Epigenetics in Pancreatic Ductal Adenocarcinoma: Impact on Biology and Utilization in Diagnostics and Treatment

Elrakaybi, Asmaa; Ruess, Dietrich Alexander; Lübbert, Michael; Quante, Michael; Becker, Heiko

doi:10.3390/cancers14235926

Cited by 9 publications

(8 citation statements)

References 191 publications

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“…Additionally, the understudied epigenetic modifications, including histone modifications, were highlighted as potential biomarkers for PDAC by Elrakaybi et al [ 92 ]. However, investigations of biomarkers and treatments focusing on epigenetic modifications still require integration with clinical data to identify patients who will benefit from a given treatment.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Ductal Adenocarcinoma (PDAC): A Review of Recent Advancements Enabled by Artificial Intelligence

Mukund,

Afridi,

Karolak

et al. 2024

Cancers

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Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most formidable challenges in oncology, characterized by its late detection and poor prognosis. Artificial intelligence (AI) and machine learning (ML) are emerging as pivotal tools in revolutionizing PDAC care across various dimensions. Consequently, many studies have focused on using AI to improve the standard of PDAC care. This review article attempts to consolidate the literature from the past five years to identify high-impact, novel, and meaningful studies focusing on their transformative potential in PDAC management. Our analysis spans a broad spectrum of applications, including but not limited to patient risk stratification, early detection, and prediction of treatment outcomes, thereby highlighting AI’s potential role in enhancing the quality and precision of PDAC care. By categorizing the literature into discrete sections reflective of a patient’s journey from screening and diagnosis through treatment and survivorship, this review offers a comprehensive examination of AI-driven methodologies in addressing the multifaceted challenges of PDAC. Each study is summarized by explaining the dataset, ML model, evaluation metrics, and impact the study has on improving PDAC-related outcomes. We also discuss prevailing obstacles and limitations inherent in the application of AI within the PDAC context, offering insightful perspectives on potential future directions and innovations.

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Section: Discussionmentioning

confidence: 99%

Pancreatic Ductal Adenocarcinoma (PDAC): A Review of Recent Advancements Enabled by Artificial Intelligence

Mukund,

Afridi,

Karolak

et al. 2024

Cancers

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“…Pancreatic ductal adenocarcinoma (PDAC) is the most common subtype of pancreatic cancer representing one of the most lethal cancers with a 5-year survival rate of less than 11% [ 1 , 2 ]. PDAC displays a large cellular heterogeneity including a highly fibrotic and immunosuppressive tumor microenvironment (TME) [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Histone Deacetylase (HDAC) Inhibitor Induces Apoptosis and Suppresses Invasion via E-Cadherin Upregulation in Pancreatic Ductal Adenocarcinoma (PDAC)

Schiedlauske,

Deipenbrock,

Pflieger

et al. 2024

Pharmaceuticals

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Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer characterized by therapy resistance and early metastasis, resulting in a low survival rate. Histone deacetylase (HDAC) inhibitors showed potential for the treatment of hematological malignancies. In PDAC, the overexpression of HDAC 2 is associated with the epithelial–mesenchymal transition (EMT), principally accompanied by the downregulation of the epithelial marker E-cadherin and increased metastatic capacity. The effector cytokine transforming growth factor-β (TGF β) is known to be a major inducer of the EMT in PDAC, leading to high metastatic and invasive potential. In addition, the overexpression of HDAC 6 in PDAC is associated with reduced apoptosis. Here, we have demonstrated that a novel HDAC 2/6 inhibitor not only significantly increased E-cadherin expression in PANC-1 cells (5.5-fold) and in 3D PDAC co-culture spheroids (2.5-fold) but was also able to reverse the TGF-β-induced downregulation of E-cadherin expression. Moreover, our study indicates that the HDAC inhibitor mediated re-differentiation resulting in a significant inhibition of tumor cell invasion by approximately 60% compared to control. In particular, we have shown that the HDAC inhibitor induces both apoptosis (2-fold) and cell cycle arrest. In conclusion, the HDAC 2/6 inhibitor acts by suppressing invasion via upregulating E-cadherin mediated by HDAC 2 blockade and by inducing cell cycle arrest leading to apoptosis via HDAC 6 inhibition. These results suggest that the HDAC 2/6 inhibitor might represent a novel therapeutic strategy for the treatment of PDAC tumorigenesis and metastasis.

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“…1 The highly proliferative and invasive PDAC epithelial cells rely on frequently mutated drivers and tumor suppressors including KRAS, TP53, CDKN2A, and SMAD4, which disrupt transcriptional regulatory elements and mRNA translation in favor of malignant proliferation. [2][3][4][5][6]7 This raises the question of whether targeting factors involved in transcription and translation such as MYC, 8 histone deacetylases, 9,10 or the components of the eukaryotic initiation factor 4F (eIF4F) complex, such as eIF4E or eIF4A could be of value in PDAC. 11,12 Histone deacetylases (HDACs) and histone acetyl transferases (HATs) play a crucial role in regulating the levels of histone acetylation that impact gene expression 9 .…”

Section: Introductionmentioning

confidence: 99%

Combined HDAC and eIF4A inhibition: A novel epigenetic therapy for pancreatic adenocarcinoma

Safari,

Scotto,

Basseville

et al. 2024

Preprint

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Pancreatic ductal adenocarcinoma-(PDAC) needs innovative approaches due to its 12% 5-year survival despite current therapies. We show marked sensitivity of pancreatic cancer cells to the combination of a novel eIF4A inhibitor, des-methyl pateamine A (DMPatA), and a histone deacetylase inhibitor, romidepsin, inducing epigenetic reprogramming as an innovative therapeutic strategy. Exploring the mechanistic activity of this combination showed that with a short duration of romidepsin at low doses, robust acetylation persisted up to 48h with the combination, while histone acetylation rapidly faded with monotherapy. This represents an unexpected mechanism of action against PDAC cells that triggers transcriptional overload, metabolic stress, and augmented DNA damage. Structurally different class I HDAC inhibitors exhibit the same hyperacetylation patterns when co-administered with DMPatA, suggesting a class effect. We show efficacy of this combination regimen against tumor growth in a MIA PaCa-2 xenograft model of PDAC with persistent hyperacetylation confirmed in tumor samples.STATEMENT OF SIGNIFICANCEPancreatic ductal adenocarcinoma, a significant clinical challenge, could benefit from the latent potential of epigenetic therapies like HDAC inhibitors-(HDIs), typically limited to hematological malignancies. Our study shows that a synergistic low dose combination of HDIs with an eIF4A-inhibitor in pancreatic cancer models results in marked pre-clinical efficacy, offering a promising new treatment strategy.

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Epigenetics in Pancreatic Ductal Adenocarcinoma: Impact on Biology and Utilization in Diagnostics and Treatment

Cited by 9 publications

References 191 publications

Pancreatic Ductal Adenocarcinoma (PDAC): A Review of Recent Advancements Enabled by Artificial Intelligence

Pancreatic Ductal Adenocarcinoma (PDAC): A Review of Recent Advancements Enabled by Artificial Intelligence

Novel Histone Deacetylase (HDAC) Inhibitor Induces Apoptosis and Suppresses Invasion via E-Cadherin Upregulation in Pancreatic Ductal Adenocarcinoma (PDAC)

Combined HDAC and eIF4A inhibition: A novel epigenetic therapy for pancreatic adenocarcinoma

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