The targeting of the HIF switch in kidney cancer

HIF 开关在肾癌中的靶向作用

• 批准号: 9094688
• 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
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9094688
• 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; Health; 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; hypoxia inducible factor 1; improved; in vivo; in vivo Model; inhibitor/antagonist; loss of function; mouse model; novel; novel strategies; outcome forecast; peptidomimetics; pre-clinical; response; small molecule; small molecule inhibitor; targeted agent; therapy resistant; tumor; tumor growth

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）是肾癌中最常见和最具侵袭性的形式，并且固有地对治疗具有耐药性。CRCC通常由von Hippel Lindau （VHL）肿瘤抑制基因失活引发，导致缺氧诱导因子HIF-1和HIF-2的组成性激活。CRCC病变表现出从早期HIF-1 -高表达到晚期HIF-2 -高表达的转变。这种“HIF开关”的机制尚不清楚。然而，高HIF-2′与发育不良增加和晚期疾病相关，而HIF-1′在晚期CRCC中经常缺失。因此，靶向导致HIF-2特异性激活的HIF开关可能具有治疗益处。我们已经确定了缺氧相关因子（HAF），通过选择性地降解HIF-1，并促进HIF-2的转激活，作为HIF-1向HIF-2转换的中介。我们发现，HAF促进了CRCC细胞中HIF-2的特异性激活，并且高HAF表达预示着转移性CRCC患者的无进展生存期显著降低。因此，我们的假设是，CRCC是由pVHL功能丧失引发的，导致由HAF介导的从HIF-1到HIF-2特异性转录的“HIF开关”，从而推动CRCC的进展。因此，靶向HAF/HIF-2轴可能对治疗CRCC有治疗益处。我们研究的总体目标是确定驱动HIF转换的机制，这可能导致更有效治疗CRCC的新策略，并确定特异性抑制HIF-2是否会产生更高的治疗效果。因此，我们的第一个目标是阐明调控HIF-2转换的分子机制，其中包括HIF-2中独特的聚脯氨酸基序的HAF sumo化和羟基化。我们的第二个目标是通过体外和体内模型以及临床CRCC样本，研究HAF/HIF-2轴在促进CRCC进展和治疗耐药性中的作用。在这里，我们将探讨HAF对体外和体内CRCC细胞抗肿瘤反应的影响，以及对原位小鼠模型中肿瘤生长/转移的影响。我们还将在VHL患者样本和多期CRCC肿瘤微阵列中研究HAF和HIF水平与肿瘤分期和患者生存之间的关系。我们的第三个目标是开发HAF/HIF-2结合的肽模拟抑制剂，作为特异性抑制HIF-2的新方法。我们的铅7残基肽特异性抑制CRCC细胞中HIF-2的活性。该肽将构成小分子肽模拟物的基础，我们将用它作为药理学探针来研究HIF-2抑制的潜在抗肿瘤活性。