HDAC inhibitor-based therapies and haematological malignancy

Stimson, Lindsay; Wood, Victoria; Khan, Omar; Fotheringham, Susan; Thangue, N B La

doi:10.1093/annonc/mdn792

Cited by 122 publications

(102 citation statements)

References 54 publications

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“…CTCL is sensitive to the effects of HDAC inhibitor-based therapy (9,11,15,16). As a consequence, we evaluated the role of HR23B as a predictive biomarker for HDAC inhibitors in CTCL, and began by studying HR23B in CTCL cell lines, including MYLA, SeAx, and HUT78.…”

Section: Hr23bmentioning

confidence: 99%

“…In this respect, the outcome of the combined treatment of HDAC inhibitor and proteasome inhibitor resulted in increased inhibitory effects on proteasome activity in a fashion that reflected levels of HR23B. From the clinical perspective, HDAC inhibitors have been studied in combination with an increasing array of anticancer agents (6,8,16), and clinical studies in which HDAC inhibitors were combined with proteasome inhibitors yielded results that suggest additive effects (7,16,20,21). For example, the combined treatment of SAHA/vorinostat with bortezomib produced encouraging clinical effects in patients with relapsed and refractory multiple myeloma (20).…”

Section: Hr23bmentioning

confidence: 99%

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HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy

Khan

Fotheringham

Wood

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

138

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Histone deacetylase (HDAC) inhibitors are emergent cancer drugs. HR23B is a candidate cancer biomarker identified in a genome-wide loss-of-function screen which influences sensitivity to HDAC inhibitors. Because HDAC inhibitors have found clinical utility in cutaneous T-cell lymphoma (CTCL), we evaluated the role of HR23B in CTCL cells. Our results show that HR23B governs the sensitivity of CTCL cells to HDAC inhibitors. Furthermore, proteasome activity is deregulated in HDAC inhibitor-treated CTCL cells through a mechanism dependent upon HR23B, and HDAC inhibitors sensitize CTCL cells to the effects of proteasome inhibitors. The predictive power of HR23B for clinical response to HDAC inhibitors was investigated through an analysis of a unique collection of CTCL biopsies taken from a phase II clinical trial, where there was a frequent coincidence between HR23B expression and clinical response to HDAC inhibitor. Our study supports the personalized medicine approach for treating cancer and the increasing drive to translate laboratory-based findings into clinical utility.cancer | histone deacetylase inhibitor | biomarker | proteasome | clinical trial I t is widely recognized that one of the most significant hurdles to developing new and efficacious cancer drugs is the absence of proven strategies that enable responsive tumors to be identified and treated with the most effective drug. Predictive biomarkers that inform on the clinical response to cancer therapies will not only assist in planning focused and hypothesis-driven clinical development programs but, once approved, provide a companion biomarker that enables patients to be stratified and aligned with an appropriate therapeutic regime (1).Aberrant epigenetic control is an early event in the onset of tumor progression, and there have been intense efforts to develop drugs that modulate epigenesis in cancer (2). One of the most promising approaches has been seen in the development of inhibitors of histone deacetylase (HDAC). HDAC is a family of enzymes that regulate the acetylation level of chromatin, together with a variety of nonhistone proteins (3). Proteins that are involved with tumor progression, including the cell cycle, apoptosis, angiogenesis, and cell invasion, are influenced by acetylation (4).HDAC inhibitors are potent antiproliferative agents in cellbased studies, where they exhibit striking effects on tumor cell proliferation (5-7). Consequently, there has been great interest in developing HDAC inhibitors as new anticancer agents, and an extensive number of clinical trials are underway in which HDAC inhibitors either alone or in combination with other agents are being evaluated (8). To date, SAHA (also known as Vorinostat and Zolinza) and more recently romidepsin (also known as depsipeptide, FK228, and Istodax) are the only HDAC inhibitorbased therapies that have achieved regulatory approval, being marketed for the treatment of advanced and refractory cutaneous T-cell lymphoma (CTCL) (9-11) (http://istodax.com) . Other than CTCL, tumor types that ha...

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Section: Hr23bmentioning

confidence: 99%

Section: Hr23bmentioning

confidence: 99%

HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy

Khan

Fotheringham

Wood

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

138

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“…Another class of epigenetic-modifying agents used clinically is histone deacetylase (HDAC) inhibitors [204][205][206][207][208]. In cancer cells, HDAC enzymes, among many other functions, can modulate chromatin configurations and mediate cancer-related gene silencing as components of repressive protein complexes containing DNMTs.…”

Section: Epigenetic Therapeutics In Cancermentioning

confidence: 99%

Cancer epigenetics: linking basic biology to clinical medicine

2011

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Cancer evolution at all stages is driven by both epigenetic abnormalities as well as genetic alterations. Dysregulation of epigenetic control events may lead to abnormal patterns of DNA methylation and chromatin configurations, both of which are critical contributors to the pathogenesis of cancer. These epigenetic abnormalities are set and maintained by multiple protein complexes and the interplay between their individual components including DNA methylation machinery, histone modifiers, particularly, polycomb (PcG) proteins, and chromatin remodeling proteins. Recent advances in genome-wide technology have revealed that the involvement of these dysregulated epigenetic components appears to be extensive. Moreover, there is a growing connection between epigenetic abnormalities in cancer and concepts concerning stem-like cell subpopulations as a driving force for cancer. Emerging data suggest that aspects of the epigenetic landscape inherent to normal embryonic and adult stem/ progenitor cells may help foster, under the stress of chronic inflammation or accumulating reactive oxygen species, evolution of malignant subpopulations. Finally, understanding molecular mechanisms involved in initiation and maintenance of epigenetic abnormalities in all types of cancer has great potential for translational purposes. This is already evident for epigenetic biomarker development, and for pharmacological targeting aimed at reversing cancerspecific epigenetic alterations.

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“…(HDACi) are an emerging class of therapeutic agents that induce tumor cell cytostasis, differentiation and apoptosis in various hematologic and solid malignancies (Mercurio et al, 2010;Stimson et al, 2009). They are known to exert their anti-tumor activity by inhibiting the HDACs, which play an important role in controlling gene expression by chromatin remodeling, that affect cell cycle and survival pathways (Stimson et al, 2009).…”

mentioning

confidence: 99%

“…They are known to exert their anti-tumor activity by inhibiting the HDACs, which play an important role in controlling gene expression by chromatin remodeling, that affect cell cycle and survival pathways (Stimson et al, 2009). Inhibitors of histone deacetylases (HDACi) also show promising anti-inflammatory properties as demonstrated in a number of animal and cellular models of inflammatory diseases and for diabetes (Christensen et al, 2011).…”

mentioning

confidence: 99%