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词条 Draft:HDAC inhibitors in cancer treatment
释义
     Approved  Phase 3 and phase 2 clinical trials  Phase I Clinical trials 

  1. References

{{AFC submission|d|context|u=2A02:C7D:B910:3D00:79DD:7B75:7CEC:C1D6|ns=118|demo=|decliner=CoolSkittle|declinets=20190310235819|ts=20180822192514}} {{AFC comment|1=The lead section needs to be rewritten, it does not introduce readers to the topic very well (starting with "also" is not good). CoolSkittle (talk) 23:58, 10 March 2019 (UTC)}}

Also in recent years, there has been an effort to develop HDIs as a cancer treatment or adjunct.[1][2] The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.[3][4] HDAC inhibitors can induce p21 (WAF1) expression, a regulator of p53's tumor suppressor activity. HDACs are involved in the pathway by which the retinoblastoma protein (pRb) suppresses cell proliferation.[5] The pRb protein is part of a complex that attracts HDACs to the chromatin so that it will deacetylate histones.[6] HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction.[7] Estrogen is well-established as a mitogenic factor implicated in the tumorigenesis and progression of breast cancer via its binding to the estrogen receptor alpha (ERα). Recent data indicate that chromatin inactivation mediated by HDAC and DNA methylation is a critical component of ERα silencing in human breast cancer cells.[8]

Approved

  • Vorinostat was licensed by the U.S. FDA in October 2006 for the treatment of cutaneous T cell lymphoma (CTCL).
  • Romidepsin (trade name Istodax) was licensed by the US FDA in Nov 2009 for cutaneous T-cell lymphoma (CTCL).
  • Chidamide approved by China in 2015 for peripheral T-cell lymphoma (PTCL).
  • Panobinostat (trade name Farydak) was licensed by the US FDA in Feb 2015 for the treatment of multiple myeloma.[9]
  • Belinostat (PXD101) has had a phase II trial for relapsed ovarian cancer, and in 2009 reported good results for T cell lymphoma. Approved July 2014 in the US for the use against peripheral T-cell lymphoma.[10]

Phase 3 and phase 2 clinical trials

Started phase III clinical trials
  • Panobinostat (LBH589) is in clinical trials for various cancers including a phase III trial for cutaneous T cell lymphoma (CTCL).
  • Valproic acid (as Mg valproate) {{as of |2011}} due to have completed phase III trials for cervical cancer[11] and ovarian cancer.[12] Has also been trialled in spinal muscular atrophy.{{citation needed|date=March 2016}}
Started pivotal phase II clinical trials
  • none since 2014 ?
Started phase II clinical trials
  • Mocetinostat (MGCD0103) is undergoing clinical trials for treatment of various cancers (including follicular lymphoma, Hodgkin lymphoma and acute myeloid leukemia).
  • Abexinostat (PCI-24781) has started a phase II trial for sarcoma,[13] and another for lymphoma[14]
  • Entinostat (MS-275) in phase II for Hodgkin lymphoma, lung cancer and breast cancer.[16]
  • SB939 starting a phase II trial for Recurrent or Metastatic Prostate Cancer (HRPC).[15] (phase I results,[16])
  • Resminostat (4SC-201) an oral pan-HDACi. Results re Hodgkin lymphoma[17] Also in trials for hepatocellular carcinoma[18] for which it has FDA Orphan Drug status,[19] and met phase II primary endpoint.[20]
  • Givinostat (ITF2357)[21] for refractory leukemias and myelomas.
  • Quisinostat (JNJ-26481585)

Phase I Clinical trials

Started phase I clinical trials
  • HBI-8000, (a benzamide HDI), inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10[22] Approved in China (for peripheral T-cell lymphoma (PTCL)) and having Orphan drug status in Japan.[23]
  • Kevetrin, selective for HDAC2.[24] Is past the 10th cohort in an Open-Label Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic study in patients with advanced solid tumors.[25] Early good results reported for Ovarian Cancer Spleen Metastasis Jan 20 2015[26]
  • CUDC-101 intended for cancer, has started clinical trials,[27] it also inhibits EGFR and HER2. Early results reported in Nov 2010.[28] Results publishes in 2014.[29]
  • AR-42[30] has started clinical trials in 2010 for various cancers (relapsed or treatment-resistant multiple myeloma, chronic lymphocytic leukemia or lymphoma).[31] The trial should report in 2013[32] In 2012 AR-42 got 2 Orphan Drug designations from the FDA for two benign tumour types.[33]
  • CHR-2845, CHR-3996[34]
  • 4SC-202 selective, for advanced hematological indications[18]
  • CG200745 for solid tumors.[35]
  • ACY-1215, selective for HDAC6, in two clinical trials for multiple myeloma in combination with bortezomib (Velcade, Takeda Millennium) and with lenalidomide (Revlimid, Celgene).[36]
  • ME-344, for solid refractory tumors[37]
  • Also sulforaphane[38][39]
Preclinical

