Predicting response to epigenetic therapy

Treppendahl, Marianne Bach; Kristensen, Lasse Sommer; Grønbæk, Kirsten

doi:10.1172/jci69737

Cited by 78 publications

(68 citation statements)

References 85 publications

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“…Decitabine (5‐aza‐2′‐deoxycytidine) is the only HMA approved by the China Food and Drug Administration. The concentration required to reverse tumor‐specific DNA methylation is much lower than that needed to produce maximal cytotoxicity 18, 19, 20. The apparent reversibility of resistance by epigenetic interference has the potential to turn the arrow of time backwards, replacing progression with regression, and thus provides a good rational for the use of low‐dose decitabine as an antidote to the resistance to current standard chemotherapies and as a blueprint to significantly extend patient survival 11, 16, 17…”

Section: Introductionmentioning

confidence: 99%

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Chen

Nie

Liu

et al. 2018

Intl Journal of Cancer

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The pressing need for improved therapeutic outcomes provides a good rationale for identifying effective strategies for alimentary tract (AT) cancer treatment. The potential re‐sensitivity property to chemo‐ and immunotherapy of low‐dose decitabine has been evident both preclinically and in previous phase I trials. We conducted a phase Ib/II trial evaluating low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory (R/R) esophageal, gastric or colorectal cancers. Forty‐five patients received either the 5‐day decitabine treatment with subsequent readministration of the previously resistant chemotherapy (decitabine‐primed chemotherapy, D‐C cohort) or the aforementioned regimen followed by cytokine‐induced killer cells therapy (D‐C and cytokine‐induced killer [CIK] cell treatment, D‐C + CIK cohort) based on their treatment history. Grade 3 to 4 adverse events (AEs) were reported in 11 (24.4%) of 45 patients. All AEs were controllable, and no patient experienced a treatment‐related death. The objective response rate (ORR) and disease control rate (DCR) were 24.44% and 82.22%, respectively, including two patients who achieved durable complete responses. Clinical response could be associated with treatment‐free interval and initial surgical resection history. ORR and DCR reached 28% and 92%, respectively, in the D‐C + CIK cohort. Consistently, the progression‐free survival (PFS) of the D‐C + CIK cohort compared favorably to the best PFS of the pre‐resistant unprimed therapy (p = 0.0001). The toxicity and ORRs exhibited were non‐significantly different between cancer types and treatment cohort. The safety and efficacy of decitabine‐primed re‐sensitization to chemoimmunotherapy is attractive and promising. These data warrant further large‐scale evaluation of drug‐resistant R/R AT cancer patients with advanced stage disease.

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Section: Introductionmentioning

confidence: 99%

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Chen

Nie

Liu

et al. 2018

Intl Journal of Cancer

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“…However, despite some successful clinical paradigms, lack of consistent clinical efficacy, off-target effects and toxicity and the incomplete understanding of mechanisms of action, have raised scepticism around the concept of 'epigenetic' therapy [Grant, 2009;Griffiths and Gore, 2013;Treppendahl et al 2014].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence

Chaidos

Caputo

Karadimitris

2015

Therapeutic Advances in Hematology

144

104

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Post-translational modifications of the nucleosomal histone proteins orchestrate chromatin organization and gene expression in normal and cancer cells. Among them, the acetylation of N-terminal histone tails represents the fundamental epigenetic mark of open structure chromatin and active gene transcription. The bromodomain and extra-terminal (BET) proteins are epigenetic readers which utilize tandem bromodomains (BRD) modules to recognize and dock themselves on the acetylated lysine tails. The BET proteins act as scaffolds for the recruitment of transcription factors and chromatin organizers required in transcription initiation and elongation. The recent discovery of small molecules capable of blocking their lysine-binding pocket is the first paradigm of successful pharmacological inhibition of epigenetic readers. JQ1 is a prototype benzodiazepine molecule and a specific BET inhibitor with antineoplastic activity both in solid tumours and haematological malignancies. The quinolone I-BET151 and the suitable for clinical development I-BET762 benzodiazepine were introduced in parallel with JQ1 and have also shown potent antitumour activity in preclinical studies. I-BET762 is currently being tested in early phase clinical trials, along with a rapidly growing list of other BET inhibitors. Unlike older epigenetic therapies, the study of BET inhibitors has offered substantial, context-specific, mechanistic insights of their antitumour activity, which will facilitate optimal therapeutic targeting in future. Here, we review the development of this novel class of epigenetic drugs, the biology of BET protein inhibition, the emerging evidence from preclinical work and early phase clinical studies and we discuss their potential role in the treatment of haematological malignancies.

