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The synergistic interaction between CD20 monoclonal antibodies and Histone Deacetylase inhibitors in B cell Non Hodgkin’s Lymphoma

The synergistic interaction between CD20 monoclonal antibodies and Histone Deacetylase inhibitors in B cell Non Hodgkin’s Lymphoma
The synergistic interaction between CD20 monoclonal antibodies and Histone Deacetylase inhibitors in B cell Non Hodgkin’s Lymphoma
Recent improvements in molecular sub typing of Non Hodgkin’s lymphomas
have resulted in targeted therapies becoming incorporated into treatment
paradigms. The anti-CD20 monoclonal antibody, Rituximab, has resulted in
dramatic improvements in survival for patients with B cell Non Hodgkin’s
lymphoma. Histone deacetylase inhibitors are a novel class of anti cancer
agents targeting epigenetic regulation.

This thesis addresses the interaction between histone deacetylase inhibitors
and anti-CD20 monoclonal antibodies, including Rituximab, both in vitro and
in vivo. The initial approach identified synergistic induction of apoptosis in a
number of B cell lines. In a Ramos xenograft model, combination treatment
with suberoylanilide hydroxamic acid (SAHA) and Rituximab reduced tumour
growth compared to either agent alone, without discernable toxicity. This
effect appears specific to CD20 since monoclonal antibodies directed to other
surface molecules (CD32b, CD22, CD37) did not exhibit cooperative effect.
Analysis of apoptotic pathways demonstrated that PARP cleavage and
caspase processing is significantly higher in cells receiving both treatments.
Co-treatment of Ramos cells with the pan caspase inhibitor QVD-OPH
abolished the synergy observed with CD20 monoclonal antibodies,
suggesting that caspase processing is necessary for synergy. Treatment of
Ramos cells stably transfected to overexpress Bcl-2 resulted in loss of
synergy with Rituximab, but not with the type II CD20 mAb B1 (Tositumomab).

Gene expression array analysis of Ramos cells was performed. Geneset
enrichment analysis identified significant regulation of NF?B target genes in
some genesets (Rituximab Vs control, p<0.001) with a number associated
with apoptosis and B cell activation (Bcl2A1, LTA, CD69) which were
confirmed using RT-Q-PCR.

This novel combination elicits the induction of apoptosis in vitro, potentially
through regulation of Bcl-2 family proteins and should be tested in a phase
I/II clinical trial.
Nolan, David Francis Luke
b93be062-e519-4677-a708-a0d2c26acd24
Nolan, David Francis Luke
b93be062-e519-4677-a708-a0d2c26acd24
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394

Nolan, David Francis Luke (2010) The synergistic interaction between CD20 monoclonal antibodies and Histone Deacetylase inhibitors in B cell Non Hodgkin’s Lymphoma. University of Southampton, School of Medicine, Doctoral Thesis, 205pp.

Record type: Thesis (Doctoral)

Abstract

Recent improvements in molecular sub typing of Non Hodgkin’s lymphomas
have resulted in targeted therapies becoming incorporated into treatment
paradigms. The anti-CD20 monoclonal antibody, Rituximab, has resulted in
dramatic improvements in survival for patients with B cell Non Hodgkin’s
lymphoma. Histone deacetylase inhibitors are a novel class of anti cancer
agents targeting epigenetic regulation.

This thesis addresses the interaction between histone deacetylase inhibitors
and anti-CD20 monoclonal antibodies, including Rituximab, both in vitro and
in vivo. The initial approach identified synergistic induction of apoptosis in a
number of B cell lines. In a Ramos xenograft model, combination treatment
with suberoylanilide hydroxamic acid (SAHA) and Rituximab reduced tumour
growth compared to either agent alone, without discernable toxicity. This
effect appears specific to CD20 since monoclonal antibodies directed to other
surface molecules (CD32b, CD22, CD37) did not exhibit cooperative effect.
Analysis of apoptotic pathways demonstrated that PARP cleavage and
caspase processing is significantly higher in cells receiving both treatments.
Co-treatment of Ramos cells with the pan caspase inhibitor QVD-OPH
abolished the synergy observed with CD20 monoclonal antibodies,
suggesting that caspase processing is necessary for synergy. Treatment of
Ramos cells stably transfected to overexpress Bcl-2 resulted in loss of
synergy with Rituximab, but not with the type II CD20 mAb B1 (Tositumomab).

Gene expression array analysis of Ramos cells was performed. Geneset
enrichment analysis identified significant regulation of NF?B target genes in
some genesets (Rituximab Vs control, p<0.001) with a number associated
with apoptosis and B cell activation (Bcl2A1, LTA, CD69) which were
confirmed using RT-Q-PCR.

This novel combination elicits the induction of apoptosis in vitro, potentially
through regulation of Bcl-2 family proteins and should be tested in a phase
I/II clinical trial.

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Published date: January 2010
Organisations: University of Southampton

Identifiers

Local EPrints ID: 162661
URI: http://eprints.soton.ac.uk/id/eprint/162661
PURE UUID: 9d9d7a65-7276-4718-9a04-d4a62eb8db65
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

Catalogue record

Date deposited: 13 Sep 2010 15:38
Last modified: 30 Jan 2020 01:30

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