Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma

Amengual, Jennifer E.; Clark-Garvey, Sean; Kalac, Matko; Scotto, Luigi; Marchi, Enrica; Neylon, Ellen; Johannet, Paul; Wei, Ying; Zain, Jasmine; O’Connor, Owen A.

doi:10.1182/blood-2013-02-485441

Cited by 54 publications

(56 citation statements)

References 46 publications

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“…One such inhibitor-called 79-6 complex-works by binding to the BCL6 BTB domain corepressor binding groove (41). Strategies such as histone deacetylation inhibition-to overcome the repressive effects of BCL6 on p53 and cell-cycle-inhibitory proteins-are also potentially interesting in DLBCL (43,44). One recent study demonstrated that treatment of DLBCL cell lines with pandeacetylone inhibitors in combination with niacinamide produced synergistic toxicity in GCB over ABC subtypes and led to acetylation of BCL6 and p53 (44).…”

Section: Pre-rituximabmentioning

confidence: 99%

“…Strategies such as histone deacetylation inhibition-to overcome the repressive effects of BCL6 on p53 and cell-cycle-inhibitory proteins-are also potentially interesting in DLBCL (43,44). One recent study demonstrated that treatment of DLBCL cell lines with pandeacetylone inhibitors in combination with niacinamide produced synergistic toxicity in GCB over ABC subtypes and led to acetylation of BCL6 and p53 (44). In a phase I proof-ofprinciple study, 24% of patients with relapsed lymphoma attained a response to vorinostat and niacinamide.…”

Section: Pre-rituximabmentioning

confidence: 99%

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Precision Treatment of Distinct Molecular Subtypes of Diffuse Large B-cell Lymphoma: Ascribing Treatment Based on the Molecular Phenotype

Dunleavy

Roschewski

Wilson

2014

Clinical Cancer Research

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Although diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, was once considered to be a single disease, novel insights into its biology have revealed that it is molecularly heterogeneous. Technologies such as gene expression profiling have revealed that DLBCL consists of at least three distinct molecular diseases that have disparate outcomes following standard therapy. These subtypes arise from different stages of B-cell differentiation and are characterized by distinct oncogenic activation mechanisms. This knowledge has led to the investigation of strategies and novel agents that have selective activity within molecular subtypes and sets the stage for an era of precision medicine in DLBCL therapeutics, where therapy can be ascribed based on molecular phenotype. This work offers the chance of improving the curability of DLBCL, particularly in the activated B-cell subtype, where standard approaches are inadequate for a high proportion of patients.

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Section: Pre-rituximabmentioning

confidence: 99%

Section: Pre-rituximabmentioning

confidence: 99%

Precision Treatment of Distinct Molecular Subtypes of Diffuse Large B-cell Lymphoma: Ascribing Treatment Based on the Molecular Phenotype

Dunleavy

Roschewski

Wilson

2014

Clinical Cancer Research

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“…Drugs such as ibrutinib, proteasome inhibitors, and lenolidomide appear to be more active in the ABC phenotype, and are now being integrated into upfront R-CHOP-based chemotherapy regimens in randomized clinical studies. In contrast, other studies have optimized histone deacetylase inhibitors to target the Bcl-6-p53 axis in GC-derived DLBCL with promising results (17). In this particular example, we have become more knowledgeable, as data and information from efforts in quantitative experimentation are translated into clinical studies.…”

Section: Introductionmentioning

confidence: 99%

Putting the Clinical and Biological Heterogeneity of Non-Hodgkin Lymphoma into Context

O’Connor

Tobinai²

2014

Clinical Cancer Research

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The lymphomas represent one of the most heterogeneous groups of malignancies in all of cancer medicine. Whether one attempts to understand these diseases in the context of their complicated ontogeny, unique biologic features, or clinical presentation, this heterogeneity has been a mixed blessing. On the one hand, it has created an ever-changing way to classify these diseases, as classification schemes have been compelled to reflect the rapidly emerging information that seems to split the disease into smaller and smaller subtypes. On the other hand, the biologic and clinical dissection of these diseases has allowed for the identification of unique biologic features-features that have led to novel targets and generated a plethora of new drugs. Virtually every subtype of non-Hodgkin lymphoma has benefited from these efforts to understand the biology of the different subtypes. This paradigm has led to new clinical trials that tailor novel drug regimens to specific biologic disease subtypes. As a prelude to this CCR Focus section, we attempt to put this evolving heterogeneity into context, bridging historical and modern-day views of classification of these diseases. Then, some of the world's leading lymphoma researchers share their perspectives on how to formulate new concepts of care in this era of biologic discovery. Over a relatively short time, the advances in lymphoma research have been nothing short of stunning. There now seems to be little doubt that these recent breakthroughs will redound favorably on the majority of patients diagnosed with a lymphoproliferative malignancy.

