HIF Inhibitors: Status of Current Clinical Development

Fallah, Jaleh; Rini, Brian I.

doi:10.1007/s11912-019-0752-z

Cited by 264 publications

(190 citation statements)

References 60 publications

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“…Hypoxic tumour cells have been found to have increased metastatic potential and resistance to radiotherapy and chemotherapy . An improved characterisation of gene regulation in response to hypoxia is of interest to further understand the fundamental biology of the hypoxic response, which in turn might help to inform the development of drugs aimed at suppressing or enhancing levels of HIF …”

Section: Introductionmentioning

confidence: 99%

Quantitative MS‐Based Proteomics: Comparing the MCF‐7 Cellular Response to Hypoxia and a 2‐Oxoglutarate Analogue

et al. 2020

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The hypoxia‐inducible factors (HIFs) are key transcription factors in determining cellular responses involving alterations in protein levels in response to limited oxygen availability in animal cells. 2‐Oxoglutarate‐dependent oxygenases play key roles in regulating levels of HIF and its transcriptional activity. We describe MS‐based proteomics studies in which we compared the results of subjecting human breast cancer MCF‐7 cells to hypoxia or treating them with a cell‐penetrating derivative (dimethyl N‐oxalylglycine; DMOG) of the stable 2OG analogue N‐oxalylglycine. The proteomic results are consistent with reported transcriptomic analyses and support the proposed key roles of 2OG‐dependent HIF prolyl‐ and asparaginyl‐hydroxylases in the hypoxic response. Differences between the data sets for hypoxia and DMOG might reflect context‐dependent effects or HIF‐independent effects of DMOG.

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Section: Introductionmentioning

confidence: 99%

Quantitative MS‐Based Proteomics: Comparing the MCF‐7 Cellular Response to Hypoxia and a 2‐Oxoglutarate Analogue

et al. 2020

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“…In this study, we demonstrated that oncogenic Ras/MEK reduces PpIX accumulation by activating the HIF-1α-FECH axis. As HIF-1α plays critical roles in developing resistance against other cancer therapeutics such as chemotherapy, radiotherapy, and immunotherapy, it is considered as a potential therapeutic target in cancer (34). There are several HIF-1 inhibitors currently being evaluated in phase II and III clinical trials (35).…”

Section: Discussionmentioning

confidence: 99%

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

Chelakkot

Liu

Yoshioka

et al. 2020

Preprint

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1The efficacy of aminolevulinic acid (5-ALA)-based photodynamic diagnosis (5-ALA-PDD) and 2 photodynamic therapy (5-ALA-PDT) is dependent on the 5-ALA-induced cancer-specific 3 accumulation of protoporphyrin IX (PpIX). We previously reported that inhibition of oncogenic 4 Ras/MEK increases PpIX accumulation in cancer cells by reducing PpIX efflux through ATP-binding 5 cassette sub-family B member 1 (ABCB1) as well as PpIX conversion to heme by ferrochelatase 6 (FECH). Here, we sought to identify the downstream pathways of Ras/MEK involved in the 7 regulation of PpIX accumulation via ABCB1 and FECH. First, we demonstrated that Ras/MEK 8 activation reduced PpIX accumulation in RasV12-transformed NIH3T3 cells and HRAS transgenic 9 mice. Knockdown of p90 ribosomal S6 kinases (RSK) 2, 3, or 4 increased PpIX accumulation in the 10 RasV12-transformed NIH3T3 cells. Further, treatment with an RSK inhibitor reduced ABCB1 11 expression and increased PpIX accumulation. Moreover, HIF-1α expression was reduced when the 12 RasV12-transformed NIH3T3 cells were treated with a MEK inhibitor, demonstrating that HIF-1α is a 13 downstream element of MEK. HIF-1α inhibition decreased the activity of FECH and increased PpIX 14 accumulation. Finally, we demonstrated the involvement of RSKs and HIF-1α in the regulation of 15 PpIX accumulation in human cancer cell lines (DLD-1, SNB-75, Hs 578T, and MDA MB 231). These 16 results demonstrate that the RSK-ABCB1 and HIF-1α-FECH axes are the downstream pathways of 17 Ras/MEK involved in the regulation of PpIX accumulation. 18 19

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“…In response to hypoxia, HIF‐1α expression is up‐regulated and the molecule translocates from the cytoplasm to the cell nucleus where it forms a functional heterodimer with the HIF‐β subunit. This complex acts as a transcriptional factor for hundreds of genes involved in angiogenesis, including vascular endothelial growth factor (VEGF), platelet‐derived growth factor (PDGF), and angiopoietin‐1 (ANGPT1) . In addition to regulating the expression of genes involved with tumor growth, invasion, and metastasis, the HIF pathway plays a key role in the development of resistance to anti‐cancer therapies and HIF‐1α facilitates escape of tumor cells from T‐cell recognition …”

Section: Summary Of the American Society Of Clinical Oncology/americamentioning

confidence: 99%

“…In fact, everolimus and temsirolimus, which are both indirect HIF inhibitors in the class of mTOR inhibitors, are effective against several tumor types, including renal cell carcinoma. There are several ongoing Phase II and III clinical trials of HIF inhibitors across several tumor types which may help to better clarify the complicated interplay between HIF inhibitors and tumorigenesis.…”

Section: Summary Of the American Society Of Clinical Oncology/americamentioning

confidence: 99%

“…59 for hundreds of genes involved in angiogenesis, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and angiopoietin-1 (ANGPT1). 65 In addition to regulating the expression of genes involved with tumor growth, invasion, and metastasis, 66 the HIF pathway plays a key role in the development of resistance to anti-cancer therapies 67 and HIF-1α facilitates escape of tumor cells from T-cell recognition. 68 Increased HIF expression in a range of human cancers is associated with poorer prognosis and outcomes.…”

Section: Ta B L E 1 Summary Of the American Society Of Clinical Oncolmentioning

confidence: 99%

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Anemia management in cancer patients with chronic kidney disease

Latcha

2019

Seminars in Dialysis

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Cancer and kidney disease are linked by causality and comorbidities. Observational data show an increased risk of malignancy as renal function declines. Erythropoietin stimulating agents (ESAs), which are the cornerstone therapy for anemia patients with chronic kidney disease and cancer, are associated with increased risks for cancer, cancer‐related mortality, progression of disease, and thromboembolic events. This article examines the recently published guidelines for ESA use in cancer patients from the American Society of Clinical Oncology and American Society of Hematology and attempts to contextualize them to the care of patients with coexistent CKD, cancer, and anemia.

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HIF Inhibitors: Status of Current Clinical Development

Cited by 264 publications

References 60 publications

Quantitative MS‐Based Proteomics: Comparing the MCF‐7 Cellular Response to Hypoxia and a 2‐Oxoglutarate Analogue

Quantitative MS‐Based Proteomics: Comparing the MCF‐7 Cellular Response to Hypoxia and a 2‐Oxoglutarate Analogue

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

Anemia management in cancer patients with chronic kidney disease

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