Vorinostat—An Overview Aditya Kumar Bubna
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Combined Treatment with Epigenetic, Differentiating, and Chemotherapeutic
Author Manuscript Published OnlineFirst on January 19, 2016; DOI: 10.1158/0008-5472.CAN-15-1619 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Combined treatment with epigenetic, differentiating, and chemotherapeutic agents cooperatively targets tumor-initiating cells in triple negative breast cancer. Vanessa F. Merino1,7, Nguyen Nguyen1,7, Kideok Jin1, Helen Sadik1, Soonweng Cho1, Preethi Korangath1, Liangfeng Han1, Yolanda M. N. Foster1, Xian C. Zhou1, Zhe Zhang1, Roisin M. Connolly1, Vered Stearns1, Syed Z. Ali2, Christina Adams2, Qian Chen3, Duojia Pan3, David L. Huso4, Peter Ordentlich5, Angela Brodie6, Saraswati Sukumar1*. 1Department of Oncology, 2Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, 3Department of Molecular Biology and Genetics, 4Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 5Syndax Pharmaceuticals, Department of Translational Medicine, Waltham, MA, USA, 6Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA. 7These authors contributed equally. *Correspondence: Saraswati Sukumar, PhD, 1650 Orleans Street, Baltimore, MD, 21231, Ph. 410-614-2479, [email protected] and Vanessa F. Merino, PhD, 1650 Orleans Street, Baltimore, MD, 21231, Ph. 410-614-4075, [email protected]. Key words: Breast, cancer, entinostat, RAR-beta, epigenetic Grant Support: This work was funded by the DOD BCRP Center of Excellence Grant W81XWH-04-1-0595 to S.S, and DOD BCRP, W81XWH-09-1-0499 to V.M. Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 19, 2016; DOI: 10.1158/0008-5472.CAN-15-1619 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. -
An Overview of the Role of Hdacs in Cancer Immunotherapy
International Journal of Molecular Sciences Review Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy Debarati Banik, Sara Moufarrij and Alejandro Villagra * Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, 800 22nd St NW, Suite 8880, Washington, DC 20052, USA; [email protected] (D.B.); [email protected] (S.M.) * Correspondence: [email protected]; Tel.: +(202)-994-9547 Received: 22 March 2019; Accepted: 28 April 2019; Published: 7 May 2019 Abstract: Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration. -
FARYDAK (Panobinostat) RATIONALE for INCLUSION in PA PROGRAM
FARYDAK (panobinostat) RATIONALE FOR INCLUSION IN PA PROGRAM Background Farydak (panobinostat) is the first histone deacetylase (HDAC) inhibitor approved to treat multiple myeloma in patients who have received at least two prior standard therapies, including bortezomib and an immunomodulatory agent. Farydak is to be used in combination with bortezomib, a type of chemotherapy, and dexamethasone, an anti-inflammatory medication. Multiple myeloma causes plasma cells to rapidly multiply and crowd out other healthy blood cells from the bone marrow. When the bone marrow has too many plasma cells, the cells may move to other parts of the body. Farydak works by inhibiting the activity of enzymes, known as histone deacetylases (HDACs). The inhibition of these enzymes may slow the over development of plasma cells in multiple myeloma patients or cause these dangerous cells to die (1). Regulatory Status FDA-approved indication: Farydak, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone, is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent (2). Farydak carries a Boxed Warning alerting patients and health care professionals that severe diarrhea and severe and fatal cardiac events, arrhythmias and electrocardiogram (ECG) changes have occurred in patients receiving Farydak. Arrhythmias may be exacerbated by electrolyte abnormalities. The most common laboratory abnormalities were low levels of phosphorus in the blood (hypophosphatemia), low potassium levels in the blood (hypokalemia), low levels of salt in the blood (hyponatremia), increased creatinine, low platelets (thrombocytopenia), low white blood cell counts (leukopenia) and low red blood cell counts (anemia). -
Phase I Trial of Carboplatin and Etoposide in Combination with Panobinostat in Patients with Lung Cancer
