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

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(由应用提供):清晰的细胞肾癌(CRCC)是肾癌最常见,最具侵略性的形式,并且对治疗具有固有的抵抗力。 CRCC通常是通过失活的von Hippel-Lindau(VHL)抑制基因的,从而导致缺氧诱导因子HIF-1和HIF-2的组成型激活。 CRCC病变显示出从早期病变中高HIF-1表达转变为晚期疾病中高HIF-2表达的证据。此“ HIF开关”的机制未知。但是,高HIF-2与发育不良和晚期疾病的增加有关,而HIF-1经常在晚期CRCC中丢失。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。我们已经通过有选择地降解HIF-1并促进HIF-2?发,我们已经确定了与HIF-1到HIF-1的转换的介体(HAF)。我们表明,HAF促进了CRCC细胞中HIF-2的特异性激活,并且在转移性CRCC患者中显着降低了无进展生存的高HAF表达预测。因此,我们的假设是CRCC是由PVHL功能丧失启动的,从而导致“ HIF开关”从HIF-1转到HAF介导的HAF介导的HIF-1特异性转录,该转录驱动CRCC进展。因此,HAF/HIF-2轴的靶向可能是治疗CRCC的治疗益处。我们研究的总体目标是确定推动HIF开关的机制,这可能会导致更有效地治疗CRCC的新策略,并确定对HIF-2的特定抑制是否会带来增加的治疗益处。因此,我们的第一个目的是阐明调节转换为HIF-2的分子机制,其中包括Haf sumoylation和HIF-2中独特多丙烯基序的Haf sumoylation和羟基化,我们的第二个目的是研究HAF/HIF-2轴对使用In Verro和Vivo crock same and Crcc and and and Crcc Crcc的贡献。在这里,我们将解决HAF对CRCC细胞在体外和体内的抗肿瘤反应的影响,以及原位小鼠模型中肿瘤生长/转移的影响。我们还将研究HAF和HIF水平与肿瘤阶段和患者存活之间的关系,VHL疾病患者的样本以及多阶段CRCC肿瘤微阵列的关系。我们的第三个目的是开发HAF/HIF-2的肽模拟抑制剂,作为一种专门抑制HIF-2的新方法。我们的铅7保留肽特异性抑制了CRCC细胞中的HIF-2活性。该肽将构成小分子肽模拟物的基础,我们将用作药物探针来研究HIF-2抑制的潜在抗肿瘤活性。

项目成果

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Mei Yee Koh其他文献

Mei Yee Koh的其他文献

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{{ truncateString('Mei Yee Koh', 18)}}的其他基金

A Role for the Novel HAF-NFkappaB Axis in Driving Obesity-Associated Liver Cancer
新型 HAF-NFkappaB 轴在驱动肥胖相关肝癌中的作用
  • 批准号:
    10446842
  • 财政年份:
    2022
  • 资助金额:
    $ 52.11万
  • 项目类别:
A Role for the Novel HAF-NFkappaB Axis in Driving Obesity-Associated Liver Cancer
新型 HAF-NFkappaB 轴在驱动肥胖相关肝癌中的作用
  • 批准号:
    10676965
  • 财政年份:
    2022
  • 资助金额:
    $ 52.11万
  • 项目类别:
A novel approach for the selective inhibition of HIF-2a in kidney cancer
选择性抑制肾癌中 HIF-2a 的新方法
  • 批准号:
    9361021
  • 财政年份:
    2017
  • 资助金额:
    $ 52.11万
  • 项目类别:
A novel approach for the selective inhibition of HIF-2a in kidney cancer
选择性抑制肾癌中 HIF-2a 的新方法
  • 批准号:
    10227021
  • 财政年份:
    2017
  • 资助金额:
    $ 52.11万
  • 项目类别:
A novel approach for the selective inhibition of HIF-2a in kidney cancer
选择性抑制肾癌中 HIF-2a 的新方法
  • 批准号:
    9767082
  • 财政年份:
    2017
  • 资助金额:
    $ 52.11万
  • 项目类别:
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
  • 财政年份:
    2014
  • 资助金额:
    $ 52.11万
  • 项目类别:
High-throughput screen for specific small-molecule inhibitors of HIF-2A activity
HIF-2A 活性特异性小分子抑制剂的高通量筛选
  • 批准号:
    8644634
  • 财政年份:
    2013
  • 资助金额:
    $ 52.11万
  • 项目类别:
High-throughput screen for specific small-molecule inhibitors of HIF-2A activity
HIF-2A 活性特异性小分子抑制剂的高通量筛选
  • 批准号:
    8262506
  • 财政年份:
    2012
  • 资助金额:
    $ 52.11万
  • 项目类别:
High-throughput screen for specific small-molecule inhibitors of HIF-2A activity
HIF-2A 活性特异性小分子抑制剂的高通量筛选
  • 批准号:
    8416335
  • 财政年份:
    2012
  • 资助金额:
    $ 52.11万
  • 项目类别:

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