Emerging therapeutic targets in human acute myeloid leukemia (part 2) – bromodomain inhibition should be considered as a possible strategy for various patient subsets

Reikvam, Håkon; Hoang, Tuyen; Bruserud, Øystein

doi:10.1586/17474086.2015.1036025

Cited by 9 publications

(4 citation statements)

References 99 publications

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“…Bromodomain-mediated interactions have key roles in transcriptional regulation and their dysfunction is implicated in a large number of diseases including cancer [183–185], atherosclerosis [186] and diabetes [187]. …”

Section: Histone Acetyltransferase (Hat) Assaysmentioning

confidence: 99%

Epigenetic assays for chemical biology and drug discovery

Gul

2017

Clin Epigenet

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The implication of epigenetic abnormalities in many diseases and the approval of a number of compounds that modulate specific epigenetic targets in a therapeutically relevant manner in cancer specifically confirms that some of these targets are druggable by small molecules. Furthermore, a number of compounds are currently in clinical trials for other diseases including cardiovascular, neurological and metabolic disorders. Despite these advances, the approved treatments for cancer only extend progression-free survival for a relatively short time and being associated with significant side effects. The current clinical trials involving the next generation of epigenetic drugs may address the disadvantages of the currently approved epigenetic drugs.The identification of chemical starting points of many drugs often makes use of screening in vitro assays against libraries of synthetic or natural products. These assays can be biochemical (using purified protein) or cell-based (using for example, genetically modified, cancer cell lines or primary cells) and performed in microtiter plates, thus enabling a large number of samples to be tested. A considerable number of such assays are available to monitor epigenetic target activity, and this review provides an overview of drug discovery and chemical biology and describes assays that monitor activities of histone deacetylase, lysine-specific demethylase, histone methyltransferase, histone acetyltransferase and bromodomain. It is of critical importance that an appropriate assay is developed and comprehensively validated for a given drug target prior to screening in order to improve the probability of the compound progressing in the drug discovery value chain.

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Section: Histone Acetyltransferase (Hat) Assaysmentioning

confidence: 99%

Epigenetic assays for chemical biology and drug discovery

Gul

2017

Clin Epigenet

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“…The possibilities of combining CK2 inhibition with other antileukemic treatments are discussed in Section 8. Recent experimental studies of the effects of CK2 suggest that other combined strategies may also become relevant, e.g., combination with bromodomain inhibitors or other epigenetic strategies [126][127][128][129], targeting of AML cell metabolism [130,131], or targeting of CK2 regulators [132].…”

Section: General Discussion: the Need For Further Studies Of Silmitas...mentioning

confidence: 99%

Casein Kinase 2 (CK2): A Possible Therapeutic Target in Acute Myeloid Leukemia

Bruserud

Reikvam

2023

Cancers

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The protein kinase CK2 (also known as casein kinase 2) is one of the main contributors to the human phosphoproteome. It is regarded as a possible therapeutic strategy in several malignant diseases, including acute myeloid leukemia (AML), which is an aggressive bone marrow malignancy. CK2 is an important regulator of intracellular signaling in AML cells, especially PI3K–Akt, Jak–Stat, NFκB, Wnt, and DNA repair signaling. High CK2 levels in AML cells at the first time of diagnosis are associated with decreased survival (i.e., increased risk of chemoresistant leukemia relapse) for patients receiving intensive and potentially curative antileukemic therapy. However, it is not known whether these high CK2 levels can be used as an independent prognostic biomarker because this has not been investigated in multivariate analyses. Several CK2 inhibitors have been developed, but CX-4945/silmitasertib is best characterized. This drug has antiproliferative and proapoptotic effects in primary human AML cells. The preliminary results from studies of silmitasertib in the treatment of other malignancies suggest that gastrointestinal and bone marrow toxicities are relatively common. However, clinical AML studies are not available. Taken together, the available experimental and clinical evidence suggests that the possible use of CK2 inhibition in the treatment of AML should be further investigated.

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“…For these patients leukemia-stabilizing treatment is possible, but the effect of such treatment varies between patients and many of them have a short survival of only a few months [ 17 , 18 , 19 , 20 ]. Furthermore, during the last decade, the biological heterogeneity with regard to leukemogenesis and chemosensitivity in AML has been extensively studied and many possible therapeutic strategies have been suggested based on experimental in vitro and in vivo studies [ 21 , 22 , 23 ]. However, even though four different approaches were recently approved for AML treatment, these strategies included more optimal use of well-known drugs or drugs that can be used only for subsets of patients [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].…”

Section: Aml Heterogeneity and Prognostic Evaluationmentioning

confidence: 99%

The Implementation of Mass Spectrometry-Based Proteomics Workflows in Clinical Routines of Acute Myeloid Leukemia: Applicability and Perspectives

Hernandez-Valladares

Bruserud

Selheim

2020

IJMS

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With the current reproducibility of proteome preparation workflows along with the speed and sensitivity of the mass spectrometers, the transition of the mass spectrometry (MS)-based proteomics technology from biomarker discovery to clinical implementation is under appraisal in the biomedicine community. Therefore, this technology might be implemented soon to detect well-known biomarkers in cancers and other diseases. Acute myeloid leukemia (AML) is an aggressive heterogeneous malignancy that requires intensive treatment to cure the patient. Leukemia relapse is still a major challenge even for patients who have favorable genetic abnormalities. MS-based proteomics could be of great help to both describe the proteome changes of individual patients and identify biomarkers that might encourage specific treatments or clinical strategies. Herein, we will review the advances and availability of the MS-based proteomics strategies that could already be used in clinical proteomics. However, the heterogeneity of complex diseases as AML requires consensus to recognize AML biomarkers and to establish MS-based workflows that allow their unbiased identification and quantification. Although our literature review appears promising towards the utilization of MS-based proteomics in clinical AML in a near future, major efforts are required to validate AML biomarkers and agree on clinically approved workflows.

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Emerging therapeutic targets in human acute myeloid leukemia (part 2) – bromodomain inhibition should be considered as a possible strategy for various patient subsets

Cited by 9 publications

References 99 publications

Epigenetic assays for chemical biology and drug discovery

Epigenetic assays for chemical biology and drug discovery

Casein Kinase 2 (CK2): A Possible Therapeutic Target in Acute Myeloid Leukemia

The Implementation of Mass Spectrometry-Based Proteomics Workflows in Clinical Routines of Acute Myeloid Leukemia: Applicability and Perspectives

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