Epigenetic therapy: Research progress of decitabine in the treatment of solid tumors

Ye, Chenlin; Jiang, Nan; Zheng, Jing; Zhang, Shumeng; Zhang, Jingchen; Zhou, Jianya

doi:10.1016/j.bbcan.2023.189066

Cited by 4 publications

(2 citation statements)

References 118 publications

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“…The RNA sequencing data were normalized by taking the log10 ratio of expression of the sample compared to the average expression of the gene across all samples. The L-score genes are described in (8); the S-score genes are described in (9). The top KRAS-dependent genes were selected as "up" genes, and the top KRASindependent genes were selected as "down" genes.…”

Section: Kras Dependency Signature Score Calculation Methodsmentioning

confidence: 99%

“…Decitabine (5-Aza-2-deoxycytidine, DEC) is approved to treat myelodysplastic syndromes and acute myeloid leukemia. Its anticancer activity has been considered in other clinical settings, with more than fifty clinical trials testing the repurposing of DEC alone or in combination with chemotherapies or immunotherapies for treating solid tumors, including breast, ovarian, colon, lung, pancreatic cancers, and sarcoma 8,9 . However, DEC treatment is associated with severe hematological toxicity in approximately 30% of cases, including G3/4 febrile neutropenia.…”

Section: Introductionmentioning

confidence: 99%

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Enhancing PDAC Therapy: Decitabine-Olaparib Synergy Targets KRAS-Dependent Tumors

Anastasio,

Felaco,

Lamolinara

et al. 2024

Preprint

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SUMMARYCurrent chemotherapies provide limited clinical benefits to patients with pancreatic ductal adenocarcinoma (PDAC), partly due to the lack of effective biomarkers for personalized therapy. KRAS activating mutations occur in almost 90% of PDAC cases, leading to a subset of tumorsdependent onKRASfor survival (dKRAS). Assessing dKRAS in PDAC can be achieved using gene expression signature scores, independent of specific KRAS mutations, allowing for personalized therapies. Previous studies have shown that dKRAS-PDAC cells are more sensitive to the FDA-approved drug decitabine (DEC), although the mechanism remains unclear. While DEC is approved for hematological tumors, its repurposing in solid tumors poses challenges due to high-dose hematological side effects. Identifying optimal pharmacological approaches and response biomarkers is crucial for the successful clinical implementation of DEC in PDAC and other solid tumors. Our investigation revealed that low-dose DEC combined with the PARP inhibitor olaparib (OLA) enhances antitumor activity in dKRAS-PDAC. Mechanistically, DEC induces DNA damage and activates an ATR/ATM-mediated DNA damage response (DDR), with PARP1-mediated DNA repair playing a crucial role. Inhibiting PARP activity with OLA enhances antitumor activity, even inBRCA1/2wild-typeand homologous recombination (HR)-proficient tumors, but it is ineffective in KRAS-independent tumors. Thus, transcriptomic-based KRAS dependency scores effectively predict the efficacy of combined therapy. Additionally, in dKRAS-PDAC tumors carrying aBRCA2mutation, low-dose DEC enhances OLA’s antitumor activity, completely inhibiting metastasis growth compared to single-drug treatments. Our findings support further clinical evaluation of DEC+OLA combination therapy in PDAC, particularly in dKRAS-positive tumors, irrespective of BRCA1/2 status. This approach extends the clinical benefit of OLA beyond BRCA status, addressing a limitation in targeted PARP inhibitor therapies. Furthermore, we highlight DDR as a key mechanism of action for DEC, beyond its role in gene expression regulation, underscoring the mode of action of this widely used anticancer drug.

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Section: Kras Dependency Signature Score Calculation Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancing PDAC Therapy: Decitabine-Olaparib Synergy Targets KRAS-Dependent Tumors

Anastasio,

Felaco,

Lamolinara

et al. 2024

Preprint

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Unfolding the complexity of epigenetics in male reproductive aging: a review of therapeutic implications

Ajayi,

Oyovwi,

Olatinwo

et al. 2024

Mol Biol Rep

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Epigenetics-targeted drugs: current paradigms and future challenges

Dai,

Qiao,

Fang

et al. 2024

Sig Transduct Target Ther

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Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifying enzymes in pathological conditions. Over the past two decades, a growing array of small molecule drugs targeting epigenetic enzymes such as DNA methyltransferase, histone deacetylase, isocitrate dehydrogenase, and enhancer of zeste homolog 2, have been thoroughly investigated and implemented as therapeutic options, particularly in oncology. Additionally, numerous epigenetics-targeted drugs are undergoing clinical trials, offering promising prospects for clinical benefits. This review delineates the roles of epigenetics in physiological and pathological contexts and underscores pioneering studies on the discovery and clinical implementation of epigenetics-targeted drugs. These include inhibitors, agonists, degraders, and multitarget agents, aiming to identify practical challenges and promising avenues for future research. Ultimately, this review aims to deepen the understanding of epigenetics-oriented therapeutic strategies and their further application in clinical settings.

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Epigenetic therapy: Research progress of decitabine in the treatment of solid tumors

Cited by 4 publications

References 118 publications

Enhancing PDAC Therapy: Decitabine-Olaparib Synergy Targets KRAS-Dependent Tumors

Enhancing PDAC Therapy: Decitabine-Olaparib Synergy Targets KRAS-Dependent Tumors

Unfolding the complexity of epigenetics in male reproductive aging: a review of therapeutic implications

Epigenetics-targeted drugs: current paradigms and future challenges

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