References

1. ^{{cite journal | vauthors = Marks PA, Dokmanovic M | title = Histone deacetylase inhibitors: discovery and development as anticancer agents | journal = Expert Opinion on Investigational Drugs | volume = 14 | issue = 12 | pages = 1497–511 | date = December 2005 | pmid = 16307490 | doi = 10.1517/13543784.14.12.1497 }}
2. ^{{cite journal | vauthors = Richon VM, O'Brien JP | title = Histone deacetylase inhibitors: a new class of potential therapeutic agents for cancer treatment | journal = Clinical Cancer Research | volume = 8 | issue = 3 | pages = 662–4 | date = March 2002 | pmid = 11895892 | url = http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11895892 }}
3. ^{{cite journal | vauthors = Monneret C | title = Histone deacetylase inhibitors for epigenetic therapy of cancer | journal = Anti-Cancer Drugs | volume = 18 | issue = 4 | pages = 363–70 | date = April 2007 | pmid = 17351388 | doi = 10.1097/CAD.0b013e328012a5db }}
4. ^{{cite journal | vauthors = Mack GS | title = To selectivity and beyond | journal = Nature Biotechnology | volume = 28 | issue = 12 | pages = 1259–66 | date = December 2010 | pmid = 21139608 | doi = 10.1038/nbt.1724 }}
5. ^{{cite journal | vauthors = Richon VM, Sandhoff TW, Rifkind RA, Marks PA | title = Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 18 | pages = 10014–9 | date = August 2000 | pmid = 10954755 | pmc = 27656 | doi = 10.1073/pnas.180316197 | bibcode = 2000PNAS...9710014R | jstor = 123305 }}
6. ^{{cite journal | vauthors = Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T | title = Retinoblastoma protein recruits histone deacetylase to repress transcription | journal = Nature | volume = 391 | issue = 6667 | pages = 597–601 | date = February 1998 | pmid = 9468139 | doi = 10.1038/35404 | bibcode = 1998Natur.391..597B }}
7. ^{{cite journal | vauthors = Matsumura T, Suzuki T, Aizawa K, Munemasa Y, Muto S, Horikoshi M, Nagai R | title = The deacetylase HDAC1 negatively regulates the cardiovascular transcription factor Krüppel-like factor 5 through direct interaction | journal = The Journal of Biological Chemistry | volume = 280 | issue = 13 | pages = 12123–9 | date = April 2005 | pmid = 15668237 | doi = 10.1074/jbc.M410578200 }}
8. ^{{cite journal | vauthors = Zhang Z, Yamashita H, Toyama T, Sugiura H, Ando Y, Mita K, Hamaguchi M, Hara Y, Kobayashi S, Iwase H | title = Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast* | journal = Breast Cancer Research and Treatment | volume = 94 | issue = 1 | pages = 11–6 | date = November 2005 | pmid = 16172792 | doi = 10.1007/s10549-005-6001-1 }}
9. ^{{cite web | url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435296.htm | title = FDA approves Farydak for treatment of multiple myeloma | work = fda.gov | accessdate = 6 October 2015 }}
10. ^{{cite news | url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403929.htm | publisher = FDA | title = FDA approves Beleodaq to treat rare, aggressive form of non-Hodgkin lymphoma | date = 3 July 2014 }}
11. ^{{ClinicalTrialsGov|NCT00532818|Hydralazine Valproate for Cervical Cancer}}
12. ^{{ClinicalTrialsGov|NCT00533299|Hydralazine Valproate for Ovarian Cancer}}
13. ^{{ClinicalTrialsGov|NCT01027910|PCI-24781 in Combination With Doxorubicin to Treat Sarcoma}}
14. ^{{ClinicalTrialsGov|NCT00724984|Study of the Safety and Tolerability of PCI-24781 in Patients With Lymphoma (PCYC-0403)}}
15. ^{{cite press release |title=S*BIO Initiates Canadian Phase 2 Clinical Trial of Oral Histone Deacetylase (HDAC) Inhibitor SB939 for the Treatment of Recurrent or Metastatic Prostate Cancer (HRPC) |publisher=S*BIO |date=September 27, 2008 |url=http://www.digitaljournal.com/pr/121708 |accessdate=September 12, 2013}}
