Teru Hideshima

Harvard Medical School, Boston, Massachusetts, United States

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Publications (310)2241.45 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876's mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development, but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell reports. 02/2015;
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    ABSTRACT: Carfilzomib, a recently FDA-approved proteasome inhibitor, has remarkable anti-myeloma (MM) activity. However, its effectiveness is limited by associated severe side-effects, short circulation half-life, and limited solubility. Here, we report the engineering of liposomal carfilzomib nanoparticles to overcome these problems and enhance the therapeutic efficacy of carfilzomib by increasing tumoral drug accumulation while decreasing systemic toxicity. In our design, carfilzomib was loaded into the bilayer of liposomes to yield stable and reproducible liposomal nanoparticles. Liposomal carfilzomib nanoparticles were efficiently taken up by MM cells, demonstrated proteasome inhibition, induced apoptosis, and exhibited enhanced cytotoxicity against MM cells. In vivo, liposomal carfilzomib demonstrated significant tumor growth inhibition and dramatically reduced overall systemic toxicity compared to free carfilzomib. Finally, liposomal carfilzomib demonstrated enhanced synergy in combination with doxorubicin. Taken together, this study establishes the successful synthesis of liposomal carfilzomib nanoparticles that demonstrate improved therapeutic index and the potential to improve patient outcome in MM.
    Journal of Controlled Release 10/2014; · 7.26 Impact Factor
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    ABSTRACT: New, next-generation targeted treatment strategies are required to improve outcomes in patients with multiple myeloma (MM). Monoclonal antibodies, cell signaling inhibitors, and selective therapies targeting the bone marrow microenvironment have demonstrated encouraging results with generally manageable toxicity in therapeutic trials of patients with relapsed and refractory disease, each critically informed by preclinical studies. A combination approach of these newer agents with immunomodulators and/or proteasome inhibitors as part of a treatment platform seems to improve the efficacy of anti-MM regimens, even in heavily pretreated patients. Future studies are required to better understand the complex mechanisms of drug resistance in MM.
    Hematology/Oncology Clinics of North America 10/2014; · 2.07 Impact Factor
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    ABSTRACT: Introduction: Multiple myeloma patients who are refractory to lenalidomide and bortezomib have a dismal prognosis. Pomalidomide is a new immunomodulatory agent approved for the treatment of relapsed and refractory multiple myeloma (RRMM) that is unique in that it demonstrates promising activity but appears to be associated with lower toxicity than thalidomide or lenalidomide.Areas covered: We review the mechanisms of action of pomalidomide, evaluate preclinical data, summarize the results of dose-finding Phase I studies and describe Phase II/III studies of this drug in combination with dexamethasone and other agents. Data presented were gathered from multiple sources, including articles from PubMed, published abstracts from the annual meetings of the American Society of Hematology and American Society of Clinical Oncology and websites such as http://clinicaltrials.gov/.Expert opinion: The regulatory approval of pomalidomide represents an important addition to a hematologist’s armamentarium for the treatment of RRMM. Pomalidomide is well tolerated and demonstrates a high level of anti-myeloma activity. Pomalidomide combined with dexamethasone should be considered as standard-of-care therapy for advanced RRMM following progression on both lenalidomide and bortezomib. Ongoing and future studies will characterize the activity of different combinations intended to improve treatment responses, and the potential role of pomalidomide as maintenance therapy.
    Expert Opinion on Orphan Drugs. 09/2014;
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    ABSTRACT: Despite promising preclinical results with mTOR kinase inhibitors in multiple myeloma (MM), resistance to these drugs may arise via feedback activation loops. This concern is especially true for IGF-1 receptor (IGF-1R), because IGF-1R signaling is downregulated by multiple AKT and mTOR feedback mechanisms. We have tested this hypothesis in MM using the novel selective mTOR kinase inhibitor AZD8055. We evaluated p-mTOR S2481 as the readout for mTORC2/Akt activity in MM cells in the context of mTOR inhibition via AZD8055, or rapamycin. We next validated AZD8055 inhibition of mTORC1 and mTORC2 functions in MM cells alone or in culture with BMSCs and growth factors. Unlike rapamycin, AZD8055 resulted in apoptosis of MM cells. AZD8055 treatment however induced upregulation of IGF-1R phosphorylation in p-Akt S473 expressing MM cell lines. Furthermore, exposure of AZD8055-treated cells to IGF-1 induced p-Akt S473 and rescued MM cells from apoptosis despite mTOR kinase inhibition and TORC2/Akt blockage. The addition of blocking IGF-1R antibody resulted in reversing this effect and increased AZD8055-induced apoptosis. Our study suggests that combination treatment with AZD8055 and IGF-1R blocking agents is a promising strategy in MM with potential IGF-1R/Akt signaling mediated survival.
