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&NA;. "LBH-589." Reactions Weekly &NA;, no. 1137 (February 2007): 17–18. http://dx.doi.org/10.2165/00128415-200711370-00054.
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Mohan, Avinash L., Anubhav G. Amin, Michael E. Tobias, Mohan K. Das, Raphael S. S. de Medeiros, Nelci Zanon, Chirag D. Gandhi, Sidnei Epelman, and Meena Jhanwar-Uniyal. "MBRS-18. TUMOR SUPPRESSOR p53 DEFINES THE THERAPEUTIC RESPONSES IN TREATMENT OF MEDULLOBLASTOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii401. http://dx.doi.org/10.1093/neuonc/noaa222.534.
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Abstract Medulloblastoma (MB) is the most common primary pediatric malignant brain tumor. Current molecular analysis classifies MB into 4 groups, classic (WNT), sonic hedgehog (Shh), group 3, and group 4. Furthermore, atypical p53 signaling is associated with disease progression and confers poor prognosis. This study investigated the correlation of mutational status of p53 and iSO17q with disease progression and metastatic potential. In addition, we used small molecule inhibitors of PI3K (Buparlisib; BKM120) and HDAC (LBH-589) on a p53-mutant MB cell line to find novel therapeutic targets. Efficacy of these drugs were assessed using functional assays (cell proliferation, migration, cell cycle and drug resistance). MB tumors (n=53) were evaluated for GLI-1, GAB-1, NPR, KV1, YAP expression and mutant p53 via immunohistochemistry and correlated to patient outcomes. Results demonstrated that: 1) high expression of GAB-1 and YAP were found in the Shh group, while KV1 expression was present in all subtypes; 2) mutant p53 expression was present in various subsets of MB with no apparent correlation with metastasis or disease progression; 3) patients displaying iSO17q (determined by fluorescence in situ hybridization (FISH) technique) exhibited metastatic disease; 4) LBH-589 and BKM120 caused both time and dose-dependent inhibition of MB cell proliferation and migration; 5) combined treatment of BKM120 and LBH-589 had a synergistic effect; 6) MB cells demonstrated drug-resistance to BKM120. In conclusion, these findings underscore use of Buparlisib and LBH-589 in treatment of MB. Further, the role of mutant p53 in disease progression remains elusive, whereas presence of iSO17q defines metastatic potential.
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Waibel, Michaela, Edwin D. Hawkins, Kelly M. Ramsbottom, Benjamin P. Martin, and Ricky W. Johnstone. "Class I/II Histone Deacetylase Inhibitors Are a Potential Therapeutic For Notch-1 Driven T Cell Acute Lymphoblastic Leukemia." Blood 122, no. 21 (November 15, 2013): 1435. http://dx.doi.org/10.1182/blood.v122.21.1435.1435.
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Abstract Introduction Although T cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease, mutations resulting in activation of the Notch-1 signalling pathway are present in over 50% of patients, thus defining Notch signaling as a central player in T-ALL disease regulation. Furthermore, despite improvement in remission rates following conventional chemotherapeutics, the prognosis for T-ALL remains poor due to disease relapse, which is often refractory to the initial therapies. Inhibitors against the γ-secretase complex, which is part of intracellular Notch-1 (ICN1) signalling, have so far shown limited efficacy and are associated with severe toxicity. Therefore, alternative approaches to treat Notch-1-driven T-ALL are required. The gene expression signature of Notch-1-mutated T-ALLs has revealed downstream activation of numerous pathways, including Myc, PI3K-AKT-mTOR and NFκB, indicating potential sensitivity to small molecule histone deacetylase inhibitors (HDACi). Therefore, the aim of this study was to use a traceable pre-clinical mouse model of Notch-1 driven T-ALL to investigate the potential of HDACi as therapy. Methods Retroviral transduction of mouse hematopoietic stem cells with constructs encoding ICN, followed by transplantation into irradiated recipient mice, is an established model of T-ALL resulting from Notch-1 activating mutations, and closely mimics human disease. For the present study, we transduced foetal liver stem cells from day E14.5 embryos with constructs expressing either ICN1-GFP, or GFP only. Cohorts of recipient mice developed leukaemia as described previously, characterized by splenomegaly, lymphadenopathy, elevated peripheral white blood cell counts, and the presence of double positive CD4+CD8+GFP+ blasts in peripheral blood, with a small fraction of recipients presenting with single positive CD4+GFP+ or CD8+GFP+ blasts. T-ALL blasts were isolated from this primary leukemia colony and transplanted into sub-lethally irradiated recipient mice. Using this model, cohorts of mice rapidly developed onset of leukemia with significant engraftment of T-ALL blasts in bone marrow, spleen, thymus, liver and detectable blasts in peripheral blood 15 days post transplant. Results GFP+ T-ALL blasts were isolated from lymph nodes and spleen and cultured in vitro in the presence of αCD3 and interleukin 2 to induce robust proliferation. Treatment of these T-ALL blasts with the pan-HDACi Panobinostat (LBH-589) induced cell death and inhibited proliferation of remaining viable blasts in a dose-dependent manner. These results illustrate that LBH-589 is a potent inhibitor of survival and proliferation of Notch driven T-ALL at low nM concentrations in vitro. Furthermore, treatment of cohorts of mice transplanted with ICN1-T-ALL with LBH-589 significantly prevented expansion of disease in vivo as determined by white blood cell counts. Additionally, we monitored leukemic cells infiltration in secondary lymphatic tissues using non-invasive GFP imaging. Whilst high GFP readings were observed in vehicle treated groups, we observed very little signal in LBH-589 treated mice confirming prevention of disease expansion. Of most importance, the effect of LBH-589 on progression of disease was reflected in a significant increase in survival of treated cohorts compared to controls. Conclusions The considerably high relapse rates of T-ALL patients demands the development of novel therapies for disease that is refractory to initial therapies. Our results indicate that LBH-589 has strong potential for development of therapies for Notch driven T-ALL and may be a useful addition to current therapies, either during initial treatment or after relapse of chemoresistant T-ALL. Moreover, we have preliminary data suggesting that LBH-589 has the ability to target the predominant oncogenic “Myc signature” associated with constitutive Notch expression. We are currently performing gene and protein expression analysis to exactly determine the molecular effects of HDACi on ICN and associated downstream effector signalling. Disclosures: Johnstone: Novartis: Research Funding.
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Ibrahim, Nageatte, Elizabeth I. Buchbinder, Scott R. Granter, Scott J. Rodig, Anita Giobbie‐Hurder, Carla Becerra, Argyro Tsiaras, Evisa Gjini, David E. Fisher, and F. Stephen Hodi. "A phase I trial of panobinostat ( LBH 589) in patients with metastatic melanoma." Cancer Medicine 5, no. 11 (October 17, 2016): 3041–50. http://dx.doi.org/10.1002/cam4.862.
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Strickler, John H., Alexander N. Starodub, Jingquan Jia, Kellen L. Meadows, Andrew B. Nixon, Andrew Dellinger, Michael A. Morse, et al. "Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors." Cancer Chemotherapy and Pharmacology 70, no. 2 (June 29, 2012): 251–58. http://dx.doi.org/10.1007/s00280-012-1911-1.
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Rosato, Roberto, Stefanie Hock, Paul Dent, Yun Dai, and Steven Grant. "LBH-589 (panobinostat) potentiates fludarabine anti-leukemic activity through a JNK- and XIAP-dependent mechanism." Leukemia Research 36, no. 4 (April 2012): 491–98. http://dx.doi.org/10.1016/j.leukres.2011.10.020.
