Epi‐immunotherapy for cancers: rationales of epi‐drugs in combination with immunotherapy and advances in clinical trials

Xu, Yang; Li, Ping; Liu, Yang; Xin, Dijia; Lei, Wen; Liang, Aibin; Han, Weidong

doi:10.1002/cac2.12313

Cited by 16 publications

(6 citation statements)

References 236 publications

(323 reference statements)

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“…Clinical trials are necessary to assess the safety and efficacy of epi-drug therapies in human patients. 237 Research in this area involves designing and conducting clinical trials that consider factors such as patient selection, dosing regimens, and end points to measure treatment response. 238 Long-term follow-up is often required to evaluate the durability of treatment effects and any potential late side effects.…”

Section: Variability With Drug Administration Strategiesmentioning

confidence: 99%

“…While many promising preclinical studies have shown the potential of epigenetic therapies, rigorous clinical validation is essential. Clinical trials are necessary to assess the safety and efficacy of epi-drug therapies in human patients . Research in this area involves designing and conducting clinical trials that consider factors such as patient selection, dosing regimens, and end points to measure treatment response .…”

Section: Future Prospects Of Epi-drug Therapymentioning

confidence: 99%

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Advances in the Delivery and Development of Epigenetic Therapeutics for the Treatment of Cancer

Ghosh,

Himaja,

Biswas

et al. 2023

Mol. Pharmaceutics

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Gene expression at the transcriptional level is altered by epigenetic modifications such as DNA methylation, histone methylation, and acetylation, which can upregulate, downregulate, or entirely silence genes. Pathological dysregulation of epigenetic processes can result in the development of cancer, neurological problems, metabolic disorders, and cardiovascular diseases. It is of promising therapeutic interest to find medications that target these epigenetic alterations. Despite the enormous amount of work that has been done in this area, very few molecules have been approved for clinical purposes. This article provides a comprehensive review of recent advances in epigenetic therapeutics for cancer, with a specific focus on emerging delivery and development strategies. Various delivery systems, including prodrugs, conjugated molecules, nanoparticles (NPs), and liposomes, as well as remedial strategies such as combination therapies, and epigenetic editing, are being investigated to improve the efficacy and specificity of epigenetic drugs (epi-drugs). Furthermore, the challenges associated with available epi-drugs and the limitations of their translation into clinics have been discussed. Target selection, isoform selectivity, physiochemical properties of synthesized molecules, drug screening, and scalability of epi-drugs from preclinical to clinical fields are the major shortcomings that are addressed. This Review discusses novel strategies for the identification of new biomarkers, exploration of the medicinal chemistry of epigenetic modifiers, optimization of the dosage regimen, and design of proper clinical trials that will lead to better utilization of epigenetic modifiers over conventional therapies. The integration of these approaches holds great potential for improving the efficacy and precision of epigenetic treatments, ultimately benefiting cancer patients.

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Section: Variability With Drug Administration Strategiesmentioning

confidence: 99%

Section: Future Prospects Of Epi-drug Therapymentioning

confidence: 99%

Advances in the Delivery and Development of Epigenetic Therapeutics for the Treatment of Cancer

Ghosh,

Himaja,

Biswas

et al. 2023

Mol. Pharmaceutics

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“…The restoration of IRF1 and IRF7 expression with AZA-analogous decitabine reactivated PD-L1 expression, and in a mouse model, a concomitant enhanced efficiency of anti-PD-1 therapy was observed [ 21 ]. In line with these results, clinical trials are testing the anti-PD-1 antibody pembrolizumab combined with demethylation agents to further examine the potential of sensitizing NSCLC patients to PD-1/PD-L1 axis immunotherapy [ 46 ].…”

Section: Introductionmentioning

confidence: 99%

Examination of the Functional Relationship between PD-L1 DNA Methylation and mRNA Expression in Non-Small-Cell Lung Cancer

Larsen

Dybdal

Daugaard

et al. 2023

Cancers

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Immunotherapy targeting the interaction between programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) is a treatment option for patients with non-small-cell lung cancer (NSCLC). The expression of PD-L1 by the NSCLC cells determines treatment effectiveness, but the relationship between PD-L1 DNA methylation and expression has not been clearly described. We investigated PD-L1 DNA methylation, mRNA expression, and protein expression in NSCLC cell lines and tumor biopsies. We used clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) to modify PD-L1 genetic contexts and endonuclease deficient Cas9 (dCas9) fusions with ten-eleven translocation methylcytosine dioxygenase 1 (TET1) and DNA (cytosine-5)-methyltransferase 3A (DNMT3A) to manipulate PD-L1 DNA methylation. In NSCLC cell lines, we identified specific PD-L1 CpG sites with methylation levels inversely correlated with PD-L1 mRNA expression. However, inducing PD-L1 mRNA expression with interferon-γ did not decrease the methylation level for these CpG sites, and using CRISPR-Cas9, we found that the CpG sites did not directly confer a negative regulation. dCas9-TET1 and dCas9-DNMT3A could induce PD-L1 hypo- and hyper-methylation, respectively, with the latter conferring a decrease in expression showing the functional impact of methylation. In NSCLC biopsies, the inverse correlation between the methylation and expression of PD-L1 was weak. We conclude that there is a regulatory link between PD-L1 DNA methylation and expression. However, since these measures are weakly associated, this study highlights the need for further research before PD-L1 DNA methylation can be implemented as a biomarker and drug target for measures to improve the effectiveness of PD-1/PD-L1 immunotherapy in NSCLC.

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“…Epidrugs are alternative strategies for a more personalized tumor treatment because they might sensitize tumors to immune checkpoint inhibitors and cell therapy, besides their effect on viral mimicry response and immune cell activation. Currently, several clinical trials on different tumor types are ongoing using epidrugs alone or in combination with other immunotherapy drugs ( Xu et al, 2022 ). There are different approaches regarding the use of epidrugs in cancer treatment, such as DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors HDACi, and bromodomain and extra-terminal motif inhibitors BETi.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic reprogramming in cancer: From diagnosis to treatment

Costa

Sales

Pinheiro

et al. 2023

Front. Cell Dev. Biol.

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Disruption of the epigenetic program of gene expression is a hallmark of cancer that initiates and propagates tumorigenesis. Altered DNA methylation, histone modifications and ncRNAs expression are a feature of cancer cells. The dynamic epigenetic changes during oncogenic transformation are related to tumor heterogeneity, unlimited self-renewal and multi-lineage differentiation. This stem cell-like state or the aberrant reprogramming of cancer stem cells is the major challenge in treatment and drug resistance. Given the reversible nature of epigenetic modifications, the ability to restore the cancer epigenome through the inhibition of the epigenetic modifiers is a promising therapy for cancer treatment, either as a monotherapy or in combination with other anticancer therapies, including immunotherapies. Herein, we highlighted the main epigenetic alterations, their potential as a biomarker for early diagnosis and the epigenetic therapies approved for cancer treatment.

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Epi‐immunotherapy for cancers: rationales of epi‐drugs in combination with immunotherapy and advances in clinical trials

Cited by 16 publications

References 236 publications

Advances in the Delivery and Development of Epigenetic Therapeutics for the Treatment of Cancer

Advances in the Delivery and Development of Epigenetic Therapeutics for the Treatment of Cancer

Examination of the Functional Relationship between PD-L1 DNA Methylation and mRNA Expression in Non-Small-Cell Lung Cancer

Epigenetic reprogramming in cancer: From diagnosis to treatment

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