    Molecular Cancer Therapeutics 08/2014; · 5.60 Impact Factor
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    ABSTRACT: The PI3K/Akt pathway plays a crucial role in the pathogenesis of multiple myeloma (MM) in the bone marrow (BM) milieu. However, efficacy of selective and potent Akt inhibition has not yet been fully elucidated. In this study, we therefore examined the biologic impact of selective and potent Akt inhibition by a novel allosteric inhibitor TAS-117. TAS-117 induced significant growth inhibition, associated with downregulation of phosphorylated Akt (p-Akt), selectively in MM cell lines with high baseline p-Akt. Cytotoxicity of TAS-117 was also observed in patients MM cells, but not in normal peripheral blood mononuclear cells. Importantly, TAS-117 induced significant cytotoxicity in MM cells even in the presence of BM stromal cells, associated with inhibition of IL-6 secretion. Oral administration of TAS-117 significantly inhibited human MM cell growth in murine xenograft models. TAS-117 triggered apoptosis and autophagy, as well as induction of endoplasmic reticulum (ER) stress response with minimal expression of CHOP, a fatal ER-stress marker. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity, associated with increased CHOP and PARP cleavage and blockade of bortezomib-induced p-Akt, suggesting that TAS-117 augments bortezomib-induced ER stress and apoptotic signaling. Carfilzomib-induced cytotoxicity was similarly enhanced by TAS-117. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity in vivo, associated with prolonged host survival. Our results show that selective and potent Akt inhibition by TAS-117 triggers anti-MM activities in vitro and in vivo, as well as enhances cytotoxicity of proteasome inhibition, providing the preclinical framework for clinical evaluation of selective Akt inhibitors, alone and in combination with proteasome inhibitors in MM.
    Cancer Research 06/2014; · 9.28 Impact Factor
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    ABSTRACT: Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels.
    Nature medicine 05/2014; · 28.05 Impact Factor
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    ABSTRACT: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5·5 months and median overall survival was 29·5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM.
    British Journal of Haematology 04/2014; · 4.94 Impact Factor
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    ABSTRACT: Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma. In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in multiple myeloma. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between multiple myeloma cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway known to promote multiple myeloma cell proliferation, survival, migration, drug resistance, and formation of multiple myeloma cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30 mix to reduce tumor burden and metastatic potential in vivo in three murine xenograft models of human multiple myeloma without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate multiple myeloma cells in vivo. Cancer Res; 74(6); 1-13. ©2014 AACR.
    Cancer Research 03/2014; · 9.28 Impact Factor
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    ABSTRACT: Bortezomib is a proteasome inhibitor with remarkable clinical antitumor activity in multiple myeloma (MM) and is under evaluation in clinical trials in various types of cancer including breast cancer. Although the initial rationale for its use in cancer treatment was the inhibition of NF-κB activity by blocking proteasomal degradation of IκBα, direct evidence indicating inhibition of constitutive NF-κB activity by bortezomib in tumor cells in patients has not yet been reported. Moreover, recent studies have shown that bortezomib activates constitutive NF-κB activity via stimulating the canonical pathway in MM cells. In this study, we first examined protein expression of IκBα after bortezomib treatment. We observed that bortezomib upregulated the phosphorylation and downregulated IκBα protein expression in a dose- and time-dependent manner in MCF7 and T47D cells, associated with phosphorylation of IKKβ. Since IκBα is an inhibitor of nuclear translocation of NF-κB, we further examined alteration of NF-κB activity by bortezomib. Importantly, bortezomib significantly upregulates NF-κB activity in both MCF7 and T47D in a dose-dependent fashion, demonstrated by electrophoretic mobility shift analysis (EMSA). Furthermore, immunocytochemical analysis confirmed enhanced nuclear translocation of p65 NF-κB (RelA) by bortezomib treatment. Supershift assay showed supershifted bands by anti-p65 and -p50 antibodies. Taken together, these results indicate that bortezomib activates the canonical NF-κB pathway in both cell lines. Finally, we demonstrated that IKKβ inhibitor enhanced cytotoxicity, associated with inhibition of NF-κB activity induced by bortezomib in MCF7 and T47D breast cancer cells.