ANTICANCER RESEARCH 33: 4475-4482 (2013) Phase I Trial of Carboplatin and Etoposide in Combination with Panobinostat in Patients with Lung Cancer AHMAD A. TARHINI1,2, HARIS ZAHOOR1, BRIAN MCLAUGHLIN1, WILLIAM E GOODING2, JOHN C. SCHMITZ2, JILL M. SIEGFRIED2, MARK A. SOCINSKI1,2 and ATHANASSIOS ARGIRIS3 1University of Pittsburgh Medical Center, 2University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, Pittsburgh, PA, U.S.A.; 3University of Texas Health Science Center at San Antonio, San Antonio, TX, U.S.A. Abstract. A phase I trial consisting of panobinostat (a apoptosis in response to HDAC inhibitors may also be HDAC inhibitor), carboplatin and etoposide was condacted in mediated by acetylation of non-histone proteins (such as patients with lung cancer. Patients and Methods: Patients HSP-90, p53, HIF1-α, α-tubulin) (5). received carboplatin AUC5 on day 1 and etoposide 100 mg/m2 Panobinostat, a hydroxamic acid derivative, is an oral pan- on days 1, 2 and 3, every 21 days. Concurrent oral deacetylase inhibitor (6). It affects proteins involved in cell-cycle panobinostat was given 3 times weekly on a 2-weeks-on and 1- regulation (p53, p21), angiogenesis (HIF-1α), gene transcription week-off schedule during the 4-6 cycles of chemotherapy and (transcription factors), protein stabilization (Hsp90) and then continued as maintenance therapy. Results: Six evaluable cytoskeleton (α-tubulin), through inhibition of HDACs (7, 8). patients were treated at the first dose level of panobinostat Panobinostat exhibits increased histone acetylation and (10 mg). Dose-limiting toxicity occurred in two patients (33%) has potent antiproliferative activity against a broad range of during the first cycle. -
Management of Multiple Myeloma: the Changing Paradigm
Management of Multiple Myeloma: The Changing Paradigm Relapsed/Refractory Disease Jeffrey A. Zonder, MD Karmanos Cancer Institute Objectives • Discuss use of standard myeloma therapies when used as therapy after relapse • Consider patient and disease factors which might impact therapy decisions. • Describe off-label options for patients who are not protocol candidates. Line ≠ Line ≠ Line ≠ … POLICE LINE – DO NOT CROSS POLICE LINE – DO NOT CROSS POLICE LINE – DO NOT CROSS POLICE LINE – DO NOT CROSS POLI LINE – DO NOT Define “Line” • A pre-defined course of therapy utilizing agents either simultaneously or sequentially – Len/Dex – Len/Dex ASCT – Vel/Dex ASCT Len/Dex – VDT-PACE ASCT TD ASCT VPT-PACE LD • Pts who have had the same # of “lines” of Rx may have had vastly different amounts of Rx What Is Relapsed/Refractory Disease? • Relapsed: recurrence after a response to therapy • Refractory: progression despite ongoing therapy What Do We Know About the Pt’s Myeloma? • What prior therapy has been used? • How well did it work? • Did the myeloma progress on active therapy? • High-risk cytogenetics/FISH/GEP? What Do We Know About the Patient? • Age • Other medical problems – Diabetes – Blood Clots • Lasting side effects from past therapies – Peripheral Neuropathy • Personal preferences and values Choosing Therapy for Relapsed/Refractory Myeloma Proteasome IMiDs Anthracyclines Alkylators Steroids HDACs Antibodies Inhibitors Thalidomide Bortezomib Doxil Melphalan Dex Panobinostat Elotuzumab Lenalidomide Carfilzomib Cytoxan Pred Vorinostat -
Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines
Targ Oncol DOI 10.1007/s11523-016-0444-7 ORIGINAL RESEARCH ARTICLE Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines Maria Pinkerneil1 & Michèle J. Hoffmann1 & Hella Kohlhof2 & Wolfgang A. Schulz1 & Günter Niegisch1 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Results 4SC-202 significantly reduced proliferation of all ep- Background Targeting of class I histone deacetylases ithelial and mesenchymal UC cell lines (IC50 0.15–0.51 μM), (HDACs) exerts antineoplastic actions in various cancer types inhibited clonogenic growth and induced caspase activity. by modulation of transcription, upregulation of tumor sup- Flow cytometry revealed increased G2/M and subG1 fractions pressors, induction of cell cycle arrest, replication stress and in VM-CUB1 and UM-UC-3 cells. Both effects were stronger promotion of apoptosis. Class I HDACs are often deregulated than with SAHA treatment. in urothelial cancer. 