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Garrido Castro, Patricia, Eddy HJ Van Roon, Sandra S. Mimoso Pinhancos, Pauline Schneider, Mark JB Kerstjens, Merel Willekes, Rob Pieters, and Ronald Stam. "The Histone Deacetylase Inhibitor Panobinostat (LBH-589) Exerts Anti-Leukaemic Activity in a MLL-Rearranged ALL Xenograft Mouse Model." Blood 124, no. 21 (December 6, 2014): 3709. http://dx.doi.org/10.1182/blood.v124.21.3709.3709.
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Abstract BACKGROUND: Infant acute lymphoblastic leukaemia (ALL) is a rare but aggressive malignancy, mainly presenting with chromosomal rearrangements of the MLL (Mixed Lineage Leukaemia) gene locus on 11q23. The majority of these MLL rearrangements involve the translocation partners AF4, AF9 or ENL within the translocation events t(4;11)(q21;q23), t(9;11)(p22;q23) and t(11;19)(q23;p13.3), respectively. The resulting fusion genes, MLL-AF4, MLL-AF9 and MLL-ENL, code for chimeric transcription regulators acting as strong oncogenic drivers, rewriting the epigenetic landscape of the cell and profoundly altering gene expression. Consequently, these cytogenetic lesions define an ALL subtype both biologically and clinically distinct from other subtypes, strongly associated with drug resistance to first-line chemotherapeutics, high relapse rates and a dismal prognosis. Hence, novel treatment strategies which specifically target the underlying molecular pathobiology of this disease are urgently needed. AIMS: Previously, our group performed extensive patient cohort profiling on both transcript and epigenetic level in order to understand the molecular events underlying the disease, and identified histone deacetylase inhibitors (HDACi) as effective therapeutic drugs both in silico and in vitro. The aim of the current study was to elucidate potential molecular mechanisms by which the candidate HDACi Panobinostat is able to target MLL-rearranged ALL (MLLr-ALL) cells, and to confirm its efficacy in vivo using pre-clinical MLLr-ALL xenograft mouse models able to recapitulate the disease phenotype observed in humans. METHODS: Immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice were injected intrafemurally with a MLL-AF4+ B-ALL cell line (SEM) genetically modified to express a luciferase reporter. These mice were subsequently either treated with low-dose (1mg/kg) or high-dose (5mg/kg) Panobinostat using a continuous 5-day-on-2-day-off regimen for a period of up to 12 weeks, or they were assigned to a control group and left untreated. Disease onset and progression was monitored using in vivo bioluminescence imaging, and systemic human ALL cell infiltration was determined by multi-colour flow cytometry and histochemistry. In addition, molecular changes induced by Panobinostat exposure in MLLr-ALL and non-MLLr-ALL cell lines were assessed in vitro using immunoblotting and cell death assays. RESULTS: High-dose Panobinostat resulted in a significantly and substantially delayed MLLr-ALL disease onset and progression in NSG mice when compared to controls; this was accompanied by a reduction of the systemic disease burden, as evidenced by significantly lower whole-body luminescence signals and substantially decreased splenomegaly. Furthermore, immunohistochemical and flow cytometric data showed hypocellularity and increased cell death in the BM of xenografted NSG mice treated with Panobinostat when compared to untreated control xenografts. This finding correlated well with in vitro results, where exposure with 5 nM Panobinostat induced cell death in MLLr-ALL cells, but not in non-MLLr ALL cells, as determined by both ANNEXINV/7AAD flow cytometry assays and immunoblotting. In addition, on a molecular level, in vitro exposure with Panobinostat induced histone H3 hyperacetylation in all leukaemic cell lines, but did not affect other histone modification marks investigated such as, i.e., histone H3K4 methylation or histone H3K79 methylation. A notable exception was observed in MLLr-ALL cell lines, where Panobinostat exposure correlated with a reduction in histone H2B ubiquitination, a histone modification recently reported to be pivotal for MLLr leukaemogenesis. Concomitantly, Panobinostat - or more generally - HDACi-mediated loss of H2B ubiquitination might play a role in the observed sensitivity of MLLr-ALL cell towards this drug class. CONCLUSIONS: Both the in vivo and the molecular in vitro results show the HDACi Panobinostat to have promising therapeutic potential against MLLr-ALL. Currently, we are investigating Panobinostat in combination with other epigenetic drugs in xenograft models with primary MLLr-ALL patient material in order to consolidate these observations, and to confirm HDACi as a novel powerful treatment strategy in MLLr-ALL. Disclosures No relevant conflicts of interest to declare.
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Li, Yan, Fang Wang, Xiaoxue Chen, Jie Wang, Yonglong Zhao, Yongjun Li, and Bin He. "Zinc-dependent Deacetylase (HDAC) Inhibitors with Different Zinc Binding Groups." Current Topics in Medicinal Chemistry 19, no. 3 (March 28, 2019): 223–41. http://dx.doi.org/10.2174/1568026619666190122144949.
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The state of histone acetylation plays a very crucial role in carcinogenesis and its development by chromatin remodeling and thus altering transcription of oncogenes and tumor suppressor genes. Such epigenetic regulation was controlled by zinc-dependent histone deacetylases (HDACs), one of the major regulators. Due to the therapeutic potential of HDACs as one of the promising drug targets in cancer, HDAC inhibitors have been intensively investigated over the last few decades. Notably, there are five HDAC inhibitors already approved to the market. Vorinostat (SAHA), Belinostat (PXD-101) and Romidepsin (FK228) have been approved by Food and Drug Administration (FDA) in USA for treating cutaneous T-cell lymphoma (CTCL) or peripheral T cell lymphoma (PTCL) while Panbinostat (LBH-589) has also been approved by the FDA for the treatment of multiple myeloma. Recently, Chidamide was approved by China Food and Drug Administration (CFDA) for the treatment of PTCL. The structural feature of almost all HDAC inhibitors consists of Cap group, linker, and zinc-binding group (ZBG). The binding of ZBG groups to zinc ion plays a decisive role in the inhibition of HDAC. Therefore, we will summarize the developed HDAC inhibitors according to different ZBG groups and discuss their binding mode with zinc ion.
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Hedin, Karen, Kimberly Kremer, Andre van Wijnen, and Jennifer Westendorf. "SAHA prevents osteoblast-mediated protection of AML cells via upregulation of Nherf-1 (TUM10P.1050)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 211.31. http://dx.doi.org/10.4049/jimmunol.194.supp.211.31.
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Abstract Osteoblasts are known to protect acute myeloid leukemia (AML) cells in the bone marrow microenvironment, however, the identity of these protective signals is not known. Because disrupting this protection could help prevent the relapse of AML patients following chemotherapy, we characterized the molecular mechanisms. We previously showed that SDF-1 (CXCL12), a chemokine abundant in the bone marrow, induces apoptosis of AML cells in cocultures unless the leukemic cells are protected via proximity to differentiating osteoblasts. Treating differentiating osteoblasts with either suberoylanilide hydroxamic acid (SAHA) or LBH-589 histone deacetylase (HDAC) inhibitor drugs inhibited their protection of AML cells. RNAseq revealed that SAHA globally inhibits osteoblast differentiation while inducing expression of the scaffold protein, Nherf-1. Remarkably, expressing Nherf-1 in differentiating osteoblasts was both required and sufficient to block osteoblast-mediated protection of AML cells. Together, these results indicate that disrupting the differentiation of osteoprogenitors in the bone marrow inhibits their ability to protect AML cells from apoptosis, and that this can be achieved via either inhibiting HDACs or overexpressing Nherf-1 in osteoblast-lineage cells. HDAC inhibitors or treatments specifically designed to induce Nherf-1 expression either during or immediately prior to chemotherapy may therefore be a useful strategy for reducing the risk of disease relapse in AML patients.
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Butler, Charles Mackie, Lydia T. Laboccetta, Alan Brisendine, Thomas E. Keane, Carol Arthur Sherman, and Harry A. Drabkin. "Phase I trial of the HDAC inhibitor LBH589 in combination with sorafenib in patients with renal cell carcinoma, non-small cell lung cancer and soft tissue sarcomas." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 440. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.440.