    International Journal of Oncology 01/2014; · 2.77 Impact Factor
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    ABSTRACT: In this prospective, multicenter, phase 2 study, 64 patients with relapsed or relapsed and refractory multiple myeloma (MM) received up to eight 21-day cycles of bortezomib 1.0 mg/m(2) (days 1, 4, 8, 11), lenalidomide 15 mg/day (days 1-14), and dexamethasone 40/20 mg/day (cycles 1-4) and 20/10 mg/day (cycles 5-8) (days of/after bortezomib dosing). Responding patients could receive maintenance therapy. Median age was 65 years, 66% were male, 58% had relapsed and 42% relapsed and refractory MM, and 53%, 75%, and 6% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Forty eight of 64 patients (75%; 90% CI, 65-84) were alive without progressive disease at 6 months (primary endpoint). The rate of partial response or better was 64%; median duration of response was 8.7 months. Median progression-free and overall survival were 9.5 and 30 months, respectively (median follow-up: 44 months). Common treatment-related toxicities included sensory neuropathy (53%), fatigue (50%), and neutropenia (42%); common grade 3/4 treatment-related toxicities included neutropenia (30%), thrombocytopenia (22%), and lymphopenia (11%). Grade 3 motor neuropathy was reported in two patients. Lenalidomide-bortezomib-dexamethasone appears effective and tolerable in patients with relapsed or relapsed and refractory MM, demonstrating substantial activity among patients with diverse prior therapies and adverse prognostic characteristics. This trial is registered with www.ClinicalTrials.gov as #NCT00378209.
    Blood 01/2014; · 9.78 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2013; · 10.16 Impact Factor
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    ABSTRACT: The outlook for patients with multiple myeloma (MM) has improved significantly with the development of new and more effective therapies, particularly the immunomodulatory agents and proteasome inhibitors. Preclinical and correlative science investigations have played a critical role in these advances, providing important insights regarding mechanisms of neoplasia, inhibition of tumor growth, and drug resistance. This review highlights the evolution of drug development in MM, the manner in which preclinical models have contributed to the process of drug discovery, and important insights gained during the current era of MM drug development.
    Seminars in Oncology 10/2013; 40(5):549-53. · 3.94 Impact Factor
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    ABSTRACT: Protein condensations, such as crystallization, liquid-liquid phase separation, aggregation, and gelation, have been observed in concentrated antibody solutions under various solution conditions. While most IgG antibodies are quite soluble, a few outliers can undergo condensation under physiological conditions. Condensation of IgGs can cause serious consequences in some human diseases and in biopharmaceutical formulations. The phase transitions underlying protein condensations in concentrated IgG solutions is also of fundamental interest for the understanding of the phase behavior of non-spherical protein molecules. Due to the high solubility of generic IgGs, the phase behavior of IgG solutions has not yet been well studied. In this work, we present an experimental approach to study IgG solutions in which the phase transitions are hidden below the freezing point of the solution. Using this method, we have investigated liquid-liquid phase separation of six human myeloma IgGs and two recombinant pharmaceutical human IgGs. We have also studied the relation between crystallization and liquid-liquid phase separation of two human cryoglobulin IgGs. Our experimental results reveal several important features of the generic phase behavior of IgG solutions: (1) the shape of the coexistence curve is similar for all IgGs but quite different from that of quasi-spherical proteins; (2) all IgGs have critical points located at roughly the same protein concentration at ∼100 mg∕ml while their critical temperatures vary significantly; and (3) the liquid-liquid phase separation in IgG solutions is metastable with respect to crystallization. These features of phase behavior of IgG solutions reflect the fact that all IgGs have nearly identical molecular geometry but quite diverse net inter-protein interaction energies. This work provides a foundation for further experimental and theoretical studies of the phase behavior of generic IgGs as well as outliers with large propensity to condense. The investigation of the phase diagram of IgG solutions is of great importance for the understanding of immunoglobulin deposition diseases as well as for the understanding of the colloidal stability of IgG pharmaceutical formulations.
