A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma

Wallace, Eli M.; Rizzi, James P.; Han, Guangzhou; Wehn, Paul M.; Cao, Zhaodan; Du, Xiaoqiang; Cheng, Tzuling; Czerwiński, Robert; Dixon, Darryl D.; Goggin, Barry S.; Grina, Jonas; Halfmann, Megan M.; Maddie, Melissa A.; Olive, Sarah R.; Schlachter, Stephen T.; Tan, Huiling; Wang, Bin; Wang, Keshi; Xie, Shanhai; Xu, Rui; Yang, Hanbiao; Josey, John A.

doi:10.1158/0008-5472.can-16-0473

Cited by 245 publications

(236 citation statements)

References 38 publications

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“…In general, transcription factors such as HIF2a have generally been considered undruggable therapeutic targets (47). Recently, several reports described the antitumor effects of a small-molecule HIF2a antagonist that binds to a hydrophobic binding pocket discovered in HIF2a PAS-B domain (16,(20)(21)(22). Although these studies showed encouraging results that validated HIF2a as a therapeutic target, certain limitations are apparent.…”

Section: Discussionmentioning

confidence: 99%

“…Although these studies showed encouraging results that validated HIF2a as a therapeutic target, certain limitations are apparent. These included preexisting drug-resistant mutations, posttreatment mutations discovered surrounding the binding pocket of this small molecule, and the dependence of some tumors on cellular pathways other than VHL-HIF (20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, potential new therapies targeting HIF2a function, including in this study, are being explored. Recently, preclinical and limited early clinical results using small-molecule inhibitors targeting HIF2a were reported (16,(20)(21)(22). In these studies, the HIF2a antagonists showed antitumor activity in several tumor cell line xenograft mouse models and patient-derived xenograft (PDX) models.…”

Section: Introductionmentioning

confidence: 99%

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HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Wong

Cheng

Hamilton

et al. 2018

Molecular Cancer Therapeutics

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Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80%-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2a (HIF2a) and that an overabundance of HIF2a functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2a that utilizes a targeting ligand that selectively binds to integrins avb3 and avb5 frequently overexpressed in ccRCC. We demonstrate that functional delivery of a HIF2a-specific RNAi trigger resulted in HIF2a gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Wong

Cheng

Hamilton

et al. 2018

Molecular Cancer Therapeutics

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“…Moreover, considering their intimate crosstalk, it is possible that some xenographs, showing even greater efficacy than conventional treatments (i.e. sunitinib) [182][183][184].…”

Section: Future Prospective In Cancer Therapeutics: Targeting Hif Andmentioning

confidence: 99%

Hypoxia and Inflammation in Cancer, Focus on HIF and NF-кB

D'Ignazio¹,

Batie²,

Rocha³

2017

Preprint

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Cancer is often characterised by the presence of hypoxia and inflammation.Paramount to the mechanisms controlling cellular responses under such stress stimuli, are the transcription factor families of Hypoxia Inducible Factor (HIF) and NuclearFactor of kappa-light-chain-enhancer of activated B cells (NF-κB). Although, a detailed understating of how these transcription factors respond to their cognate stimulus is well established, it is now appreciated that HIF and NF-κB undergo extensive crosstalk, in particular in pathological situations such as cancer. Here, we focus on the current knowledge on how HIF is activated by inflammation and how NF-κB is modulated by hypoxia. We summarise the evidence for the possible mechanism behind this activation and how HIF and NF-κB function impacts cancer, focusing on colorectal, breast and lung cancer. We discuss possible new points of therapeutic intervention aiming to harness the current understanding of the HIF-NF-κB crosstalk.

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“…These findings support a potential reversible hypermethylation process in patients with an SDH mutation, suggesting a possible therapeutic pathway. Moreover, over the last several years, new molecules to inhibit HIF2α have been developed, especially in the treatment of clear cell carcinoma of the kidney (33). PT2385 is one such molecule and it binds to a HIF-2α unique protein pocket in the PAS-B domain, and thus, prevents the HIF-2α-ARNT dimerization and the formation of an active HIF-2 transcription complex.…”

Section: Familial Catecholamine-hypersecreting Tumours In Succinate Dmentioning

confidence: 99%

The clinical genetics of phaeochromocytoma and paraganglioma

Gunawardane

Grossman

2017

Arch. Endocrinol. Metab.

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Phaeochromocytoma and paraganglioma are rare catecholamine-producing tumours, recognised to have one of the richest hereditary backgrounds of all neoplasms, with germline mutations seen in approximately 30% of patients. They can be a part of genetic syndromes such as MEN 2 or Neurofibromatosis type 1, or can be found as apparently sporadic tumours. Germline mutations are almost always found in syndromic patients. Nonetheless, apparently sporadic phaeochromocytoma too show high germline mutation rates. Early detection of a genetic mutation can lead to early diagnosis of further tumours via surveillance, early treatment and better prognosis. Apart from this, the genetic profile has important relevance for tumour location and biochemical profile, and can be a useful predictor of future tumour behaviour. It also enables family screening and surveillance. Moreover, recent studies have demonstrated significant driver somatic mutations in up to 75% of all tumours. Arch Endocrinol Metab. 2017;61(5):490-500

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A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma

Cited by 245 publications

References 38 publications

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Hypoxia and Inflammation in Cancer, Focus on HIF and NF-кB

The clinical genetics of phaeochromocytoma and paraganglioma

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