4SC-202, a novel oral benzamide type Conclusion Specific pharmacological inhibition of class I HDAC inhibitor (HDACi) specific for class I HDACs HDACs by 4SC-202 impairs UC cell viability, inducing cell HDAC1, HDAC2 and HDAC3 and the histone demethylase cycle disturbances and cell death. Combined inhibition of LSD1, shows substantial anti-tumor activity in a broad range HDAC1, HDAC2 and HDAC3 seems to be a promising treat- of cancer cell lines and xenograft tumor models. ment strategy for UC. Aim The aim of this study was to investigate the therapeutic potential of 4SC-202 in urothelial carcinoma (UC) cell lines. Methods We determined dose response curves of 4SC-202 by KeyPoints MTT assay in seven UC cell lines with distinct HDAC1, 4SC-202 exerts significant antineoplastic effects on HDAC2 and HDAC3 expression profiles. -
Current Understanding of Epigenetics Mechanism As a Novel Target In
Keyvani‑Ghamsari et al. Clin Epigenet (2021) 13:120 https://doi.org/10.1186/s13148‑021‑01107‑4 REVIEW Open Access Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance Saeedeh Keyvani‑Ghamsari1, Khatereh Khorsandi2* , Azhar Rasul3 and Muhammad Khatir Zaman4 Abstract At present, after extensive studies in the feld of cancer, cancer stem cells (CSCs) have been proposed as a major fac‑ tor in tumor initiation, progression, metastasis, and recurrence. CSCs are a subpopulation of bulk tumors, with stem cell‑like properties and tumorigenic capabilities, having the abilities of self‑renewal and diferentiation, thereby being able to generate heterogeneous lineages of cancer cells and lead to resistance toward anti‑tumor treatments. Highly resistant to conventional chemo‑ and radiotherapy, CSCs have heterogeneity and can migrate to diferent organs and metastasize. Recent studies have demonstrated that the population of CSCs and the progression of cancer are increased by the deregulation of diferent epigenetic pathways having efects on gene expression patterns and key pathways connected with cell proliferation and survival. Further, epigenetic modifcations (DNA methylation, histone modifcations, and RNA methylations) have been revealed to be key drivers in the formation and maintenance of CSCs. Hence, identifying CSCs and targeting epigenetic pathways therein can ofer new insights into the treatment of cancer. In the present review, recent studies are addressed in terms of the characteristics of CSCs, the resistance thereof, and the factors infuencing the development thereof, with an emphasis on diferent types of epigenetic changes in genes and main signaling pathways involved therein. Finally, targeted therapy for CSCs by epigenetic drugs is referred to, which is a new approach in overcoming resistance and recurrence of cancer. -
In Patients with Metastatic Melanoma Nageatte Ibrahim1,2, Elizabeth I
Cancer Medicine Open Access ORIGINAL RESEARCH A phase I trial of panobinostat (LBH589) in patients with metastatic melanoma Nageatte Ibrahim1,2, Elizabeth I. Buchbinder1, Scott R. Granter3, Scott J. Rodig3, Anita Giobbie-Hurder4, Carla Becerra1, Argyro Tsiaras1, Evisa Gjini3, David E. Fisher5 & F. Stephen Hodi1 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 2Currently at Merck & Co.,, Kenilworth, New Jersey 3Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 4Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 5Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts Keywords Abstract HDAC, immunotherapy, LBH589, melanoma, MITF, panobinostat Epigenetic alterations by histone/protein deacetylases (HDACs) are one of the many mechanisms that cancer cells use to alter gene expression and promote Correspondence growth. HDAC inhibitors have proven to be effective in the treatment of specific Elizabeth I. Buchbinder, Dana-Farber Cancer malignancies, particularly in combination with other anticancer agents. We con- Institute, 450 Brookline Avenue, Boston, ducted a phase I trial of panobinostat in patients with unresectable stage III or 02215, MA. Tel: 617 632 5055; IV melanoma. Patients were treated with oral panobinostat at a dose of 30 mg Fax: 617 632 6727; E-mail: [email protected] daily on Mondays, Wednesdays, and Fridays (Arm A). Three of the six patients on this dose experienced clinically significant thrombocytopenia requiring dose Funding Information interruption. Due to this, a second treatment arm was opened and the dose Novartis Pharmaceuticals Corporation was changed to 30 mg oral panobinostat three times a week every other week provided clinical trial support, additional (Arm B). -
