New Approaches to Targeting Epigenetic Regulation in Bladder Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Epigenetics and Bladder Cancer
2.1. Writers
2.1.1. DNA Methyltransferases (DNMTs)
2.1.2. Histone-Lysine N-Methyltransferases (HMTs)
2.1.3. Histone Acetyltransferases (HATs)
2.2. Erasers
2.2.1. Histone Deacetylases (HDACs)
2.2.2. DNA Demethylases
2.2.3. Histone Demethylases (HDMs)
2.3. Readers
2.3.1. Bromodomain and Extraterminal Domain (BET)
2.3.2. Methyl-CpG-Binding Domain (MBD) Proteins
3. Pre-Clinical and Clinical Trials
3.1. DNA Methyltransferases (DNMTs)
3.2. Histone Methyltransferases (HMTs)
3.3. Histone Acetyltransferases (HATs)
3.4. Histone Deacetylases (HDACs)
3.5. Histone Methylation Readers
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
BET | bromodomain and extraterminal domain |
CBP | CREB-binding protein |
DNMT | DNA methyltransferase |
EZH2 | enhancer of zeste 2 |
HAT | histone acetyltransferase |
HDAC | histone deacetylase |
HMT | histone-lysine N-methyltransferase |
MBD | methyl-CpG-binding domain |
MIBC | muscle invasive bladder cancer |
NMIBC | non-muscle invasive bladder cancer |
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Trial Identifier | Start Date | Expected End Date | Drug | Combination | Phase | Inclusion Cohort | Status | Results |
---|---|---|---|---|---|---|---|---|
DNMT inhibitors | ||||||||
NCT04851834 | 25 August 2021 | November 2023 | NTX-301 | Platinum-based chemotherapy | 1/2 | Locally advanced or metastatic bladder cancer; refractory/intolerant to standard of care therapies | Recruiting | Pending |
NCT03179943 | 27 November 2017 | July 2022 | Guadecitabine | Atezolizumab | 2 | Advanced or metastatic urothelial carcinoma; must have received/been ineligible for CTx; must have had received PD-L1 or PD-1 targeting agent | Active—not recruiting | Pending |
ISRCTN16332228 | 1 March 2016 | 10 July 2018 | Guadecitabine | Cisplatin and gemcitabine | 1b/2a | Incurable metastatic bladder cancer | Completed | Guadecitabine 20 mg/m2 is the recommended dose [55] |
NCT00978250 | 20 August 2009 | 11 April 2019 | 5-Fluoro-2′-Deoxycytidine | Tetrahydrouridine | 2 | Advanced or metastatic urothelial carcinoma; received at least one line of standard therapy | Completed | Well-tolerate; AUC increase 4-fold; progression-free survival above expected [58] |
NCT02030067 | December 2013 | July 2019 | RX-3117 | N/A (monotherapy) | 1 | Advanced bladder cancer | Completed | Not reported |
NCT00030615 | December 2001 | September 2008 | Decitabine | N/A (monotherapy) | 1 | Advanced or metastatic bladder cancer for which all other treatment has failed | Completed | Not reported |
NCT02223052 | 27 October 2014 | 11 June 2018 | CC-486 (oral form of azacitidine) | N/A (monotherapy) | 1 | Metastatic or inoperable bladder cancer | Completed | Not reported |
NCT01478685 | 29 November 2011 | 17 November 2015 | CC-486 (oral form of azacitidine) | Carboplatin or ABI-007 | 1 | Relapsed or refractory urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra | Completed | CC-486 is tolerated as a priming agent with carboplatin and ABI-007 [56] |
NCT00005639 | March 2000 | July 2005 | Azacitidine | Phenylbutyrate | 1 | Locally advanced or metastatic bladder cancer | Completed | Three doses were well-tolerated [57] |
NCT02959437 | 27 February 2017 | 15 February 2019 | Azacitidine | Pembrolizumab and epacadostat | 1/2 | Advanced or metastatic solid tumour, which has failed prior standard therapy | Terminated (by sponsors) | Not reported |
EZH2 inhibitors | ||||||||
