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Romidepsin in the Treatment of Hematologic Malignancies Romidepsin in the t R eatment of h ematologic m alignancies December 2008 www.clinicaladvances.com Volume 6, Issue 12, Supplement 20 Faculty H. Miles Prince, MD Director, Centre for Blood Cell Therapies Peter MacCallum Cancer Centre St Andrew’s Place, East Melbourne, Victoria, Australia Romidepsin in the treatment Bertrand Coiffier, MD of hematologic malignancies Professor of Hematology Head of Department of Hematology Hospices Civils de Lyon Université Claude Bernard Lyon, France A Compendium of Case Studies Ellen J. Kim, MD Assistant Professor of Dermatology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Alain H. Rook, MD Professor of Dermatology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Supported through an educational grant from Gloucester Pharmaceuticals clinical advances in hematology & oncology Volume 6, issue 12, supplement 20 december 2008 1 case study compendium The Potential of Histone Deacetylase Inhibitors for the Treatment of Lymphoma And Multiple Myeloma H. Miles Prince, MD Director, Centre for Blood Cell Therapies, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, Victoria, Australia Overview has been observed in cancer cells in both hematologic and solid malignancies.5-8 Histones comprise a family of nuclear proteins that inter- Moreover, both HDACs and HATs activities are act with DNA, resulting in DNA being coiled around a recruited to target genes in complexes that contain histone octameric core within the nucleosome. Histone sequence specific transcription factors. Several different deacetylase (HDAC) enzymes catalyze the deacetylation transcription factors are assembled with these complexes of lysine residues in the histone N-terminal tails and are including Bcl-6, Mad-1, PML, and ETO.9 Indeed, there also found in large multiprotein complexes with tran- are several examples in which HDACs are functionally scriptional co-repressors. Human HDACs are classified involved in oncogenic translocation products in cancer into 4 classes based on their similarity to yeast factors, development.10-13 For example, Bcl-6, a transcription with 18 different HDACs identified to date.1 The physi- factor overexpressed in approximately 40% of diffuse ologic counterparts of HDACs are histone acetyltrans- large B-cell lymphomas (DLBCLs), recruits HDAC2 to ferases (HATs). repress growth through regulating target genes. In vitro The organization of chromatin into either a relatively treatment of DLBCL cells with HDAC inhibitors causes open or condensed form affects key molecular processes hyperacetylation of Bcl-6, release of HDAC2 from the such as transcription, DNA repair, recombination, and complex, resulting in reactivation of repressed target genes replication, and there is clear evidence that gene expres- and subsequent apoptosis of lymphoma cells.13 sion controlled by epigenetic changes can play an impor- HDAC inhibitors, a new class of chemotherapeutic tant role in cancer onset and progression.2,3 Increased agents, have been shown to have potent anticancer activi- acetylation of histones H3 and H4 is associated with open ties in preclinical studies and are currently in various stages and active chromatin and increased transcription, whereas of clinical development.1 deacetylation of these histone residues is associated with Increased acetylation of specific residues in histones condensed chromatin and transcriptional repression.4 H3 and H4 is associated with open and active chromatin Alteration in the balance of activity between these and increased mRNA transcription; however, the exact enzymes, in association with aberrant gene transcription, final pathways that lead to the anticancer effects observed Included in Index Medicus/PubMed/Medline Disclaimer Funding for this Case Study Compendium has been provided through an educational grant from Gloucester Pharmaceuticals. Support of this monograph does not imply the supporters’ agreement with the views expressed herein. Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc., the supporters, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation. ©2008 Millennium Medical Publishing, Inc. 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. 