Peripheral T-Cell Lymphomas
Critical Reviews in Oncology/Hematology 99 (2016) 214–227 CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Contents lists available at ScienceDirect Critical Reviews in Oncology/Hematology jo urnal homepage: www.elsevier.com/locate/critrevonc Panoptic clinical review of the current and future treatment of relapsed/refractory T-cell lymphomas: Peripheral T-cell lymphomas a,∗ b c c d Pier Luigi Zinzani , Vijayveer Bonthapally , Dirk Huebner , Richard Lutes , Andy Chi , e,f Stefano Pileri a Institute of Hematology ‘L. e A. Seràgnoli’, Policlinico Sant’Orsola-Malpighi, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy b 1 Global Outcomes and Epidemiology Research (GOER), Millennium Pharmaceuticals Inc., 40 Lansdowne Street, Cambridge, MA 02139, USA c 1 Oncology Clinical Research, Millennium Pharmaceuticals Inc., 35 Lansdowne Street, Cambridge, MA 02139, USA d 1 Department of Biostatistics, Millennium Pharmaceuticals Inc., 40 Lansdowne Street, Cambridge, MA 02139, USA e Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University School of Medicine, Via Massarenti 8, 40138 Bologna, Italy f Unit of Hematopathology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy Contents 1. Introduction . 214 2. Methodology. .215 3. Treatment of relapsed/refractory PTCL . 215 3.1. Conventional chemotherapy in relapsed/refractory PTCL. .215 3.2. Approved therapies in relapsed/refractory PTCL . 216 3.3. Investigational and off-label therapies in relapsed/refractory PTCL . 222 4. Concluding remarks . 224 Conflict of interest . 224 Funding . 224 Acknowledgments. .224 References . 224 Biography . 227 a r t i c l e i n f o a b s t r a c t Article history: Peripheral T-cell lymphomas (PTCLs) tend to be aggressive and chemorefractory, with about 70% of Received 29 June 2015 patients developing relapsed/refractory disease. -
Effect of Givinostat, an HDAC Inhibitor, on Disease Milestones in Duchenne Muscular Dystrophy Boys Paolo Bettica1, M.D., Ph.D., Giacomo P
Effect of Givinostat, an HDAC inhibitor, on disease milestones in Duchenne Muscular Dystrophy boys Paolo Bettica1, M.D., Ph.D., Giacomo P. Comi2, M.D., Enrico Bertini3, M.D., Giuseppe Vita3, M.D., Eugenio Mercuri4, M.D, Sara Cazzaniga1§, M.Sc. 1 Italfarmaco S.p.A., Italy; 2 Dino Ferrari Centre Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Italy; 3 Bambino Gesù Children's Hospital, IRCCS, Rome. Italy; 3 University of Messina, NEMO Clinical Centre, Messina, Italy; 4 Catholic University, Rome, Italy; Corresponding Author§ email: [email protected] PHASE 3 TRIAL Phase 3, multicentre, double blind, placebo controlled (2:1) study in 242 patients to What happens at study visits? • demonstrate that Givinostat oral suspension preserves muscle mass and slows down disease Informed Consent Paperwork • progression. The study is ongoing in USA, Canada and European countries. A total of 15 visits (every 3 months): • Blood draw more frequently during the first 3 months: • first month: weekly • second month: every 2 weeks • from the third month: every 3 months What does participant entail?: • Surveys (baseline, at 12 and 18 months) and Diaries • must be ambulant DMD boys from 6 years (every visit) of age, • Muscle tests every 3 months (6MWT, NSAA, 4SC, QMT) • on stable corticosteroid for at least 6 • Pulmonary Function test baseline, at 12 and 18 months months prior to start the treatment, • Thigh muscle MRI: baseline, at 12 and 18 months • able to perform the 4 stairs climb in no • Upon successful completion of the study, participants, more than 8 seconds and time to stand up regardless the ability to walk, will have the opportunity to in ≥ 3 and less than 10 seconds, enter into long term safety study and they will ALL receive the • do the MRI scan drug Givinostat Mechanism of Action in Duchenne Downstream effects of the Impact on the lack of dystrophin epigenetic effects of the lack of dystrophin Mechanical effects : . -