16. ^{{cite press release |title=S*BIO's Oral Histone Deacetylase (HDAC) Inhibitor SB939 Shows Tolerability and Safety in Phase 1 Clinical Trial in Patients with Advanced Hematologic Malignancies |publisher=S*BIO |date=December 7, 2010 |url=http://www.prnewswire.com/news-releases/sbios-oral-histone-deacetylase-hdac-inhibitor-sb939-shows-tolerability-and-safety-in-phase-1-clinical-trial-in-patients-with-advanced-hematologic-malignancies-111436719.html |accessdate=September 12, 2013}}
17. ^{{cite press release |title=52nd ASH Annual Meeting Presentation of Initial Phase II Data from the Saphire Hodgkin's Lymphoma Trial with Resminostat |publisher=4SC |date=December 1, 2010 |url=https://www.drugs.com/clinical_trials/52nd-ash-annual-meeting-presentation-initial-phase-ii-data-saphire-hodgkin-s-lymphoma-trial-10770.html |accessdate=September 12, 2013}}
18. ^1 {{cite news |url = http://www.genengnews.com/gen-news-highlights/yakult-pays-4sc-6m-up-front-for-japanese-rights-to-phase-ii-anticancer-drug/81245000/|date = April 14, 2011|title = Yakult Pays 4SC €6M Up Front for Japanese Rights to Phase II Anticancer Drug|work = Genetic Engineering & Biotechnology News|accessdate = September 12, 2013}}
19. ^{{cite press release |title=FDA Grants Orphan Drug Designation to 4SC's Oral Pan-HDAC Inhibitor Resminostat for the Treatment of Hepatocellular Carcinoma |publisher=4SC |date=July 12, 2011 |url=http://www.businesswire.com/news/home/20110711007001/en/FDA-Grants-Orphan-Drug-Designation-4SCs-Oral |accessdate=September 12, 2013}}
20. ^{{cite news |url=http://www.bioworld.com/content/strong-phase-ii-resminostat-data-send-4sc-shooting-0 |title=Strong Phase II Resminostat Data Send 4SC Shooting Up |date=January 20, 2012 |work=BioWorld Today |first=Cormac |last=Sheridan}}
21. ^1 {{cite journal | vauthors = Tan J, Cang S, Ma Y, Petrillo RL, Liu D | title = Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents | journal = Journal of Hematology & Oncology | volume = 3 | pages = 5 | date = February 2010 | pmid = 20132536 | pmc = 2827364 | doi = 10.1186/1756-8722-3-5 }}
22. ^{{cite web|url=http://www.prnewswire.com/news-releases/huya-bioscience-international-grants-an-exclusive-license-for-hbi-8000-in-japan-and-other-asian-countries-to-eisai-300212563.html|title=HUYA Bioscience International Grants An Exclusive License For HBI-8000 In Japan And Other Asian Countries To Eisai|first=HUYA Bioscience|last=International|date=|website=www.prnewswire.com|accessdate=8 April 2018}}
23. ^ 
24. ^{{cite press release |title=Cellceutix Anti-Cancer Drug Shown to Regulate HDAC2, a Major Therapeutic Target for Treatment of a Broad Range of Cancers |publisher=Cellceutix |date=January 17, 2012 |url=http://www.marketwire.com/press-release/cellceutix-anti-cancer-drug-shown-regulate-hdac2-major-therapeutic-target-treatment-otcbb-ctix-1607249.htm |accessdate=September 12, 2013}}
25. ^{{cite web|url=https://www.clinicaltrials.gov/ct2/show/NCT01664000?term=cellceutix&rank=3|title=Clinical Trials NCT01664000}}
26. ^{{cite press release |title=Cellceutix Reports Spleen Lesion ‘Disappears’ in Patient with Metastatic Stage 4 Ovarian Cancer in Clinical Trial of Anti-Cancer Drug Kevetrin|publisher=Cellceutix |date=January 20, 2015 |url= http://cellceutix.com/cellceutix-reports-spleen-lesion-disappears-in-patient-with-metastatic-stage-4-ovarian-cancer-in-clinical-trial-of-anti-cancer-drug-kevetrin/#sthash.mdEr4PPB.dpbs|accessdate=January 20, 2015}}
27. ^http://www.themarketfinancial.com/stock-alert-for-curis-inc-cris/4078{{full citation needed|date=September 2013}}{{dead link|date=September 2013}}
28. ^{{cite press release |title=Curis Presents CUDC-101 Phase I Clinical Data and CU-201 Preclinical Data at 22nd EORTC-NCI-AACR Symposium |publisher=Curis |date=November 18, 2010 |url=http://investors.curis.com/releasedetail.cfm?ReleaseID=632954 |accessdate=September 12, 2013}}