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“…83 Rational targeting of actionable mutated genes in DLBCL is nevertheless a challenge, particularly after the discovery of an unexpected high grade of mutational/genetic heterogeneity found in the different NGS studies of human DLBCLs, 72 and following the observations that ongoing acquisition of mutations and intratumoral clonal heterogeneity are frequent findings in DLBCL. 13 Both the prognostic and predictive value of these mutations is still a matter of active research.…”

mentioning

confidence: 99%

“…66 Opportunities for targeting GC-DLBCL have also emerged from the study by Amengual and co-workers, which recently demonstrated that treatment of DLBCL cell lines with pan-DAC inhibitors in combination with niacinamide produces synergistic cytotoxicity in GC-DLBCL, correlated with acetylation of both Bcl6 and p53. 83 Rational targeting of actionable mutated genes in DLBCL is nevertheless a challenge, particularly after the discovery of an unexpected high grade of mutational/genetic heterogeneity found in the different NGS studies of human DLBCLs, 72 and following the observations that ongoing acquisition of mutations and intratumoral clonal heterogeneity are frequent findings in DLBCL. 13 Both the prognostic and predictive value of these mutations is still a matter of active research.…”

mentioning

confidence: 99%

B-cell lymphoma mutations: improving diagnostics and enabling targeted therapies

et al. 2014

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Correspondence: mapiris@humv.es B-cell lymphomas comprise an increasing number of clinicopathological entities whose characterization has historically been based mainly on histopathological features. In recent decades, the analysis of chromosomal aberrations as well as gene and miRNA expression profile studies have helped distinguish particular tumor types and also enabled the detection of a number of targets with therapeutic implications, such as those activated downstream of the B-cell receptor. Our ability to identify the mechanisms involved in B-cell lymphoma pathogenesis has been boosted recently through the use of Next Generation Sequencing techniques in the analysis of human cancer. This work summarizes the recent findings in the molecular pathogenesis of B-cell neoplasms with special focus on those clinically relevant somatic mutations with the potential to be explored as candidates for the development of new targeted therapies. Our work includes a comparison between the mutational indexes and ranges observed in B-cell lymphomas and also with other solid tumors and describes the most striking mutational data for the major B-cell neoplasms. This review describes a highly dynamic field that currently offers many opportunities for personalized therapy, although there is still much to be gained from the further molecular characterization of these clinicopathological entities. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nthe high mutational index (MI; number of mutations/megabase (Mb)) of tobacco-associated lung cancer and UV-induced melanoma (MI > 7), to the lower rates for the non-hypermutated form of colorectal carcinoma (MI = 3.2) and breast cancer (MI = 1.4). [26][27][28][29][30][31] Despite there being no established correlation between mutational load and clinical outcome, and considering that the current data have been generated using different NGS platforms, including whole genome (WGS), whole exome (WES) and whole transcriptome (mRNA-seq) approaches, we have compared the mutational index data of B-cell lymphomas obtained from independent NGS studies ( Figure 1 and Table 1) and found that, in general, B-cell lymphomas have a mutational load that is lower than in UV-induced melanomas or tobacco-associated lung cancer, and roughly comparable to that seen in solid tumors in adults. Of the B-cell lymphomas, aggressive B-cell lymphomas (i.e. BL: MI = 4.2; DLCBL: MI = 1.7-3.2) have a higher MI than the other low-grade B-cell lymphomas analyzed (MM, SMLZ, CLL, MCL and HCL: MI ≤ 1). Analyzing the nucleotide substitutions, the rate between transitions (A/G or C/T base changes) versus transversions (C,T/A,G) (Figure 1), we observed that percentage differences between these nucleotide substitutions seem to be more restricted (mostly not exceeding 65% of transitions) in B-cell lymphomas than in the solid tumors induced by tobacco or UV radiation (melanoma > 72%) ( Figure 1 and Table 1).More remarkable results are summarized below. Chronic lymphocytic leukemiaCell survival in chronic lymphocytic leukem...

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Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma

Cited by 54 publications

References 46 publications

Precision Treatment of Distinct Molecular Subtypes of Diffuse Large B-cell Lymphoma: Ascribing Treatment Based on the Molecular Phenotype

Precision Treatment of Distinct Molecular Subtypes of Diffuse Large B-cell Lymphoma: Ascribing Treatment Based on the Molecular Phenotype

Putting the Clinical and Biological Heterogeneity of Non-Hodgkin Lymphoma into Context

B-cell lymphoma mutations: improving diagnostics and enabling targeted therapies

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