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“…10,11,33 Thus, it is vital to understand the site-specific and global factors influencing DNA demethylation and remethylation kinetics as this may provide insight into the mechanisms of drug action and potentially differential responses, which have thus far been difficult to predict. 30 Our data indicate that CpGs across the genome differ in both their susceptibility to DAC-induced demethylation as well as their propensity for remethylation after drug removal. We find that CpG islands are not the major targets of DACinduced demethylation, in line with their low initial methylation, and consistent with the observation that few transcriptional changes in DAC treatment are explained by relief of promoter CGI hypermethylation.…”

Section: Discussionmentioning

confidence: 70%

“…29,30 A number of mechanisms have been proposed to account for the antitumor activity of DNA methyltransferase inhibitors, including the reactivation of cancer testes antigens stimulating an immune response, 31 reactivation of silenced tumor suppressor genes, repression of oncogenes through loss of gene body methylation, 10 and most recently, the activation endogenous retroviruses, leading to the cytoplasmic accumulation of double-stranded RNAs and the triggering of an antiviral interferon response. 32,33 In solid tumor model systems low-dose DAC treatment has been shown to result in prolonged demethylation and a sustained, heritable inhibition of the tumorigenic potential of cancer-initiating/ stem-like populations.…”

Section: Discussionmentioning

confidence: 99%

Factors affecting the persistence of drug-induced reprogramming of the cancer methylome

et al. 2016

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Aberrant DNA methylation is a critical feature of cancer. Epigenetic therapy seeks to reverse these changes to restore normal gene expression. DNA demethylating agents, including 5-aza-2 0 -deoxycytidine (DAC), are currently used to treat certain leukemias, and can sensitize solid tumors to chemotherapy and immunotherapy. However, it has been difficult to pin the clinical efficacy of these agents to specific demethylation events, and the factors that contribute to the durability of response remain largely unknown. Here we examined the genome-wide kinetics of DAC-induced DNA demethylation and subsequent remethylation after drug withdrawal in breast cancer cells. We find that CpGs differ in both their susceptibility to demethylation and propensity for remethylation after drug removal. DAC-induced demethylation was most apparent at CpGs with higher initial methylation levels and further from CpG islands. Once demethylated, such sites exhibited varied remethylation potentials. The most rapidly remethylating CpGs regained >75% of their starting methylation within a month of drug withdrawal. These sites had higher pretreatment methylation levels, were enriched in gene bodies, marked by H3K36me3, and tended to be methylated in normal breast cells. In contrast, a more resistant class of CpG sites failed to regain even 20% of their initial methylation after 3 months. These sites had lower pretreatment methylation levels, were within or near CpG islands, marked by H3K79me2 or H3K4me2/3, and were overrepresented in sites that become aberrantly hypermethylated in breast cancers. Thus, whereas DAC-induced demethylation affects both endogenous and aberrantly methylated sites, tumorspecific hypermethylation is more slowly regained, even as normal methylation promptly recovers. Taken together, these data suggest that the durability of DAC response is linked to its selective ability to stably reset at least a portion of the cancer methylome.

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Predicting response to epigenetic therapy

Cited by 78 publications

References 85 publications

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence

Factors affecting the persistence of drug-induced reprogramming of the cancer methylome

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