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440 Background: LBH589 is a novel histone deacetylase inhibitor (HDACi) that induces apoptosis of tumor cells. In renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) cell lines, the combination of sorafenib and HDACi was found to have synergistic inhibition, which correlated with the induction of an ER stress response. In this phase I study, we evaluated the combination of LBH589 and sorafenib in previously treated patients with RCC (9pts), soft tissue sarcomas (1pt), and NSCLC (6pts). The trial was designed to determine the safety profile and maximum tolerated dose of LBH589 and sorafenib when administered concurrently. Methods: Patients were dosed with either i.v. or oral LBH 589 (three times per week, continuously) every twenty eight days in combination with standard daily dose sorafenib (400 mg bid). The dose escalation was based on a “3+3” algorithmic design. LBH was initially administered at an i.v. dose of 5 mg/m2 with escalation to 10 mg/m2. Due to the manufacturer’s phase-out of the i.v. formulation, this was then changed to an oral formulation administered three times a week (doses 15 mg, 20 mg, and 25 mg). Results: Sixteen patients, median age 57 years, have been treated. Dose limiting toxicities were observed with grade 4 thrombocytopenia in two patients at the oral dose of 25 mg. There were no other grade 4 events. Grade 3 events included fatigue (2 pts), hypophosphatemia (2 pts), hypertension (1 pts), anemia (1 pt), rash (1 pt) and hand-foot erythroderma (1 pt). Common toxicities for the combination were fatigue (81%), weight loss (62%), loss of appetite (56%), diarrhea (56%), rash (50%), thrombocytopenia (31%), and hand-foot erythroderma (25%). No patients had significant QT prolongation. There was 1 partial response in a patient with lung cancer (31 weeks). Stable disease was noted in seven patients with RCC (78+, 48, 47, 31, 21, 17, and 10+ weeks). Seven patients had progressive disease Conclusions: The administration of oral LBH589 at a dose of 20 mg was found to be well tolerated and will be used in the expansion phase of the trial. Prolonged stable disease was observed in patients previously treated with sorafenib alone, sunitinib and axitinib.
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Shioi, Ryuta, Fumika Karaki, Hiromasa Yoshioka, Tomomi Noguchi-Yachide, Minoru Ishikawa, Kosuke Dodo, Yuichi Hashimoto, Mikiko Sodeoka, and Kenji Ohgane. "Image-based screen capturing misfolding status of Niemann-Pick type C1 identifies potential candidates for chaperone drugs." PLOS ONE 15, no. 12 (December 14, 2020): e0243746. http://dx.doi.org/10.1371/journal.pone.0243746.
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Niemann-Pick disease type C is a rare, fatal neurodegenerative disorder characterized by massive intracellular accumulation of cholesterol. In most cases, loss-of-function mutations in the NPC1 gene that encodes lysosomal cholesterol transporter NPC1 are responsible for the disease, and more than half of the mutations are considered to interfere with the biogenesis or folding of the protein. We previously identified a series of oxysterol derivatives and phenanthridine-6-one derivatives as pharmacological chaperones, i.e., small molecules that can rescue folding-defective phenotypes of mutated NPC1, opening up an avenue to develop chaperone therapy for Niemann-Pick disease type C. Here, we present an improved image-based screen for NPC1 chaperones and we describe its application for drug-repurposing screening. We identified some azole antifungals, including itraconazole and posaconazole, and a kinase inhibitor, lapatinib, as probable pharmacological chaperones. A photo-crosslinking study confirmed direct binding of itraconazole to a representative folding-defective mutant protein, NPC1-I1061T. Competitive photo-crosslinking experiments suggested that oxysterol-based chaperones and itraconazole share the same or adjacent binding site(s), and the sensitivity of the crosslinking to P691S mutation in the sterol-sensing domain supports the hypothesis that their binding sites are located near this domain. Although the azoles were less effective in reducing cholesterol accumulation than the oxysterol-derived chaperones or an HDAC inhibitor, LBH-589, our findings should offer new starting points for medicinal chemistry efforts to develop better pharmacological chaperones for NPC1.
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Sun, Jenny, Lian Xu, Hsiuyi Tseng, Bryan Ciccarelli, Mariateresa Fulciniti, Zachary Hunter, Kaveh Maghsoudi, et al. "Histone Deacetylase Inhibitors Demonstrate Significant Preclinical Activity as Single Agents, and in Combination with Bortezomib in Waldenstrom's Macroglobulinemia." Blood 114, no. 22 (November 20, 2009): 4785. http://dx.doi.org/10.1182/blood.v114.22.4785.4785.
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Abstract Abstract 4785 Waldenstrom's Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration of CD19+ cells and production of a monoclonal IgM protein. Despite advances in treatment, WM remains incurable. As part of these efforts we sought to define the role of HDAC-inhibitors in WM. Gene expression profiling of bone marrow CD19+ cells from 30 WM patients and 10 healthy donors showed over-expression of HDAC4, HDAC9, and Sirt5 in WM patients. Evaluation of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA or Vorinostat), Trichostatin A (TSA), LBH-589 (Panobinostat), and sirtinol demonstrated dose dependent killing of BCWM.1 cells with IC50 of 3.5 uM, 70 nM, 0.8 uM, and 30 uM, respectively, whilst the combination of these agents with bortezomib resulted in at least additive tumor cell killing. TSA is more potent than bortezomib in inducing apoptosis in primary WM tumor cells in patients with prior treatment. TSA and bortezomib showed synergistic effect in 25% of the patients samples tested. We also observed that TSA and bortezomib-induced apoptosis of BCWM.1 cells depended on the activation of a similar set of caspases. Conversely, changes in cell cycle regulators were distinctly different between TSA and bortezomib treated BCWM.1 cells. The results of these studies demonstrate over-expression of distinct members of HDAC in WM cells, and provide a framework for the examination of HDAC-inhibitors as monotherapy, as well as combination therapy with bortezomib in the treatment of WM. Disclosures: No relevant conflicts of interest to declare.
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Xu, Xuelian, Chengzhi Xie, Holly Edwards, Hui Zhou, Steven Buck, Larry Matherly, Jeffrey Taub, and Yubin Ge. "Inhibition of Histone Deacetylases 1 and 6 Enhances Ara-C-Induced Apoptosis In Pediatric Acute Myeloid Leukemia Cells." Blood 116, no. 21 (November 19, 2010): 3275. http://dx.doi.org/10.1182/blood.v116.21.3275.3275.