2 clinical advances in hematology & oncology Volume 6, issue 12, supplement 20 december 2008 Romidepsin in the t R eatment of h ematologic m alignancies in various tumor types remain to be fully elucidated. Table 1. Clinical Trials Involving HDAC Inhibitors in There is nevertheless clear evidence that key activities of Patients With Lymphoma HDAC inhibitors include: 1. induction of tumor cell apoptosis and suppres- Study Disease Phase N Response sion of cell proliferation by activation of cell cycle checkpoints at G1/S or G2/M; Vorinostat PR 8 2. induction of cellular differentiation; Duvic29 CTCL II 33 3. suppression of angiogenesis; (4 SS) 4. enhancement of host immune surveillance. CR 1, Olsen30 CTCL IIb 74 PR 21 Induction of apoptosis by HDAC inhibition has been HL/DLBCL/ CR 1, O’Connor28 I 31 linked to alterations in gene expression resulting in CTCL/Other PR 4, SD 3 upreg ulation of proapoptotic genes (Bax, Bak, Bim, TP2, Crump41 DLBCL I 18 CR 1, SD 1 Apaf-1, Trail, DR4, DR5, Bmf) and downregulation of Indolent CR 1, antiapoptotic genes (Bcl-2, Bcl-XL, XIAP, Survivin, Akt, Kirschbaum49 II 15 c-FLIP, c-RAF, Mcl-1).14-16 Moreover, HDAC inhibitors B-cell NHL PR 1, SD 3 can induce a cell-cycle checkpoint at the G1/S transition17 Romidepsin through transcriptional activation of CDKN1A encoding CR 3, waf1/cip1 Piekarz35 PTCL I/II 39 the cyclin-dependent kinase inhibitor p21 . PR 8, SD 5 Furthermore, the molecular basis of the anticancer CR 4, effects of HDAC inhibitors may well go beyond inhibi- Piekarz35 CTCL I/II 71 PR 18, tion of histone acetylation. A growing list of nonhistone SD 9 targets involved in regulation of cell proliferation, cell CR 1, death, and cell migration have been identified, including 36 p53, Ku70, alpha tubulin, and Hsp-90. Thus, acetylation- Lerner CTCL I/II 45 PR 11, SD 17 dependent changes in the activities of such proteins may play an equally important role in mediating the anticancer Panobinostat effects of HDAC inhibitors.15,18,19 CR 2, Prince62 CTCL I 11 Several families of HDAC inhibitors can be discer- PR 3, SD 2 ned, divided by their chemical structure, with varying ability to inhibit the various classes of HDACs. These CR=complete remission; CTCL=cutaneous T-cell lymphoma; compounds have demonstrated in vivo and in vitro DLBCL=diffuse large B-cell lymphoma; HL=Hodgkin lymphoma; activity against both hematologic and nonhematologic NHL=non-Hodgkin lymphoma; PR=partial remission; malignancies alone or in combination with traditional PTCL=peripheral T-cell lymphoma; SD=stable disease; chemotherapeutic agents.1 SS=Sézary Syndrome. Clinical Studies of HDAC Inhibitors In Lymphoma concentrations of 1–5 µm, with selective induction of apoptosis in CTCL cell lines and greater apoptosis of Cutaneous T-cell Lymphoma peripheral blood lymphocytes from patients with CTCL Vorinostat The most studied HDAC inhibitor in than the peripheral blood lymphocytes of healthy cutan­­eous T-cell lymphoma (CTCL) is suberoylanilide donors. These proapoptotic changes occur selectively hydroxamic acid (vorinostat; Table 1). Vorinostat is an despite the accumulation of acetylated histones and the orally bioavailable pan-HDAC inhibitor.20 Early in vitro induction of cell-cycle arrest occurring in both normal studies showed vorinostat to facilitate the transcription of and tumor cells.27 genes governing growth arrest, differentiation, and both Favorable preclinical studies and the response of a caspase-dependent and -independent apoptosis.21 Mecha- CTCL patient in a phase I trial28 led to the initiation of a nisms of action include increased expression of the cell single-center phase II dose-finding trial of oral vorinostat cycle–arrest inducer p21waf1/cip1, which is independent of to determine response rate and duration in patients with the tumor suppressor p53, abrogation of Bcl-2/Bcl-XL, relapsed or refractory stage IA–IVB CTCL. Thirty-three activation of Bid and Bim,22-24 increase in the proapop- patients, 28 with advanced-stage CTCL, with a median totic protein Bax, and activation of caspases 3 and 8.23,25,26 of 5 prior therapies (range, 1–15), were enrolled in 1 of Activity in CTCL cell lines has been demonstrated at 3 sequential dosing cohorts. Eight patients achieved a clinical advances in hematology & oncology Volume 6, issue 12, supplement 20 december 2008 3 case study compendium partial response (PR), including 7 with advanced-stage and 6+ months, respectively. One patient remained in an disease and 4 with Sézary syndrome, the leukemic form ongoing CR off therapy after 5 years, and 1 patient who of CTCL. The median time to response (TTR) and time achieved PR continues to receive romidepsin for more to progression (TTP) for responders was 11.9 and 30.2 than 69 months. RNA analysis of both normal and malig- weeks, respectively. Moreover, 14 of
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