Targeting PRC2 for the treatment of cancer: an updated patent review (2016 - 2020)

Dockerill, Milly; Gregson, Clare; O’Donovan, Daniel H.

doi:10.1080/13543776.2021.1841167

Cited by 33 publications

(33 citation statements)

References 52 publications

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“…EZH2 is overexpressed in numerous tumor entities, including neuroblastoma, small cell carcinoma, and prostate cancer, and is frequently associated with aggressive disease, leading to its classification as an oncogene 12,35 . As the major H3K27me3 methyltransferase, EZH2 is commonly believed to execute its tumorpromoting function via transcriptional repression of tumor suppressor genes.…”

Section: Discussionmentioning

confidence: 99%

EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

et al. 2022

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Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. In the current study, we show that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracts FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induces robust MYC(N) degradation and inhibits tumor cell growth in MYC(N) driven neuroblastoma and small cell lung carcinoma. Here, we demonstrate the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.

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Section: Discussionmentioning

confidence: 99%

EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

et al. 2022

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“…Tazemetostat (EPZ-6438), a EZH2 selective inhibitor, was approved for the treatment of advanced epithelioid sarcoma and its effect in enhancing the therapeutic response to 5-fluorouracil in colorectal cancers has been recently confirmed [223]. Other EZH2 inhibitors are now under clinical evaluation and offer alternative approaches to target this HMT [224]. lncRNAs are also a promising source to develop new target therapies in the future.…”

Section: Other Epigenetic Therapiesmentioning

confidence: 99%

The Role of Epigenetics in the Progression of Clear Cell Renal Cell Carcinoma and the Basis for Future Epigenetic Treatments

Angulo

Manini

López

et al. 2021

Cancers

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Clear cell renal cell carcinoma (ccRCC) is curable when diagnosed at an early stage, but when disease is non-confined it is the urologic cancer with worst prognosis. Antiangiogenic treatment and immune checkpoint inhibition therapy constitute a very promising combined therapy for advanced and metastatic disease. Many exploratory studies have identified epigenetic markers based on DNA methylation, histone modification, and ncRNA expression that epigenetically regulate gene expression in ccRCC. Additionally, epigenetic modifiers genes have been proposed as promising biomarkers for ccRCC. We review and discuss the current understanding of how epigenetic changes determine the main molecular pathways of ccRCC initiation and progression, and also its clinical implications. Despite the extensive research performed, candidate epigenetic biomarkers are not used in clinical practice for several reasons. However, the accumulated body of evidence of developing epigenetically-based biomarkers will likely allow the identification of ccRCC at a higher risk of progression. That will facilitate the establishment of firmer therapeutic decisions in a changing landscape and also monitor active surveillance in the aging population. What is more, a better knowledge of the activities of chromatin modifiers may serve to develop new therapeutic opportunities. Interesting clinical trials on epigenetic treatments for ccRCC associated with well established antiangiogenic treatments and immune checkpoint inhibitors are revisited.

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“…Tazemetostat is a KMT inhibitor targeting EZH2 (Italiano et al, 2018) and G9a (Soumyanarayanan and Dymock, 2016;Dockerill et al, 2020) that has been approved for the treatment of sarcomas (Italiano et al, 2018;Gounder et al, 2020) and sensitizes ovarian cells to DNA damage (Karakashev et al, 2020). Therefore, we tested whether tazemetostat could also impair the H4K20me2 as part of the DDR in sarcoma cells treated with doxorubicin.…”

Section: Tazemetostat Impairs H4k20me2 the Dna Damage Response Induced By Doxorubicinmentioning

confidence: 99%

Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy

Campillo-Marcos

Monte-Serrano

Navarro-Carrasco

et al. 2021

Front. Cell Dev. Biol.

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BackgroundChromatin is dynamically remodeled to adapt to all DNA-related processes, including DNA damage responses (DDR). This adaptation requires DNA and histone epigenetic modifications, which are mediated by several types of enzymes; among them are lysine methyltransferases (KMTs).MethodsKMT inhibitors, chaetocin and tazemetostat (TZM), were used to study their role in the DDR induced by ionizing radiation or doxorubicin in two human sarcoma cells lines. The effect of these KMT inhibitors was tested by the analysis of chromatin epigenetic modifications, H4K16ac and H4K20me2. DDR was monitored by the formation of γH2AX, MDC1, NBS1 and 53BP1 foci, and the induction of apoptosis.ResultsChaetocin and tazemetostat treatments caused a significant increase of H4K16 acetylation, associated with chromatin relaxation, and increased DNA damage, detected by the labeling of free DNA-ends. These inhibitors significantly reduced H4K20 dimethylation levels in response to DNA damage and impaired the recruitment of 53BP1, but not of MDC1 and NBS1, at DNA damaged sites. This modification of epigenetic marks prevents DNA repair by the NHEJ pathway and leads to cell death.ConclusionKMT inhibitors could function as sensitizers to DNA damage-based therapies and be used in novel synthetic lethality strategies for sarcoma treatment.

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Targeting PRC2 for the treatment of cancer: an updated patent review (2016 - 2020)

Cited by 33 publications

References 52 publications

EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

The Role of Epigenetics in the Progression of Clear Cell Renal Cell Carcinoma and the Basis for Future Epigenetic Treatments

Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy

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