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Abstract Abstract 3275 Acute myeloid leukemia (AML) accounts for one-fourth of acute leukemias in children, but is responsible for more than half of the leukemia deaths in this patient population. Resistance to cytarabine (ara-C)-based chemotherapy is a major cause of treatment failure in this disease. Therefore, new therapies for children with AML are urgently needed. Among the newer agents that have been recently investigated in high-risk AML in adults, histone deacetylase (HDAC) inhibitors [HDACIs, e.g., valproic acid (VPA) and Vorinostat (SAHA)] are particularly notable. The ability of HDACIs to induce cell differentiation, cell cycle arrest, and apoptosis in human leukemic cells, but not in normal cells, has stimulated significant interest in their potential as anti-leukemia agents. Numerous HDACIs have been developed during the last decade and the majority of these are in clinical trials including the novel class I-selective HDACIs, MS-275 and MGCD0103, and pan-HDACIs, LBH-589 and PXD101. Despite the well-characterized molecular and cellular effects of HDACIs, single-agent activity for this class of drugs has been modest. However, the clinical usefulness of HDACIs may be increased through rationally designed combination strategies including HDACIs with standard chemotherapy drugs. We previously hypothesized that VPA synergizes with ara-C, resulting in enhanced antileukemic activity in pediatric AML, by inducing apoptosis. We examined the impact of VPA on ara-C cytotoxicities in a panel of pediatric AML cell lines and diagnostic blast samples from children with de novo AML and demonstrated highly synergistic antileukemic activities of combined ara-C and VPA. This was especially pronounced in samples with t(8;21). Our mechanistic studies revealed that induction of DNA damage and Bim underlay the synergistic antileukemic activities of this drug combination. The present study was designed to identify members of the HDAC family which were deteminants of ara-C sensitivities, and to select the optimal HDACIs that were most efficacious when combined with ara-C for treating AML. Expression profiles of HDACs 1–11 in 4 clinically relevant pediatric AML cell lines (THP-1, Kasumi-1, MV4-11, and CMS) suggested that HDACs 5 and 11 were likely not involved due to marginal or lack of expression. The remaining class II HDACs and the entire class I enzymes could be relevant to HDACI anti-leukemic activities, based on the relationships between HDAC levels and HDACI cytotoxicities and responses to the combined VPA and ara-C, although the impact of class I HDACs seemed to predominate. Treatment of THP-1 cells with structurally-diverse HDACIs [SAHA (a pan-HDACI), VPA (a relatively class I selective-HDACI), and MS-275 (a class I selective-HDACI)] and enzymatic assays following immunoprecipitation of class I HDACs, revealed that inhibition of class I HDACs could augment ara-C-induced apoptosis. However, class II HDACs (e.g., HDAC6) were also implicated since SAHA was also effective. shRNA knockdown of HDACs 1 or 6 resulted in ∼2-fold increased apoptosis induced by ara-C in THP-1 AML cells (p<0.05). This was accompanied by substantially increased expression of Bim (2.3- and 1.4-fold, respectively). Down-regulation of HDAC2 resulted in ∼30% decreased ara-C-induced apoptosis. In contrast, shRNA knockdown of HDACs 3 and 4 had no effects on ara-C-induced apoptosis in THP-1 cells. At clinically achievable concentrations, HDACIs that simultaneously inhibited both HDACs 1 and 6 showed the best anti-leukemic activities and significantly enhanced ara-C-induced apoptosis in pediatric AML sublines including THP-1 and Kasumi-1. Our results further establish that HDACs are promising therapeutic targets for treating pediatric AML and identified HDACs 1 and 6 as the most relevant drug targets. Accordingly, treating pediatric AML patients with pan-HDACIs may be more beneficial than HDAC isoform-specific drugs. Based on our results, incorporation of pan-HDACIs (e.g., LBH-589 and PXD101) into ara-C-based clinical trials for treating pediatric AML should be strongly considered. Disclosures: No relevant conflicts of interest to declare.
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Thelen, Paul, Rolf-Hermann Ringert, and Arne Strauß. "Histone deacetylase inhibitor (HDACi) LBH589 interference with androgen receptor expression transcriptional activity in prostate cancer cells." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e15156-e15156. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e15156.
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e15156 Background: Development of incurable castration resistant prostate cancer (CRPC) is intrinsically tied to androgen receptor (AR) deregulation. Our previous research demonstrated that the estrogen receptor-β regulates AR transcriptional activity when relieved from epigenetic repression by HDACi treatments. Here we investigated the HDACi LBH589 established clinically in cancer treatments for its therapeutic function in CRPC. Methods: LBH589 (obtained from Novartis, Switzerland) was used (1 through 100µM) to treat representative CRPC-cell models i.e. LNCaP with an AR mutation and VCaP featuring AR overexpression. We investigated tumor cell proliferation with a BrdU-test and investigated AR including AR splice variants, PSA, PCA3,TMPRSS2-ERG, IGF-axis genes and ERβ expression by real-time RT-PCR, ELISA and Western blots. Results: LBH589 treatment even at low concentrations of 1µM reduced excessively AR expression in LNCaP and diminished even overexpressed AR to moderate levels in VCaP. Accordingly, tumor cell proliferation and the expression of androgen regulated genes PSA, PCA-3 and TMPRSS2-ERG (in VCaP) decreased. Furthermore, the expression of IGF-1 receptor and IGF-1 was reduced. Whereas, the expression of pro-apoptotic, anti-proliferative IGFBP-3 and the expression of tumor suppressor ERβ were increased, even at highest LBH589 concentrations. Conclusions: The main target in CRPC therapy is the AR equipped with resurgent activity by gain of function and overexpression. HDACi treatments with LBH 589 while restoring ERβ expression directly intervenes with this AR surge resulting in reduced tumor cell proliferation and tumor cells adopt a less malignant phenotype. Such measures in the core of CRPC deregulations alone or in combination with further anti-androgen treatments might reduce the potential of escape mechanisms of CRPC-tumors in future therapy approaches.
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Iancu-Rubin, Camelia, Faye Feller, David Gajzer, John Mascarenhas, and Ronald Hoffman. "Targeting Non-Histone Protein Acetylation Impairs Platelet Production During Normal Megakaryocytopoiesis." Blood 116, no. 21 (November 19, 2010): 2610. http://dx.doi.org/10.1182/blood.v116.21.2610.2610.
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Abstract Abstract 2610 Megakaryocytopoiesis consists of a succession of events in which MK progenitors initially proliferate and acquire lineage-specific markers, followed by polyploidization and cytoplasmic maturation. MK maturation culminates in the formation of cytoplasmic extensions (i.e. proplatelets) that leads to platelet shedding into the circulation. Panobinostat (LBH589) is a histone deacetylase inhibitor that has antiproliferative and cytotoxic effects on several types of cancer cells including blood cells from patients with hematological malignancies. One of the major adverse events associated with LBH589 treatment is thrombocytopenia. In this study, we hypothesize that the effects of LBH589 on thrombopoiesis might occur by targeting acetylation of histone and/or non-histone proteins resulting in defective platelet production. To test this hypothesis we investigated the effects of LBH589 on megakaryocytopoiesis in MK cell lines (i.e. HEL JAK2V617F positive cells) and in primary human MK. First, we tested the effects of LBH589 on the ability of human CD34+ cells to generate MK colony forming units (CFU-MKs). Neither CFU-MK or CFU-MIX derived colony formation was reduced in the presence of LBH589. To evaluate the effects of LBH589 on parameters of MK maturation, MK were generated in vitro from peripheral blood-derived CD34+ cells by employing an expansion culture system containing SCF and TPO for 6 days followed by 8 additional days incubation in the presence of TPO. These studies were pursued in the presence or absence of LBH589. Treatment with LBH589 did not significantly influence the number of CD61+ MK (i.e. control = 55.8%; 2.5nM LBH589 = 45.2%, p value=0.109; 5nM LBH589=38.5%, p value=0.095, of viable 7-AAD−/CD61+ cells) or the degree of polyploidization (i.e. control = 17.4%; 2.5nM LBH589 = 14.4%86.7, p value=0.157; 5nM LBH 589=12.8%, p value=0.116, cells with >4N DNA content). Culture-derived platelets were analyzed phenotypically and quantitated by means of dual labeling with anti-CD41 antibodies and with thiazole orange (TO) in order to identify new reticulated platelets. The percentage of CD41+/TO+ platelets derived from MK generated in the presence of LBH589 was significantly reduced (i.e. 2.5nM LBH589=11%, p value 0.046 and 5nM LBH589=9%, p value=0.011, CD41+/TO+ cells) as compared with MK generated in the absence of LBH589 (18.5% CD41+/TO+ cells). These findings were consistent with the observation of significant numbers of proplatelet-bearing MKs in control cultures but not in LBH 589-treated cultures. Collectively, these data suggest that LBH589 impairs platelet production while having a minimal effect on MK commitment, cytoplasmic maturation or polyploidization. To better understand the mechanisms responsible for such effects on thrombopoiesis, RNA extracted from control MK and from MK treated in vitro with LBH589 was analyzed by real time quantitative PCR to evaluate GATA-1 and NF-E2 expression. GATA-1 and NF-E2 mRNA levels were unchanged after treatment with LBH589. We found, however, that LBH589 induced a 4.8 to 7.5-fold increase in histone H3 acetylation. These data suggest that the negative impact of LBH589 on MK maturation was not mediated by its effects on chromatin but rather was possibly due to its effects on acetylation of nonhistone proteins. We demonstrated that LBH589 treatment increased acetylation of tubulin, a non-histone cytoplasmic protein that is a component of the microtubule (MT) cytoskeleton. The later stages of MK maturation are highly dependent on MT which represent the structural scaffold for proplatelet extension and enables the transport of cytoplasmic organelles into nascent platelets. The changes in the acetylation status of tubulin are critical for proper MT function and are mediated by HDAC6 which we found by Western blot analysis to be inhibited by LBH589 treatment. Based on these findings we suggest that LBH589-induced changes in tubulin acetylation result in aberrant MT function which in turn, leads to defective proplatelet and platelet formation. These nonhistone protein modifications might serve as a drug target for the development of novel agents (LBH589) to treat patients with extreme thrombocytosis due to underlying myeloproliferative neoplasms. Disclosures: Iancu-Rubin: Novartis: Research Funding. Hoffman:Novartis: Research Funding.