NCT03854474 | 17 May 2019 | 30 June 2023 | Tazemetostat (EPZ-6438) | Pembrolizumab | 1/2 | Locally advanced or metastatic urothelial carcinoma with progression during or following platinum-based CTx (or ineligible for CTx) | Recruiting | Pending |
NCT03525795 | 14 December 2017 | 12 June 2019 | CPI-1205 | Ipilimumab | 1/2 | Unresectable or metastatic urothelial carcinoma (urethra, bladder, ureters, or renal pelvis) | Completed | Not reported |
HDAC inhibitors | ||||||||
NCT02619253 | 14 January 16 | 31 May 2023 | Vorinostat | Pembrolizumab | 1/2 | Urothelial cell carcinoma—previously treated and progressive disease, locally advanced or metastatic; must have received a prior platinum-based regimen in the metastatic setting | Active, not recruiting | Pending |
NCT00045006 | July 2001 | July 2008 | Vorinostat | N/A (monotherapy) | 1 | Advanced or metastatic bladder cancer that is refractory to standard treatment | Completed | Not reported |
NCT00565227 | April 2007 | November 2008 | Vorinostat | Docetaxel | 1 | Bladder/urothelial cancer that has progressed after chemotherapy | Terminated (toxicity) | Not reported |
NCT00363883 | June 2006 | December 2010 | Vorinostat | N/A (monotherapy) | 2 | Bladder/urothelial TCC that has recurred or progressed on platinum-based CTx | Terminated (futility) | Limited efficacy and significant toxicity [59] |
NCT05154994 | 14 January 2022 | 30 November 2023 | Belinostat | Tremelimumab and durvalumab | 1 | Urothelial carcinoma with metastatic disease or with unresectable, locally advanced disease | Recruiting | Pending |
NCT00413075 | June 2006 | August 2011 | Belinostat | N/A (monotherapy) | 1 | Primary or metastatic solid tumour refractory to standard treatment | Completed | Not reported |
NCT00413322 | September 2005 | March 2008 | Belinostat | 5-Fluorouracil | 1 | Advanced bladder cancer with progression on standard treatment | Completed | Not reported |
NCT00421889 | August 2005 | February 2009 | Belinostat | Carboplatin or paclitaxel | 1/2 | Urothelial carcinoma, received up to three CTx regimens in advanced disease setting | Completed | No published results; partial response in 4/15 patients |
NCT01638533 | 12 June 2012 | 29 November 2018 | Romidepsin | N/A (monotherapy) | 1 | Recurrent bladder cancer and concurrent hepatic impairment | Active, not recruiting | Similar toxicity to other HDAC inhibitors [60] |
NCT00087295 | June 2004 | April 2006 | FR901228 (Romidepsin) | N/A (monotherapy) | 2 | Metastatic or poorly differentiated TCC; progression after one CTx regimen | Terminated (poor accrual) | Not reported |
NCT01552434 | 16 March 2012 | 31 March 2022 | Valproic acid | Bevacizumab and temsirolimus | 1 | Metastatic urothelial cancer that is refractory to standard therapy | Active, not recruiting | Pending |
NCT01738815 | December 2011 | May 2013 | Valproic acid | N/A (monotherapy) | 1 | Suspected or confirmed bladder tumour | Completed | Not reported |
NCT03978624 | 23 September 2020 | 1 October 2023 | Entinostat | Pembrolizumab | 2 | MIBC ineligible for or refused neoadjuvant cisplatin-based CTx; pre-cystectomy | Recruiting | Pending |
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Thompson, D.; Lawrentschuk, N.; Bolton, D. New Approaches to Targeting Epigenetic Regulation in Bladder Cancer. Cancers 2023, 15, 1856. https://doi.org/10.3390/cancers15061856
Thompson D, Lawrentschuk N, Bolton D. New Approaches to Targeting Epigenetic Regulation in Bladder Cancer. Cancers. 2023; 15(6):1856. https://doi.org/10.3390/cancers15061856
Chicago/Turabian StyleThompson, Daryl, Nathan Lawrentschuk, and Damien Bolton. 2023. "New Approaches to Targeting Epigenetic Regulation in Bladder Cancer" Cancers 15, no. 6: 1856. https://doi.org/10.3390/cancers15061856