疗 CRCC 的新策略，并确定 HIF-2 的特异性抑制是否会产生更大的治疗效果。，我们的首要目标是阐明调节 HIF-2 转换的分子机制，其中包括 HIF-2 内独特聚脯氨酸基序的 HAF SUMO 化和羟基化。我们的第二个目标是利用体外和体内模型以及临床 CRCC 样本研究 HAF/HIF-2 轴在促进 CRCC 进展和治疗耐药方面的贡献。在这里，我们将讨论 HAF 对抗 - 的影响。我们还将研究 VHL 疾病患者样本中 HAF 和 HIF 水平与肿瘤分期和患者生存率之间的关系。我们的第三个目标是开发 HAF/HIF-2 的肽模拟抑制剂。结合作为特异性抑制 HIF-2 的新方法。我们的前导 7 残基肽特异性抑制 CRCC 细胞中的 HIF-2 活性，该肽将构成小分子肽模拟物的基础，我们将其用作药理学探针。研究 HIF-2 抑制的潜在抗肿瘤活性。