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Cassier, Philippe Alexandre, Anne Lefranc, Nicolas Penel, Christine Chevreau, Binh Bui Nguyen, Axel Le Cesne, Isabelle Laure Ray-Coquard, et al. "Efficacy and safety of panobinostat (LBH-589), a histone-deacetylase inhibitor (HDACi), in patients (pts) with advanced, previously treated soft tissue sarcoma (STS) and sex cord tumors (SCT): A study from the French Sarcoma Group." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10027. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10027.
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10027 Background: Treatment options are limited for pts with advanced pretreated STS. HDACi have shown activity in preclinical models of STS and SCT Methods: Pts with advanced pretreated STS and SCT were enrolled in this open label, single arm, multicenter phase II study. Panobinostat was given orally, 40 mg thrice per week. The primary end-point was 3-month progression-free rate according to RECIST 1.1 using central review. Fleming-A’Hern single-stage design for phase II trials was used, and assuming a type I error alpha of 5% with 90% power, 15/47 pts were needed to be progression free at 3 months to reject a rate of 20%. Results: Fifty three pts were enrolled between January 2010 and January 2011. Median age was 59 (range 21-79) years, and 22 (42%) pts were males, 13 had translocation-related sarcoma (TRS) and 4 had SCT. All but 5 pts had metastatic disease. The most common sites were the lung and the liver. All but one pt had documented disease progression prior to study entry. The median number of prior lines of therapy was 2 (range 1-7). Panobinostat dose was lowered to 20 mg thrice a week after 11 pts were enrolled based on the recommendation of an independent safety committee. Fifty-two pts were evaluable for toxicity (1 pt never received treatment), 48 pts (92%) reported at least one adverse event (AE) and 22 (42%) reported at least one treatment-related grade 3 or 4 AE. The most common grade 3/4 AEs were thrombocytopenia, fatigue and anemia. Fifty pts were evaluable for the primary end-point, of these, 12 pts (24%, 95%CI[13-38%]) were progression-free at 3 months, including 4/13 pts (31%, 95%CI[9-61%]) with TRS and 2/4 pts (50%, 95%CI[7-93%]) with SCT. No CR was seen, two patients (4%) with SCT had a PR and 19 pts (37%) had SD as their best response. Seven pts were progression-free at 6 months: 2 pts with SCT, 2 with TRS, 1 with liposarcoma, 1 with malignant solitary fibrous tumor and 1 with leiomyosarcoma. Conclusions: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited although some patients had prolonged SD. Activity in pts with SCT warrants further investigation.
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Nishida, Hiroko, Mari Fujiwara, Mutsumi Hayashi, and Michiie Sakamoto. "Abstract 5473: Isoform-selective HDAC inhibition up-regulates CD26 expression on multiple myeloma cells and augments cytotoxic efficacy by humanized monoclonal antibody." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5473. http://dx.doi.org/10.1158/1538-7445.am2022-5473.
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Abstract Objective: CD26, a 110-kDa transmembrane glycoprotein, which is expressed on several tumor cells including malignant lymphoma, has been implicated in tumorigenesis, whereas, its roles in plasma cell malignancies remain elusive. Recently, we have identified that CD26 is uniformly and intensely expressed in osteoclasts, while its expression in plasma cells of patients with multiple myeloma (MM) reveals heterogenous. Decreased expression levels of CD26 in MM cells are one of the mechanisms underlying resistance to humanized anti-CD26 monoclonal antibody (mAb) therapy. In the present study, we clarify the impact of epigenetic modification by HDAC inhibition (HDACi) with isoform-selective or broad inhibitors on the regulation of CD26 in MM cells and its mechanisms, thereby affecting the performance of humanized CD26mAb. Methods and Results: Immunostaining of bone marrow tissues of MM showed that CD26pos/CD138pos plasma cells were detected in several patients but not in others. So, first, we investigated the impact of HDACi on CD26 expression of MM cells. Although the cell surface expression of CD26 was relatively low or not detected on 5 MM cell lines (KMS26, KMS27, KMS28, KMS11, RPMI8226), the increased expression in CD26 levels was detectable within 24 h of the treatment with HDAC1i; FK228, HDAC3i; BG45, MS-275, RG2833 or HDAC6i; nexturastat A, tubastatin A, ACY-1215 as well as broad HDACi; LBH-589, SAHA. It increased further and maximum increase was observed at 72 h of the treatment by each HDACi. Then, subsequent removal of HDACi resulted in a decline of CD26 expression on MM cells to pre-treated levels. In addition, the levels of CD26mRNA were concomitantly enhanced, which was paralleled with an increase in the induction of CD26 protein in MM cells. Next, we examined the effect of HDACi on the viability of CD26neg MM cells in the absence or presence of CD26mAb. The mAb alone did not induce lysis of CD26neg MM cell lines at any doses, whereas, combining HDACi plus CD26mAb (10 μg/ml) synergistically facilitated lysis of CD26neg MM cells via direct effects as well as NK cell-mediated ADCC by mAb. Of note, HDACi plus CD26mAb in combination readily augmented lysis of CD26neg cell populations, refractory to HDACi or mAb alone. Furthermore, to elucidate the mechanisms of CD26 up-regulation in MM cells by HDACi, we performed chromatin immunoprecipitation assay on CD26 gene promoter. Each HDACi increased acetylation of histone 3 lysine 27 (H3K27Ac), concomitant with enhanced binding of Sp1 at the 5’ flanking region of the CD26 gene containing Sp1 binding sites in CD26neg MM cells, which is suggestive of transactivation of CD26 gene by HDACi targeting HDAC1, 3 or 6. Conclusion: Combination with isoform-selective HDACi not only shows anti-MM activity but supports as immunopotentiators by sensitizing CD26neg MM cells to CD26mAb and augment its cytotoxicity against MM cells. Citation Format: Hiroko Nishida, Mari Fujiwara, Mutsumi Hayashi, Michiie Sakamoto. Isoform-selective HDAC inhibition up-regulates CD26 expression on multiple myeloma cells and augments cytotoxic efficacy by humanized monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5473.
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Imai, Yoichi, Eri Ohta, Yanhua Wang, Yukiko Kitagawa, Ye Ding, Osamu Yamada, Yoshiro Maru, and Toshiko Motoji. "MLL-HOXA9 and Calcineurin Are Novel Therapeutic Targets in Multiple Myeloma." Blood 120, no. 21 (November 16, 2012): 4007. http://dx.doi.org/10.1182/blood.v120.21.4007.4007.
