HIF2a inhibitors for the treatment of VHL disease

Metelo, Ana M.; Noonan, Haley R.; Iliopoulos, Othon

doi:10.18632/oncotarget.4564

Cited by 20 publications

(16 citation statements)

References 7 publications

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“…97,98 Small-molecule inhibitors of both HIF-1 and HIF-2 are also available or in development which can dampen the anti-immune effects of hypoxia, particularly in suppressive myeloid cells and tumors. 99,100 Specific inhibitors of suppressive enzymes induced in myeloid cells including Arginase, inducible nitric oxide synthase and indoleamine 2 3-dioxygenase are now also widely available. The challenge ahead is to determine experimentally which of these approaches act to diminish hypoxia-induced immune suppression without also impeding some aspect of antitumor immunity.…”

Section: Resultsmentioning

confidence: 99%

Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer

et al. 2016

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Tumors use several strategies to evade the host immune response, including creation of an immune-suppressive and hostile tumor environment. Tissue hypoxia due to inadequate blood supply is reported to develop very early during tumor establishment. Hypoxic stress has a strong impact on tumor cell biology. In particular, tissue hypoxia contributes to therapeutic resistance, heterogeneity and progression. It also interferes with immune plasticity, promotes the differentiation and expansion of immune-suppressive stromal cells, and remodels the metabolic landscape to support immune privilege. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. In this regard, manipulating host-tumor interactions in the context of the hypoxic tumor microenvironment may be important in preventing or reverting malignant conversion. We will discuss how tumor microenvironment-driven transient compositional tumor heterogeneity involves hypoxic stress. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of conventional therapies as well as cancer immunotherapy. Thus, understanding how tumor and stromal cells respond to hypoxia will allow for the design of innovative cancer therapies that can overcome these barriers. A better understanding of hypoxia-dependent mechanisms involved in the regulation of immune tolerance could lead to new strategies to enhance antitumor immunity. Therefore, discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance. In this context, critical hypoxia-associated pathways are attractive targets for immunotherapy of cancer. In this review, we summarize current knowledge regarding the molecular mechanisms induced by tumor cell hypoxia with a special emphasis on therapeutic resistance and immune suppression. We emphasize mechanisms of manipulating hypoxic stress and its associated pathways, which may support the development of more durable and successful cancer immunotherapy approaches in the future.

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Section: Resultsmentioning

confidence: 99%

Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer

et al. 2016

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“…Germline mutations in this VHL gene could lead to the VHL disease [26], an autosomal dominant familial cancer syndrome which has an upward tendency to the development of spinal and cerebellar haemangiobastoma, retinal angioma and clear-cell renal cell carcinoma (ccRCC) [27][28][29]. In addition, we could also find that the somatic VHL mutations in patients with sporadic renal cell carcinoma [30].…”

Section: Discussionmentioning

confidence: 95%

The Expression of VHL (Von Hippel-Lindau) After Traumatic Spinal Cord Injury and Its Role in Neuronal Apoptosis

Hao

Chen

et al. 2016

Neurochem Res

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The VHL (Von Hippel-Lindau) gene is a tumor suppressor gene, which is best known as an E3 ubiquitin ligase that negatively regulates the hypoxia inducible factor. The inactivation of VHL gene could result in the abnormal synthesis of VHL protein, which is in contact with the development and occurrence of renal clear cell carcinoma. However, the expression and possible function of VHL in central nervous system (CNS) is still unclear. To examine the function of VHL in CNS injury and repair, we used an acute spinal cord injury (SCI) model in adult rats. Western blot analysis showed an important upregulation of VHL protein, reaching a peak at day 3 and then declined during the following days. Double immunofluorescence staining showed that VHL was co-expressed with neurons, but not with astrocytes and microglia. Moreover, we detected that active caspase-3 had co-localized with VHL in neurons after SCI. Additionally in vitro, VHL depletion, by short interfering RNA, significantly reduced neuronal apoptosis. In conclusion, these data suggested that the change of VHL protein expression was related to neuronal apoptosis after SCI.

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“…The normal function of von Hippel-Lindau (VHL) tumor suppressor can abolish the hypoxia-inducible transcription factor (HIF) and HIF acts as an important oncogene to promote renal tumor growth [25][26][27][28]. BMP1 and HIF1A were positively correlated with the malignant grade of astrocytomas [29], but no research reported their direct or indirect relationship.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of BMP1 reflects poor prognosis in clear cell renal cell carcinoma

Xiao

Wang

et al. 2019

Cancer Gene Ther

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Clear cell renal cell carcinoma (ccRCC) is the highest mortality, invasion, and metastasis subtype of renal cell carcinoma. Bone morphogenetic protein (BMP) family has recently emerged as a group of cancer-related proteins in multiple pathogenesis of cancers. Currently, little is known about the prediction role of BMPs in ccRCC. Therefore, we screened The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) database for ccRCC patients with complete clinical information and BMP family expression data. Multivariate analysis showed that high expression of BMP1 was associated with shorter overall survival (OS) (P = 0.001), and shorter disease-free survival (DFS) (P = 0.018). Gene set enrichment analysis (GSEA) showed BMP1 was associated with epithelial-mesenchymal transition (EMT), G2M checkpoint, angiogenesis, hypoxia pathway, and Kirsten rat sarcoma viral oncogene (KRAS) signaling. Knockdown BMP1 suppressed malignancy of ccRCC in vitro and in vivo. Our results indicated that high expressions of BMP1 were poor prognostic factors and gene therapy could be an effective treatment for ccRCC.

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HIF2a inhibitors for the treatment of VHL disease

Cited by 20 publications

References 7 publications

Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer

Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer

The Expression of VHL (Von Hippel-Lindau) After Traumatic Spinal Cord Injury and Its Role in Neuronal Apoptosis

Overexpression of BMP1 reflects poor prognosis in clear cell renal cell carcinoma

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