Chromatin Accessibility Landscape of Cutaneous T Cell Lymphoma and Dynamic Response to HDAC Inhibitors

Qu, Kun; Zaba, Lisa C.; Satpathy, Ansuman T.; Giresi, Paul G.; Li, Rui; Jin, Yongdong; Armstrong, Randall; Chen, Jin; Schmitt, Nathalie; Rahbar, Ziba; Ueno, Hideki; Greenleaf, William J.; Kim, Youn H.; Chang, Howard Y.

doi:10.1016/j.ccell.2017.05.008

Cited by 146 publications

(140 citation statements)

References 62 publications

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“…We speculate that this differential response to HDACi treatment is related to individual variation in chromatin accessibility. For example, in clinical studies testing the efficacy of HDACi drugs as cancer treatments, the pattern of transcription factor occupancy in cells from individual T‐cell lymphoma patients predicts HDACi treatment efficacy . In responsive patients, HDACi treatment is correlated with a rise in DNA accessibility, whereas non‐responders show negligible changes in accessibility following treatment.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor treatment promotes spontaneous caregiving behaviour in non‐aggressive virgin male mice

Mayer

Crepeau

Duque-Wilckens

et al. 2019

J Neuroendocrinology

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The majority of mammalian species are uniparental, with the mother solely providing care for young conspecifics, although fathering behaviours can emerge under certain circumstances. For example, a great deal of individual variation in response to young pups has been reported in multiple inbred strains of laboratory male mice. Furthermore, sexual experience and subsequent cohabitation with a female conspecific can induce caregiving responses in otherwise indifferent, fearful or aggressive males. Thus, a highly conserved parental neural circuit is likely present in both sexes; however, the extent to which infants are capable of activating this circuit may vary. In support of this idea, fearful or indifferent responses toward pups in female mice are linked to greater immediate early gene (IEG) expression in a fear/defensive circuit involving the anterior hypothalamus compared to that in an approach/attraction circuit involving the ventral tegmental area. However, experience with infants, particularly in combination with histone deacetylase inhibitor (HDACi) treatment, can reverse this pattern of pup‐induced activation of fear/defence circuitry and promote approach behaviour. Thus, HDACi treatment may increase the transcription of primed/poised genes that play a role in the activation and selection of a maternal approach circuit in response to pup stimuli. In the present study, we investigated whether HDACi treatment would impact behavioural response selection and associated IEG expression changes in virgin male mice that are capable of ignoring, attacking or caring for pups. The results obtained indicate that systemic HDACi treatment induces spontaneous caregiving behaviour in non‐aggressive male mice and alters the pattern of pup‐induced IEG expression across a fear/defensive neural circuit.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor treatment promotes spontaneous caregiving behaviour in non‐aggressive virgin male mice

Mayer

Crepeau

Duque-Wilckens

et al. 2019

J Neuroendocrinology

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“…13 Responses were found to be strongly associated with concurrent gains in chromatin accessibility. 13 Responses were found to be strongly associated with concurrent gains in chromatin accessibility.…”

Section: Predictive Biomarkers?mentioning

confidence: 96%

“…Qu et al recently described the chromatin accessibility profiles of CTCL and analyzed the dynamic changes associated with HDACi response and resistance. 13 Responses were found to be strongly associated with concurrent gains in chromatin accessibility. Such profiling assays could be analyzed as predictive biomarkers in future studies.…”

Section: Predictive Biomarkers?mentioning

confidence: 96%

A phase 1 study to assess the safety, tolerability, and pharmacokinetics of CXD101 in patients with advanced cancer

Eyre

Collins

Gupta

et al. 2018

Cancer

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BACKGROUND: In the current study, the authors sought to determine the maximum tolerated dose (MTD) of the novel class 1 selective histone deacetylase inhibitor CXD101 in a dose escalation study in patients with advanced solid tumors or recurrent/refractory lymphoma. METHODS: The authors escalated the dose of CXD101 from 1 mg twice daily orally for 5 days in a 21-day cycle (3+3 design). RESULTS: A total of 39 patients were enrolled, 36 of whom received CXD101. Of the 30 patients in the escalation cohort, 29 were evaluable for determination of the dose-limiting toxicity (DLT). DLTs were noted at doses of 16 mg twice daily (1 of 6 patients), 20 mg twice daily (1 of 6 patients), and 24/25 mg twice daily (2 of 5 patients, both of whom developed neutropenic fever). The MTD was 20 mg twice daily, which achieved maximal plasma concentrations (±standard deviation) of 231 ± 76 nM to 342 ± 126 nM, which was within the biologically active range. Six patients received 20 mg twice daily in an expansion cohort. The most frequent adverse events were fatigue, nausea, and reversible cytopenia. Key grade 3 to 4 adverse events (according to Common Terminology Criteria for Adverse Events criteria [version 4.03]) included thrombocytopenia (11%), neutropenia (17%), and neutropenic fever (2%) across the 133 CXD101 cycles given. The toxicity profile was similar to that of licensing studies with other histone deacetylase inhibitors. In 22 evaluable patients receiving a dose of ≥16 mg twice daily (17 of whom had lymphoma and 5 of whom had solid tumors), 3 partial responses (2 in patients with classic Hodgkin lymphoma after allogenic stem cell transplantation and 1 in a patient with angioimmunoblastic T-cell lymphoma) and 1 complete response (in a patient with follicular lymphoma) were noted (overall response rate of 18%) in addition to 9 patients who achieved durable stable disease. Responses were noted predominantly among patients with lymphoma (tumor reduction noted in 63% of patients on standard computed tomography). CONCLUSIONS: The MTD in the current study was found to be 20 mg twice daily. Encouraging and durable activity was observed in patients with Hodgkin lymphoma, T-cell lymphoma, and follicular lymphoma. Cancer 2019;125:99-108.

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“…For example, researchers have shown that the T cells of the immune system change at the epigenomic level during aging or functional exhaustion 4,5 . The response of certain cancer patients to a drug treatment can be predicted from DNA accessibility of target loci during treatment 6 . Whether a person smokes cigarettes, and thus may be at risk for myriad cancers, can be inferred from DNA methylation patterns 7 .…”

Section: To the Editormentioning

confidence: 99%

Challenges and recommendations for epigenomics in precision health

et al. 2017

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Chromatin Accessibility Landscape of Cutaneous T Cell Lymphoma and Dynamic Response to HDAC Inhibitors

Cited by 146 publications

References 62 publications

Histone deacetylase inhibitor treatment promotes spontaneous caregiving behaviour in non‐aggressive virgin male mice

Histone deacetylase inhibitor treatment promotes spontaneous caregiving behaviour in non‐aggressive virgin male mice

A phase 1 study to assess the safety, tolerability, and pharmacokinetics of CXD101 in patients with advanced cancer

Challenges and recommendations for epigenomics in precision health

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