Targeting Mantle Cell Lymphoma with a Strategy of Combined Proteasome and Histone Deacetylase Inhibition

  • Michael Batalo
  • Prithviraj Bose
  • Beata Holkova
  • Steven GrantEmail author
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT)


Although approved for over a decade, the clinical utility of proteasome inhibitors (PIs) remains largely restricted to the treatment of patients with multiple myeloma (MM) and mantle cell lymphoma (MCL). This has fueled interest in understanding mechanisms of resistance to their antineoplastic actions, leading to the development of new and improved PIs (e.g., carfilzomib, ixazomib, marizomib) and rational combinations with other novel classes of targeted agents. With respect to the latter, histone deacetylase inhibitors (HDACIs) represent one of the most extensively studied classes of agents. PIs and HDACIs interact at multiple levels to trigger synergistic cell killing in a variety of tumor types through multiple mechanisms, including induction of oxidative stress and DNA damage, PI-mediated inhibition of the cytoprotective NF-κB pathway activated by HDACIs, and promotion of proteotoxic stress through simultaneous proteasome inhibition and disruption of aggresome formation and chaperone proteins, leading to the accumulation of misfolded proteins. Clinically, this combination may be closest to regulatory approval in MM, but represents a promising avenue of investigation in MCL, a relatively uncommon but challenging disease that has been the focus of much recent attention given Food and Drug Administration approvals in 2013 for the immunomodulatory drug lenalidomide and the first-in-class Bruton’s tyrosine kinase inhibitor, ibrutinib. In this chapter, we discuss the mechanisms of action of and interactions between PIs and HDACIs with an MCL focus and review the relevant preclinical and clinical data.


Mantle cell lymphoma Proteasome inhibitor Histone deacetylase inhibitor Apoptosis NF-κB Aggresome ER stress Unfolded protein response Hsp90 Rational combinations Targeted therapies Clinical trials 



Activated B-cell


Acute myeloid leukemia


Ataxia telangiectasia mutated


ATM and Rad3 related


B-cell receptor


Bruton’s tyrosine kinase


Cyclin-dependent kinases


Chromatin licensing and DNA replication factor-1


Cellular FLICE-like inhibitory protein


CAAT-/enhancer-binding protein homologous protein


Cutaneous T-cell lymphoma


DNA damage response


Diffuse large B-cell lymphoma


DNA methyltransferase 1


Double-strand breaks


Endoplasmic reticulum


Extracellular signal-regulated kinase


Follicular lymphoma


FADD-like IL-1β-converting enzyme


Germinal center


Gene expression profiling


Glycogen synthase kinase-3-beta


Histone acetyl transferases


Histone deacetylase


Histone deacetylase inhibitor


Human homolog of MDM4


Heat shock protein 90


Immunoglobulin heavy chain variable region


IκB kinase


I kappa B


Janus kinase


Jun N-terminal kinase


Mitogen-activated protein kinase


Mantle cell lymphoma


Myeloid cell leukemia 1


Murine double minute homolog 2


Mantle cell lymphoma international prognostic index


Multiple myeloma


Mammalian target of rapamycin


Nuclear factor kappa B


Nonhomologous end joining


Non-Hodgkin lymphomas


Overall response rate


Protein kinase RNA-like ER kinase


Proteasome inhibitor


PR domain zinc finger protein 1, Blimp1


Retinoblastoma protein


Rituximab, cyclophosphamide, doxorubicin, vincristine prednisone


Reactive oxygen species


Signal transducer and activator of transcription


Time to progression


Unfolded protein response


Ubiquitin proteasome system


Vascular endothelial growth factor


X-linked inhibitor of apoptosis



This work was supported in part by the following awards to Dr. Grant: R01 CA167708-01A1 and R01 CA100866-09 from the National Institutes of Health, an award from the Leukemia and Lymphoma Society, and an award from Onyx Pharmaceuticals, Inc.


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Michael Batalo
    • 1
  • Prithviraj Bose
    • 1
    • 2
  • Beata Holkova
    • 1
    • 2
  • Steven Grant
    • 1
    • 2
    • 3
    • 4
    • 5
    • 6
    Email author
  1. 1.Department of Internal MedicineVirginia Commonwealth UniversityRichmondUSA
  2. 2.Massey Cancer CenterVirginia Commonwealth UniversityRichmondUSA
  3. 3.Department of Microbiology and ImmunologyVirginia Commonwealth UniversityRichmondUSA
  4. 4.Department of Biochemistry and Molecular BiologyVirginia Commonwealth UniversityRichmondUSA
  5. 5.Department of Human and Molecular GeneticsVirginia Commonwealth UniversityRichmondUSA
  6. 6.Institute of Molecular MedicineVirginia Commonwealth UniversityRichmondUSA

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