On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models

Cho, Hyejin; Du, Xiaoqiang; Rizzi, James P.; Liberzon, Ella; Chakraborty, Abhishek A.; Gao, Wenhua; Carvo, Ingrid; Signoretti, Sabina; Bruick, Richard K.; Josey, John A.; Wallace, Eli M.; Kaelin, William G.

doi:10.1038/nature19795

Cited by 375 publications

(398 citation statements)

References 15 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: 96%

“…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%

“…These encouraging results lend validation towards developing novel therapeutics that target the pVHL/HIF2a pathway. However, these studies also uncovered several preclinical mouse models that are not responsive to these HIF2a antagonists (20,21). In some models, the lack of antitumor activity was attributed to missense mutations that resulted in amino acid substitutions surrounding the binding pocket of HIF2a antagonists (20,21).…”

Section: Introductionmentioning

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: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…This inhibitor can suppress the tumor progression in the preclinical models of VHL-inactive ccRCC, and demonstrate much better activity than sunitinib, the first line agent for the ccRCC treatment in clinic. Besides, PT2385, an analogue of PT2399, has already been on-going in the Phase I clinical research by Peloton Therapeutics Cho et al, 2016).…”

mentioning

confidence: 99%

Targeting SPOP with small molecules provides a novel strategy for kidney cancer therapy

Zheng

Yang

2016

Sci. China Life Sci.

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Renal cell carcinoma (RCC), accounting for 4% of all cancers, is the second most common cancer in urology. The most common form of RCC is clear cell RCC (ccRCC), with a ratio over 70%. Early-phase kidney diseases usually show rare symptoms in clinic; unfortunately, most patients are diagnosed with kidney cancer at the end stage, at which point the cancer is both resistant to chemotherapy and metastatic, thus leading to high mortality. Understanding cancer biology enables manipulation of disease targets by using small-molecule modulators, which eventually drive the development of novel therapeutic agents for ccRCC. In this insight, we would like to briefly outline several promising and revolutionizing targets and the target-based design of therapeutic agents for ccRCC.Interleukin-2 (Aldesleukin) and interferon are common immunotherapy for patients with metastatic RCC, while their effectiveness is still controversial. In 2015, the first checkpoint inhibitor nivolumab (Opdivo, BMS) with improved overall survival for the RCC therapy was approved by the FDA (Food and Drug Administration) as a single agent in the second-line setting, which is a monoclonal antibody targeting PD-1 in order to suppress the growth of ccRCC cells. Comparing checkpoint-inhibitor based combinations with other anti-tumor agents in the first-line setting are ongoing in phase III for *Corresponding author (email: yangcg@simm.ac.cn) ccRCC therapy. With several checkpoint inhibitors alone or in combination, this field is promising and evolving rapidly (Curtis et al., 2016).Hereditary or sporadic ccRCC always demonstrates correlation with the inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), lowing ubiquitination level of the down-stream protein hypoxic stress and hypoxia-inducible factor α (HIFα), and bringing about its stabilization and accumulation in ccRCC cells. Cellular stimuli activate the phosphoinositide 3-kinase (PI3K)/Akt (protein kinase) pathway and mammalian target of rapamycin (mTOR), which can also raise the HIFα protein level in ccRCC cells. Consequently, the activated transcription factor HIF increases the transcription level of hypoxia-related genes, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), and results in tumor-inclined cell proliferation, migration, and permeation. There is considerable pharmaceutical research into drug discovery by targeting protein phosphorylation signaling pathways. Indeed, the FDA has approved several agents targeting ccRCC-closely related proteins for the metastatic RCC therapy. Temsirolimus (Torisel, Wyeth), an inhibitor of mTOR conplex1 (mTORC1), shows good antitumor activity in patients with metastatic RCC. VEGF receptor (VEGFR) and PDGF receptor (PDGRF) tyrosine kinases inhibitors sunitinib (Sutent, Pfizer) and sorafenib (Nexavar, Bayer) are released to the market for the treatment of RCC.

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Pathophysiology of Gastroesophageal Reflux Disease

Paris

Souza

2021

The Esophagus

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On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models

Cited by 375 publications

References 15 publications

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Targeting SPOP with small molecules provides a novel strategy for kidney cancer therapy

Pathophysiology of Gastroesophageal Reflux Disease

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