    The Journal of Chemical Physics 09/2013; 139(12):121904. · 3.12 Impact Factor
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    ABSTRACT: Histone deacetylases (HDACs) represent novel molecular targets for the treatment of various types of cancers, including multiple myeloma (MM). Many HDAC inhibitors have already shown remarkable anti-tumor activities in the preclinical setting; however, their clinical utility is limited due to unfavorable toxicities associated with their broad range HDAC inhibitory effects. Isoform-selective HDAC inhibition may allow for MM cytotoxicity without attendant side effects. In this study, we demonstrated that HDAC3 knockdown and a small molecule HDAC3 inhibitor BG45 trigger significant MM cell growth inhibition via apoptosis, evidenced by caspase and PARP cleavage. Importantly, HDAC3 inhibition downregulates phosphorylation (tyrosine 705 and serine 727) of STAT3. Neither IL-6 nor bone marrow stromal cells overcome this inhibitory effect of HDAC3 inhibition on p-STAT3 and MM cell growth. Moreover, HDAC3 inhibition also triggers hyperacetylation of STAT3, suggesting crosstalk signaling between phosphorylation and acetylation of STAT3. Importantly, inhibition of HDAC3, but not HDAC1 or HDAC2, significantly enhances bortezomib-induced cytotoxicity. Finally, we confirm that BG45 alone and in combination with bortezomib trigger significant tumor growth inhibition in vivo in a murine xenograft model of human MM. Our results indicate that HDAC3 represents a promising therapeutic target, and validate a prototype novel HDAC3 inhibitor BG45 in MM.Leukemia accepted article preview online, 5 August 2013. doi:10.1038/leu.2013.231.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2013; · 10.16 Impact Factor
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    ABSTRACT: We recently demonstrated that Nicotinamide phosphoribosyltransferase (Nampt) inhibition depletes intracellular NAD+ content leading, to autophagic multiple myeloma (MM) cell death. Bortezomib has remarkably improved MM patient outcome, but dose-limiting toxicities and development of resistance limit its long-term utility. Here we observed higher Nampt mRNA levels in bortezomib-resistant patient MM cells, which correlated with decreased overall survival. We demonstrated that combining the NAD+ depleting agent FK866 with bortezomib induces synergistic anti-MM cell death and overcomes bortezomib-resistance. This effect is associated with: 1) activation of caspase-8, caspase-9, caspase-3, PARP and down-regulation of Mcl-1; 2) enhanced intracellular NAD+ depletion; 3) inhibition of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities; 4) inhibition of NF-kappa B signaling; and 5) inhibition of angiogenesis. Furthermore, Nampt knockdown significantly enhances the anti-MM effect of bortezomib, which can be rescued by ectopically overexpressing Nampt. In a murine xenograft MM model, low-dose combination FK866 and Bortezomib is well tolerated, significantly inhibits tumor growth, and prolongs host survival. Taken together, these findings indicate that intracellular NAD+ level represents a major determinant in the ability of bortezomib to induce apoptosis in MM cells and provide proof-of-concept for the combination with FK866 as a new strategy to enhance sensitivity or overcome resistance to bortezomib.