29. ^{{cite journal|url=http://clincancerres.aacrjournals.org/content/early/2014/08/08/1078-0432.CCR-14-0570|title=Phase I first-in-human study of CUDC-101, a multi-targeted inhibitor of HDACs, EGFR and HER2 in patients with advanced solid tumors|first1=Toshio|last1=Shimizu|first2=Patricia M.|last2=LoRusso|first3=Kyriakos|last3=Papadopoulos|first4=Amita|last4=Patnaik|first5=Muralidhar|last5=Beeram|first6=Lon S.|last6=Smith|first7=Drew|last7=Rasco|first8=Theresa A.|last8=Mays|first9=Glenda|last9=Chambers|first10=Anna W.|last10=Ma|first11=Jing|last11=Wang|first12=Robert|last12=Laliberte|first13=Maurizio|last13=Voi|first14=Anthony|last14=Tolcher|date=8 August 2014|publisher=|journal=Clinical Cancer Research|pages=clincanres.0570.2014|accessdate=8 April 2018|via=clincancerres.aacrjournals.org|doi=10.1158/1078-0432.CCR-14-0570|pmid=25107918}}
30. ^{{cite book |last=Huang |first=Po-Hsien | name-list-format = vanc |year=2010 |title=Novel Small Molecules Regulating The Histone Marking, AR Signaling, And AKT Inhibition In Prostate Cancer |url=http://rave.ohiolink.edu/etdc/view?acc_num=osu1268095745 |type=PhD Thesis |publisher=Ohio State University}}{{page needed|date=September 2013}}
31. ^{{cite press release |title=Second Ohio State cancer drug begins clinical trials testing |publisher=Ohio State University Medical Center |date=June 18, 2010 |url=http://phys.org/news196080640.html |accessdate=September 12, 2013}}
32. ^{{ClinicalTrialsGov|NCT01129193|AR-42 in Treating Patients With Advanced or Relapsed Multiple Myeloma, Chronic Lymphocytic Leukemia, or Lymphoma}}
33. ^{{cite press release |title=Arno Therapeutics Receives Two Orphan-Drug Designations for AR-42 in Treatment of Central-Nervous-System Tumors |publisher=Arno Therapeutics |date=February 21, 2012 |url=https://www.reuters.com/article/2012/02/21/idUS119494+21-Feb-2012+BW20120221 |accessdate=September 12, 2013}}
34. ^{{cite news |url = http://www.genengnews.com/gen-news-highlights/cti-pays-chroma-5m-up-front-for-american-continent-rights-to-late-stage-cancer-drug/81244815/|date = March 14, 2011|title = Cell Therapeutics Pays Chroma $5M Up Front for Rights to Late-Stage Cancer Drug|work = Genetic Engineering & Biotechnology News}}
35. ^{{cite journal | vauthors = Oh ET, Park MT, Choi BH, Ro S, Choi EK, Jeong SY, Park HJ | title = Novel histone deacetylase inhibitor CG200745 induces clonogenic cell death by modulating acetylation of p53 in cancer cells | journal = Investigational New Drugs | volume = 30 | issue = 2 | pages = 435–42 | date = April 2012 | pmid = 20978925 | doi = 10.1007/s10637-010-9568-2 }}
36. ^{{cite news |url = http://www.genengnews.com/gen-news-highlights/celgene-invests-15m-in-acetylon-to-support-hdac-inhibitor-development/81246342/|title = Celgene Invests $15M in Acetylon to Support HDAC Inhibitor Development|date = February 9, 2012|work = Genetic Engineering & Biotechnology News}}
37. ^{{cite press release |title=MEI Pharma's Mitochondrial Inhibitor Drug Candidate ME-344 Named One of Top 10 Oncology Products for 2012 |publisher=MEI Pharma |date=November 19, 2012 |url=http://www.marketwatch.com/story/mei-pharmas-mitochondrial-inhibitor-drug-candidate-me-344-named-one-of-top-10-oncology-products-for-2012-2012-11-19 |accessdate=September 12, 2013}}
38. ^{{Cite book|url=https://books.google.com/books?id=rgK0CgAAQBAJ|title=Critical Dietary Factors in Cancer Chemoprevention|last=Ullah|first=Mohammad Fahad|last2=Ahmad|first2=Aamir |name-list-format = vanc |date=2015-10-06|publisher=Springer|isbn=9783319214610|language=en}}
39. ^{{cite journal | vauthors = Ho E, Clarke JD, Dashwood RH | title = Dietary sulforaphane, a histone deacetylase inhibitor for cancer prevention | journal = The Journal of Nutrition | volume = 139 | issue = 12 | pages = 2393–6 | date = December 2009 | pmid = 19812222 | pmc = 2777483 | doi = 10.3945/jn.109.113332 }}
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