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Abstract Abstract 4007 Multiple myeloma is one of incurable hematological malignancies and many novel drugs including histone deacetylase (HDAC) inhibitors are currently undergoing preclinical and clinical evaluation. Treatment of U266 and KMS-11, multiple myeloma cell lines, by LBH589, an HDAC inhibitor, inhibited proliferation and induced apoptosis of these cell lines at low nanomolar concentrations. Here, we discovered that expression of HOXA9, a homeobox protein, was suppressed in the presence of LBH589. Transcription of HOXA9 mRNA immediately decreased in LBH589-treated myeloma cell lines. HOXA9 is a candidate oncogene in multiple myeloma and knockdown of HOXA9 is shown to block proliferation of myeloma cell lines. Our results suggest that HOXA9 is one of the targets of anti-myeloma effects elicited by HDAC inhibitors. MLL (mixed-lineage leukemia), a trithorax group protein, is shown to be essential for persistent expression of HOXA9 in human leukemia cells. We examined the effect of LBH589 on MLL in myeloma cell lines and found that expression of MLL protein was suppressed without decrease of MLL mRNA. These results indicate that LBH589 induces degradation of MLL protein. In the previous studies, it was shown that HDAC inhibitors targeted heat shock protein 90 (HSP90). The molecular chaperone HSP90 is essential for the protein-folding ability of several proteins. We evaluated the expression of MLL in myeloma cell lines treated by HSP90 inhibitor. We found that the expression of MLL proteins was suppressed by the treatment of 17-AAG, an inhibitor of HSP90. These results suggest that HDAC inhibitors induce degradation of MLL proteins via inhibition of chaperone function of HSP90. This inhibition of MLL-HOXA9 by HDAC inhibitors are supposed to block proliferation of myeloma cells. Furthermore, we tried to find a cooperative factor of MLL to investigate the roles of MLL in pathophysiology of multiple myeloma. For this purpose, we picked up PPP3CA, catalytic subunit of calcineurin, as one of the molecules. Those were highly co-expressed with MLL in multiple myeloma patients. We revealed that PPP3CA was degraded by the treatment of LBH 589 or 17-AAG. These results suggest that PPP3CA is protected from protein degradation by HSP90 as in the case of MLL and that LBH589 induces degradation of PPP3CA through inhibition of chaperone function of HSP90. We also found that co-treatment of myeloma cell lines by LBH589 and FK506 showed more anti-proliferative effect than LBH589 alone. FK506 selectively inhibits the function of calcineurin B, regulatory subunit of calcineurin. Expression of PPP3CB, the other isozyme of catalytic subunit of calcineurin, was upregulated when myeloma cell lines were treated with LBH589 and this upregulation of PPP3CB was supposed to be the result of compensation for downregulation of PPP3CA. It is suggested that combination of FK506 with LBH589 should display enhanced anti-myeloma effects by inhibiting the interaction between upregulated PPP3CB and calcineurin B. These results indicate that calcineurin-signaling pathway plays an important role in the persistent proliferation of myeloma cells. Surprisingly, bortezomib also suppressed expression of PPP3CA via inhibition of HDAC6. Our study is the first report to demonstrate that MLL-HOXA9 and calcineurin are the important targets of HDAC inhibitors in the treatment for multiple myeloma. MLL and PPP3CA, catalytic subunit of calcineurin, are highly co-expressed in multiple myeloma patients. These results suggest that HDAC inhibitors including LBH589 display anti-myeloma effects by inhibiting both MLL-HOXA9 and calcineurin pathways. These findings will lead to understanding of a novel mechanism of survival and growth of myeloma cells and be helpful to establish a new strategy of therapy for multiple myeloma. Disclosures: No relevant conflicts of interest to declare.
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Rio-Machin, Ana, Gonzalo Gomez-Lopez, Alba Maiques-Diaz, Sara Alvarez, Maria Jose Calasanz, Jude Fitzgibbon, and Juan C. Cigudosa. "HDAC Inhibitors As Novel Targeted Therapies for NUP98-HOXA9 AML Patients." Blood 128, no. 22 (December 2, 2016): 2685. http://dx.doi.org/10.1182/blood.v128.22.2685.2685.
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Abstract Background: The chromosomal translocation t(7;11)(p15,p15) encodes the oncogenic transcription factor NUP98-HOXA9 which results in a fusion of the nucleoporin 98kDa (NUP98) and homeobox A9 (HOXA9) genes. The oncogenic mechanisms underlying this translocation remain poorly understood and patients are currently inadequately served by traditional cytotoxic chemotherapy regimens. Aims:To decipher the underlying biology of the NUP98-HOXA9 fusion protein and develop rational therapeutic strategies targeting its oncogenic mechanism. Methods: Human cellular models expressing NUP98-HOXA9, HOXA9 wt or NUP98 wt were established by retroviral transduction of HEK293FT human cell line and human hematopoietic progenitors (CD34+, hHP) isolated from donor cord blood. Chromatin immunoprecepitation experiments followed by sequencing (ChIP-seq) and quantitative ChIP (qChIP) were used to define fusion specific binding locations. Cloning regulatory regions of selected target genes in a luciferase vectorconfirmed the direct involvement of NUP98-HOXA9 in their regulation. RTQ-PCR and gene expression microarrays were used to evaluate expression levels. Co-Immunoprecipitation experiments validated protein-protein interactions and drug treatments were performed at IC50. Cell viability was analysed by apoptosis, proliferation and Colony Forming Unit assays. Results:Comparison of ChIP-seq data from HEK293FTmodels of NUP98-HOXA9, HOXA9 wt or NUP98 wt respectively, identified 4,471 target genomic regions of the fusion protein (FDR < 0.05), located within +4/-4 kb from the annotated Transcription Start Site (TSS) of 1,363 genes, with 399 genes common to HOXA9 wt and 5 to NUP98 wt. The NUP98-HOXA9 binding sites included enhancers of MEIS1, HOXA9 and PBX3 (PBX3 and HOXA9 were common to NUP98 wt and MEIS1 to HOXA9 wt). Together these transcription factors form a key activator complex that regulates the expression of genes involved in leukemogenesis and its overexpression is significant related to adverse prognosis in AML. Luciferase assays showed that the upregulation of this leukemic axis was directly induced by the interaction of NUP98-HOXA9 with the corresponding enhancer regions of MEIS1, HOXA9 and PBX3. Treatment of cells with HXR9, a specific peptide inhibitor of HOXA9 and PBX3 interaction, led to a selective decrease in the proliferation of hHP expressing NUP98-HOXA9, confirming the relevance of these target genes to its oncogenic mechanism. Combining ChIP-seq and gene expression data of three independent clones of hHP expressing NUP98-HOXA9 and patient samples (n = 5) harbouring t(7;11)(p15,p15) revealed a dual regulatory role of the fusion protein, in both repressing and activating target gene transcription where, for example, MEIS1, HOXA9, PBX3 and AFF3 were found overexpressed and BIRC3, SMAD1, FILIP1L and PTEN downregulated. Interactions of NUP98-HOXA9 with p300 and HDAC1 were shown to drive this transcriptional activation and repression, respectively. We found using qChIP experiments that p300 bound to the regulatory regions of the overexpressed genes only when NUP98-HOXA9 was present, whereas we observed significant enrichment of HDAC1 binding to the promoter regions of the downregulated genes when the fusion protein was expressed. Taking advantage of this latter observation, we demonstrated a dramatic inhibitory effect on the viability of hHP expressing NUP98-HOXA9after the treatment with subtherapeutic doses (IC50 = 4nM) of the HDAC inhibitor LBH-589 (Panobinostat) with no effect in control hHP transduced with an empty vector. Conclusion: An improved understanding of the pathobiology underlying recurrent translocation events in AML is a critical first step for the development of rational, targeted therapies. Here, we identify upregulation of the targetable MEIS1-HOXA9-PBX3 complex underpinning the leukemogenic activity of NUP98-HOXA9. Its activity in repressing transcription mediated through interaction with HDAC1, has been shown to be also a key pathogenic mechanism that can be exploited through use of HDAC inhibitors and potentially lead to a promising new therapy for this high-risk group of patients. Disclosures No relevant conflicts of interest to declare.