    Blood 07/2013; · 9.78 Impact Factor
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    ABSTRACT: Small molecule multi-targeted CDK inhibitors (CDKIs) are of particular interest due to their potent antitumor activity independent of p53 gene alterations. P53 deletion is associated with a very poor prognosis in multiple myeloma (MM). In this regard, we tested the anti-MM activity of RGB-286638, an indenopyrazole-derived CDKI with Ki-nanomolar activity against transcriptional CDKs. We examined RGB-286638's mode-of-action in MM cell lines with wild type (wt)-p53 and those expressing mutant p53. RGB-286638 treatment resulted in MM cytotoxicity in vitro associated with inhibition of MM tumor growth and prolonged survival in vivo. RGB-286638 displayed caspase-dependent apoptosis in both wt-p53 and mutant-p53 cells that was closely associated with the downregulation of RNA polymerase II phosphorylation and inhibition of transcription. RGB-286638-triggered p53 accumulation via nucleolar stress and loss of Mdm2, accompanied by induction of p53 DNA binding activity. Additionally, RGB-286638 mediated p53-independent activity, which was confirmed by cytotoxicity in p53-knockdown and p53-mutant cells. We also demonstrated downregulation of oncogenic miR-19, miR-92a-1, and miR-21. Our data provide the rationale for the development of transcriptional CDK inhibitors as therapeutic agents, which activate p53 in competent cells, while circumventing p53 deficiency through alternative p53-independent cell death mechanisms in p53-mutant/deleted cells.Leukemia accepted article preview online, 28 June 2013; doi:10.1038/leu.2013.194.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2013; · 10.16 Impact Factor
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    ABSTRACT: Multiple myeloma (MM) is an incurable neoplasm caused by proliferation of malignant plasma cells in the bone marrow (BM). MM is characterized frequently by a complete or partial deletion of chromosome 13q14, seen in more than 50% of patients at diagnosis. Within this deleted region the tripartite motif containing 13 (TRIM13, also termed RFP2) gene product has been proposed to be a tumour suppressor gene (TSG). Here, we show that low expression levels of TRIM13 in MM are associated with chromosome 13q deletion and poor clinical outcome. We present a functional analysis of TRIM13 using a loss-of-function approach, and demonstrate that TRIM13 downregulation decreases tumour cell survival as well as cell cycle progression and proliferation of MM cells. In addition, we provide evidence for the involvement of TRIM13 downregulation in inhibiting the NF kappa B pathway and the activity of the 20S proteasome. Although this data does not support a role of TRIM13 as a TSG, it substantiates important roles of TRIM13 in MM tumour survival and proliferation, underscoring its potential role as a novel target for therapeutic intervention.
    British Journal of Haematology 05/2013; · 4.94 Impact Factor
  • Blood. 2013 Apr 11;121(15):2975-87. 04/2013; 121(15):2975-87.
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    Teru Hideshima, Kenneth C Anderson
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    ABSTRACT: Histone lysine acetylation is regulated by both histone deacetylases (HDACs) and histone acetyl transferases. Inhibition of deacetylases induces hyperacetylate of target proteins and has a crucial role in the epigenetic regulation of gene expression mediating cell survival and proliferation. Therefore, HDAC inhibitors have emerged as novel therapeutic agents for cancers, including multiple myeloma (MM). Recent studies revealed that HDAC inhibitors trigger hyperacetylation of not only histones, but also non-histone proteins regulating cell growth and survival, revealing the complexity of mechanism of action of HDAC inhibitors. Many HDAC inhibitors have already shown significant anti-MM activities in preclinical studies and are under evaluation in clinical trials.
    International journal of hematology 03/2013; · 1.17 Impact Factor

Publication Stats

24k Citations
2,241.45 Total Impact Points


  • 1999–2014
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1970–2014
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2012
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2002–2012
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 2008
    • University of Rochester
      • James P. Wilmot Cancer Center
      Rochester, NY, United States
  • 2007
    • Università degli Studi di Bari Aldo Moro
      Bari, Apulia, Italy
  • 2006–2007
    • University of Pittsburgh
      • • Division of General Internal Medicine
      • • Division of Hematology/Oncology
      Pittsburgh, PA, United States
  • 2005–2006
    • Mayo Foundation for Medical Education and Research
      • Division of Hematology
      Scottsdale, AZ, United States
  • 2004
    • The Jikei University School of Medicine
      • Department of Pediatrics
      Tokyo, Tokyo-to, Japan
    • University of Leeds
      • School of Medicine
      Leeds, ENG, United Kingdom