Belinostat (Beleodaq®)
Belinostat (Beleodaq®) Belinostat (Beleodaq®) Pronounced: be-lin-oh-stat Classification: Histone Deacetylase Inhibitor About Belinostat (Beleodaq®) Belinostat is in a class of anti-cancer therapies called histone deacetylase (HDAC) inhibitors. Histone deacetylation is a biochemical process that is thought to play a role in promoting tumor growth. It does this by silencing some tumor suppressor genes, as well as other genes that are responsible for cell cycle progression, cell proliferation, programmed cell death (apoptosis), and differentiation (transformation of young cells into specialized cells). Therefore, blocking histone deacetylation may allow the body to block tumor growth and prevent progression. How to Take Belinostat Belinostat is given by intravenous (IV, into a vein) infusion. The dose and how often you receive this medication is based on your weight and will be decided by your provider. Your dose may be reduced if you are having severe side effects. Possible Side Effects of Belinostat There are a number of things you can do to manage the side effects of belinostat. Talk to your care team about these recommendations. They can help you decide what will work best for you. These are some of the most common or important side effects: Nausea and/or Vomiting Talk to your oncology care team so they can prescribe medications to help you manage nausea and vomiting. In addition, dietary changes may help. Avoid things that may worsen the symptoms, such as heavy or greasy/fatty, spicy or acidic foods (lemons, tomatoes, oranges). Try saltines, or ginger ale to lessen symptoms. Call your oncology care team if you are unable to keep fluids down for more than 12 hours or if you feel lightheaded or dizzy at any time. -
Safety and Efficacy of the Maximum Tolerated Dose of Givinostat in Polycythemia Vera
Leukemia (2020) 34:2234–2237 https://doi.org/10.1038/s41375-020-0735-y LETTER Chronic myeloproliferative neoplasms Safety and efficacy of the maximum tolerated dose of givinostat in polycythemia vera: a two-part Phase Ib/II study 1 2 3 4 5,6 Alessandro Rambaldi ● Alessandra Iurlo ● Alessandro M. Vannucchi ● Richard Noble ● Nikolas von Bubnoff ● 7 8 9 10 11 12 Attilio Guarini ● Bruno Martino ● Antonio Pezzutto ● Giuseppe Carli ● Marianna De Muro ● Stefania Luciani ● 13 14 15 16 17 Mary Frances McMullin ● Nathalie Cambier ● Jean-Pierre Marolleau ● Ruben A. Mesa ● Raoul Tibes ● 3 3 18 18 18 Alessandro Pancrazzi ● Francesca Gesullo ● Paolo Bettica ● Sara Manzoni ● Silvia Di Tollo Received: 15 October 2019 / Revised: 6 December 2019 / Accepted: 29 January 2020 / Published online: 11 February 2020 © The Author(s) 2020. This article is published with open access To the Editor: Recently, ropeginterferon α-2b was approved by European Medicinal Agency as first line for patients without symp- Polycythemia vera (PV) is a chronic myeloproliferative tomatic splenomegaly [3]. Ruxolitinib is second-line for neoplasm (cMPN) characterized by stem cell-derived clonal patients who are refractory and/or intolerant to hydroxyurea myeloproliferation resulting in panmyelosis with persis- [4]; other treatments include busulfan, pipobroman [5], and 1234567890();,: 1234567890();,: tently raised hematocrit, increased risk of thrombotic com- nonpegylated and pegylated interferons (off-label) [1, 6, 7], plications, and predisposition to evolve to myelofibrosis or but use is limited by side effects and safety concerns. leukemia [1]. Therapy is currently based on phlebotomy to Additional, targeted therapies are therefore needed. normalize hematocrit, and aspirin. Hydroxyurea is used as Up to 98% of patients with PV bear the JAK2V617F gene first line when cytoreduction is necessary [1], although mutation, which activates erythropoietin receptor signaling toxicity can result in inadequate disease management [2].