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Offidani, Massimo, Federica Cavallo, Claudia Polloni, Anna Marina Liberati, Stelvio Ballanti, Stefano Pulini, Massimo Catarini, et al. "Melphalan, Thalidomide and Prednisone (MPT) Combined with Oral Panobinostat In Patients with Relapsed/Refractory MM: a Phase I-II Study." Blood 116, no. 21 (November 19, 2010): 3019. http://dx.doi.org/10.1182/blood.v116.21.3019.3019.
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Abstract Abstract 3019 Background: Panobinostat (LBH-589) is a pan-deacetilase inhibitor that targets histone proteins increasing tumor suppressor gene activities leading to cell-cycle and differentiation arrest besides to target non-histone proteins such as HSP90, aggressomes, p53, HIF-1a, and a-tubulin somehow promoting cell death. Panobinostat, combined with steroids and/or immunomodulatory drugs, demonstrated additive/synergistic activity in Multiple Myeloma (MM) and ability to overcome previous chemoresistance. Several combination studies with Panobinostat plus novel drugs are now ongoing in MM. Methods: This is a multicenter, open-label, phase I-II study exploring the combination of a standard therapy such as MPT (Melphalan 0.18 mg/kg per os for 4 days, Prednisone 1.5 mg/kg per os for 4 days, Thalidomide 50 mg/day continuously) with Panobinostat 15 mg p.o. thrice weekly for 3 weeks in a 28-day cycle to assess safety profile and activity of this combination in patients with relapsed/refractory MM having adequate performance status and haematological, cardiac, liver and neurological functions. The study was designed according to the Briant and Day method that plans a “dose-escalation phase” to determine both the MTD and the activity of the study drug and an “expansion-phase” in which the MTD of the study drug is used to further assess its safety and efficacy. Despite in the first phase of this study 19 patients were planned according to the study design, protocol was amended after 13 patients had been enrolled since more than 50% grade 3–4 toxicity occurred although response criteria were met. Therefore, Panobinostat was reduced to 10 mg p.o. thrice weekly for 3 weeks in a 28-day cycle whereas the dose of drugs of the MPT combination was not modified. Toxicity and response were assessed according to CTC version 4 and IMWG criteria, respectively. Results: As of February 2010, 24 patients were enrolled in this study. Median age was 71.5 years (range 40–81 years) and 12 patients (50%) had ISS 2–3 score. Patients had received a median of 2 prior therapies (range 1–6) and 5 (21%) three or more prior lines of therapy. Sixteen (73%), 13 (54%), 18 (75%), 11 (46%) and 9 (37.5%) patients had been previously treated with ASCT, thalidomide, bortezomib, lenalidomide and all 3 new-drugs, respectively. Seven patients (29%) were refractory to the last therapy. Twelve patients (50%) had a disease history longer than 5 years. In the first 13 patients treated with Panobinostat 15 mg, grade 3–4 thrombocytopenia and neutropenia occurred in 6 (46%) and 9 patients (69%), respectively. Moreover, 4 patients (31%) developed non-hematological adverse events such as fatigue, constipation, infection and arrythmia. In the group of 11 patients treated with Panobinostat 10 mg, grade 3–4 thrombocytopenia decreased to 18% (2 patients) but neutropenia was still high (8 patients: 72.5%). Three patients (27%) had grade 3–4 non-hematological toxicity (one fatigue and two constipation). No patients had QTcF prolongation or severe neuropathy. Dose adjustment was necessary in 9 patients (37.5%, all due to hematological toxicity) while 6 patients (25%) interrupted the protocol because of side effects (5 due to no resolution of grade 3–4 hematological toxicity within 4 weeks and one due to atrial fibrillation). One patient (4%) died on study due to sepsis during prolonged neutropenia. Response ≥ PR were observed in 12 patients (50%) including 4 VGPR and 8 PR. Additionally, 2 patients had MR and 8 SD. Only 2 patients progressed during treatment. There was no difference between the two cohorts of patients (Panobinostat 15 mg and Panobinostat 10 mg) in terms of response ≥ PR (54% vs 45.5%) or disease progression (7.5% vs 9%). Notably, response was obtained also in 2/7 patients (28%) who progressed during bortezomib or IMIDs. Conclusions: This study suggests that MPT-Panobinostat combination has an encouraging anti-myeloma activity since responses were still seen in patients with advanced stage or resistant to new drugs diseases. Different schedules of Panobinostat/melphalan should be explored to reduce haematological toxicity. Disclosures: Offidani: Celgene: Honoraria. Off Label Use: Panobinostat in relapsed/refractory multiple myeloma. Cavallo:Celgene: Honoraria. Polloni:Celgene: Honoraria. Ballanti:Celgene: Honoraria. Catarini:Celgene: Honoraria. Alesiani:Celgene: Honoraria. Corvatta:Celgene: Honoraria. Gentili:Celgene: Honoraria. Boccadoro:Celgene: Honoraria, Research Funding. Leoni:Celgene: Honoraria. Palumbo:Celgene: Honoraria, Research Funding.
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Iancu-Rubin, Camelia, David Gajzer, Goar Mosoyan, John Mascarenhas, and Ronald Hoffman. "Panobinostat (LBH589)-Mediated Acetylation of Tubulin Plays a Role in Megakaryocyte Maturation and Platelet Release." Blood 118, no. 21 (November 18, 2011): 704. http://dx.doi.org/10.1182/blood.v118.21.704.704.
