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

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

Abstract

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.

Keywords

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

Abbreviations

ABC

Activated B-cell

AML

Acute myeloid leukemia

ATM

Ataxia telangiectasia mutated

ATR

ATM and Rad3 related

BCR

B-cell receptor

BTK

Bruton’s tyrosine kinase

CDK

Cyclin-dependent kinases

CDT1

Chromatin licensing and DNA replication factor-1

c-FLIP

Cellular FLICE-like inhibitory protein

CHOP

CAAT-/enhancer-binding protein homologous protein

CTCL

Cutaneous T-cell lymphoma

DDR

DNA damage response

DLBCL

Diffuse large B-cell lymphoma

DNMT1

DNA methyltransferase 1

DSB

Double-strand breaks

ER

Endoplasmic reticulum

ERK

Extracellular signal-regulated kinase

FL

Follicular lymphoma

FLICE

FADD-like IL-1β-converting enzyme

GC

Germinal center

GEP

Gene expression profiling

GSK3β

Glycogen synthase kinase-3-beta

HAT

Histone acetyl transferases

HDAC

Histone deacetylase

HDACI

Histone deacetylase inhibitor

HDM4

Human homolog of MDM4

Hsp90

Heat shock protein 90

IgVH

Immunoglobulin heavy chain variable region

IKK

IκB kinase

IκB

I kappa B

JAK

Janus kinase

JNK

Jun N-terminal kinase

MAPK

Mitogen-activated protein kinase

MCL

Mantle cell lymphoma

Mcl-1

Myeloid cell leukemia 1

MDM2

Murine double minute homolog 2

MIPI

Mantle cell lymphoma international prognostic index

MM

Multiple myeloma

mTOR

Mammalian target of rapamycin

NF-κB

Nuclear factor kappa B

NHEJ

Nonhomologous end joining

NHL

Non-Hodgkin lymphomas

ORR

Overall response rate

PERK

Protein kinase RNA-like ER kinase

PI

Proteasome inhibitor

PRDM1

PR domain zinc finger protein 1, Blimp1

Rb

Retinoblastoma protein

R-CHOP

Rituximab, cyclophosphamide, doxorubicin, vincristine prednisone

ROS

Reactive oxygen species

STAT

Signal transducer and activator of transcription

TTP

Time to progression

UPR

Unfolded protein response

UPS

Ubiquitin proteasome system

VEGF

Vascular endothelial growth factor

XIAP

X-linked inhibitor of apoptosis

Notes

Acknowledgements

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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