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Abstract Abstract 704 Panobinostat (LBH589) is a histone deacetylase inhibitor (HDACi) which has been shown to have therapeutic effects against several types of human cancers. One of the major dose-limiting toxicities associated with the use of LBH589 has been thrombocytopenia. In this study, we investigated the mechanisms underlying thrombocytopenia induced by LBH589. Thrombocytopoiesis is the result of a highly regulated process in which bone marrow (BM) megakaryocyte (MK) progenitors proliferate and acquire lineage-specific markers in the early stages, followed by polyploidization, maturation and platelet formation in the later stages. We evaluated the effects of LBH589 on thrombocytopoiesis, by utilizing an in vitro system in which MK were generated from human BM-derived CD34+ hematopoietic progenitor cells. At low nanomolar concentrations, LBH589 did not interfere with either cellular proliferation or the ability of CD34+ cells to generate MK: both control and LBH589-treated CD34+ cells expanded 2.5 to 5 fold and generated a comparable number of CD61+ MK progenitors. This was also confirmed by MK colonies assay and suggested that LBH589 treatment does not affect the proliferation and commitment of CD34+ cells towards MK lineage. We next evaluated the effects of LBH589 on MK maturation and platelet production. The percentage of mature CD61+/CD42b+ MK generated in the presence of LBH589 was 3-fold lower compared to that generated in the absence of LBH589. Interestingly, the fraction of CD61+/CD42b+ MK generated in cultures in which LBH589 was withdrawn during the maturation step was only 1.4 lower than that found in control cultures, indicating that the negative effects of LBH589 on MK maturation are reversible, confirming similar observations made during clinical trials of LBH589. Culture-derived platelets were analyzed phenotypically and quantitated after dual labeling with anti-CD41 antibodies and thiazole orange (TO). The percentage of CD41+/TO+ platelets derived from MK generated in the presence of LBH589 was significantly reduced (11%) as compared with MK generated in the absence of LBH589 (18.5%). These findings were consistent with the presence of significant numbers of proplatelet-bearing MKs being observed in control cultures but not in LBH 589-treated cultures. Collectively, these data indicate that LBH589 impairs the ability of MK to mature and release platelets. To better understand the mechanisms responsible for these later stage effects on thrombocytopoiesis, we investigated the potential molecular targets of LBH589 in MK lineage. MK maturation is highly dependent on microtubule (MT) cytoskeleton which represents the structural scaffold for proplatelet extension and ensures the transport of cytoplasmic organelles into nascent platelets. Acetylation of tubulin, a non-histone protein which is critical for proper MT function, is a hallmark of polymerized MT and is mediated by HDAC6, a target of LBH589 inhibition. Based on this, we hypothesized that LBH589 treatment might induce changes in tubulin acetylation that in turn result in alterations in MT cytoskeleton. To test this hypothesis, we assessed tubulin acetylation and demonstrated that treatment with LBH589 resulted in an increase in the levels of acetylated tubulin. To determine if LBH589-induced changes in tubulin acetylation resulted in alterations in MT dynamics, we performed Western blot analysis of polymerized vs. soluble (depolymerized) tubulin in the presence or absence of LBH589. The ratio of soluble:polymerized tubulin in control MK was up to 2-fold greater than that found in MK treated with LBH589. In other words, LBH589 treatment induced an increase in the levels of polymerized MT which correlated with an increase in tubulin acetylation. These changes in MT dynamics at molecular levels were reflected by morphological alterations of cytoskeleton organization as visualized by microscopic analysis.Based on these findings we suggest that LBH589-induced changes in tubulin acetylation results in aberrant cytoskeletal organization that in turn leads to defective MK maturation and platelet release. In summary, we demonstrate that the negative effects of LBH589 on thrombocytopoiesis are mediated by targeting acetylation of tubulin. Furthermore, these studies suggest that tubulin can serve as a drug target for HDACi such as LBH589 to treat patients with extreme thrombocytosis. Disclosures: No relevant conflicts of interest to declare.
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Henderson, Ying C., Abdallah S. R. Mohamed, Anastasios Maniakas, Yunyun Chen, Reid T. Powell, Shaohua Peng, Maria Cardenas, et al. "A High-throughput Approach to Identify Effective Systemic Agents for the Treatment of Anaplastic Thyroid Carcinoma." Journal of Clinical Endocrinology & Metabolism, June 12, 2021. http://dx.doi.org/10.1210/clinem/dgab424.
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Abstract Background Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development. Material and Methods Twelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft (PDX) models were used to validate the selected agents. Results Seventeen compounds were effective, and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the US Food and Drug Administration for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and 2 PDX models; and docetaxel demonstrated significant TGI only in the context of mutant TP53. Conclusions HTS identified classes of systemic agents that demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early-phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.
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Gahr, S., S. Zopf, TT Wissniowski, D. Strobel, and M. Ocker. "Tumorregress eines fortgeschrittenen Hepatozellulären Karzinoms (HCC) infolge einer antitumoralen Therapie mit Sorafenib und Panobinostat (LBH 589)." Zeitschrift für Gastroenterologie 48, no. 08 (August 2010). http://dx.doi.org/10.1055/s-0030-1264102.
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Zopf, S., P. Di Fazio, S. Gahr, D. Strobel, MF Neurath, and M. Ocker. "The pan-deacetylase inhibitor panobinostat (LBH 589) inhibits DNA methyltransferases in HCC in vitro and in vivo." Zeitschrift für Gastroenterologie 49, no. 01 (January 2011). http://dx.doi.org/10.1055/s-0030-1269612.
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Xu, Yan, Yuanxin Miao, Botao Cai, Qingping Yi, Xuejun Tian, Qihai Wang, Dan Ma, Qiong Luo, Feng Tan, and Yongfeng Hu. "A histone deacetylase inhibitor enhances rice immunity by derepressing the expression of defense-related genes." Frontiers in Plant Science 13 (November 2, 2022). http://dx.doi.org/10.3389/fpls.2022.1041095.
Full textAbstract:
Histone deacetylase (HDAC) inhibitors (HDACis) have been widely used in plants to investigate the role of histone acetylation, particularly the function of HDACs, in the regulation of development and stress response. However, how histone acetylation is involved in rice (Oryza sativa L.) disease resistance has hardly been studied. In this paper, four HDACis including Sodium butyrate (NaBT), Suberoylanilide Hydroxamic Acid (SAHA), LBH-589 and Trichostatin A (TSA) were used to treat rice seedlings at different concentrations before inoculation of Magnaporthe oryzae. We found that only 10mM NaBT treatment can significantly enhanced rice blast resistance. However, treatment of the four HDACis all increased global histone acetylation but at different sites, suggesting that the inhibition selectivity of these HDACis is different. Notably, the global H3K9ac level was dramatically elevated after both NaBT and LBH589 treatment although LBH589 could not enhance rice blast resistance. This indicates that the HDACs they inhibit target different genes. In accordance with the phenotype, transcriptomic analysis showed that many defense-related genes were up-regulated by NaBT treatment. Up-regulation of the four genes bsr-d1, PR10B, OsNAC4, OsKS4 were confirmed by RT-qPCR. ChIP-qPCR results revealed that H3K9ac level on these genes was increased after NaBT treatment, suggesting that these defense-related genes were repressed by HDACs. In addition, by promoter motif analysis of the genes that induced by both NaBT treatment and rice blast infection, we found that the motifs bound by ERF and AHL transcription factors (TFs) were the most abundant, which demonstrates that ERF and AHL proteins may act as the candidate TFs that recruit HDACs to defense-related genes to repress their expression when plants are not infected by rice blast.
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Pojani, Eftiola, and Daniela Barlocco. "Romidepsin (FK228), An Histone Deacetylase Inhibitor, and its Analogues in Cancer Chemotherapy." Current Medicinal Chemistry 27 (February 3, 2020). http://dx.doi.org/10.2174/0929867327666200203113926.
Full textAbstract:
Background: Human HDACs represent a group of enzymes able to modify histone and non-histone proteins, which interact with DNA to generate chromatin. The correlation between irregular covalent modification of histones and tumor development has been proven over the last decades. Therefore, HDAC inhibitors are considered as potential drugs in cancer treatment. Romidepsin (FK228), Belinostat (PXD-101), Vorinostat (SAHA), Panobinostat (LBH-589) and Chidamide were approved by FDA as novel antitumor agents. Objective: The aim of this review article is to highlight the structure-activity relationships of several FK228 analogues as HDAC inhibitors. In addition, the synergistic effects of a dual HDAC/PI3K inhibition by some derivatives have been investigated. Materials and Methods: PubMed, MEDLINE, CAPLUS, SciFinder Scholar database were considered by selecting articles which fulfilled the objectives of this review, dating from 2015 till present time. Results: HDAC inhibitors have a significant role in cancer pathogenesis and evolution. Class I HDAC isoformrs are expressed in many tumor types, therefore, potent and selective Class I HDAC inhibitors are of great interest as candidate therapeutic agents with limited side effects. By structure-based optimization, several FK228 analogues [15 (FK-A5), 22, 23, 26 (FK-A11)] were identified, provided with significant activity against Class I HDAC enzymes and dose dependent antitumor activity. Compound 26 was recognized as an interesting HDAC/PI3K dual inhibitor (IC50 against p110α of 6.7 µM while for HDAC1 inhibitory activity IC50 was 0.64 nM). Conclusion: Romidepsin analogues HDAC inhibitors have been confirmed as useful anticancer agents. In addition, dual HDAC/PI3K inhibition showed by some of them exhibited synergistic effects in inducing apoptosis in human cancer cells. Further studies on FK228 analogues may positively contribute to the availability of potent agents in tumor treatment.