Logic-based modeling and drug repurposing for the prediction of novel therapeutic targets and combination regimens against E2F1-driven melanoma progression DOI Creative Commons
Nivedita Singh,

Faiz M. Khan,

Lakshmi Bala

et al.

BMC Chemistry, Journal Year: 2023, Volume and Issue: 17(1)

Published: Nov. 22, 2023

Abstract Melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 activation downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation E2F1-governed GRNs holds potential prevent metastasis however, these entail complex feedback feedforward motifs among various layers, which make it difficult identify druggable components. To this end, computational approaches such as mathematical modeling virtual screening are important tools unveil dynamics signaling critical components that could be further explored targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells reconstruct core network underlying melanoma. Using logic-based in silico perturbation experiments network, identified simultaneous Protein kinase B (AKT1) oncoprotein murine double minute 2 (MDM2) drastically reduces EMT structures two protein signatures, strategies were performed FDA-approved drug library. Furthermore, combining repurposing computer-aided design techniques, followed molecular simulation analysis, potent drugs (Tadalafil Finasteride) can efficiently inhibit AKT1 MDM2 proteins. We propose considered for development management Graphical abstract

Language: Английский

Advances in Melanoma: From Genetic Insights to Therapeutic Innovations DOI Creative Commons
Fernando Valdez-Salazar,

Luis Alberto Jiménez-Del Río,

Jorge Ramón Padilla‐Gutiérrez

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(8), P. 1851 - 1851

Published: Aug. 14, 2024

Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between alterations, such as mutations BRAF, NRAS, KIT, pathogenesis. The MAPK PI3K/Akt/mTOR signaling pathways are highlighted for their roles tumor growth resistance mechanisms. Additionally, this delves impact of epigenetic modifications, including DNA methylation histone changes, on progression. microenvironment, characterized by immune cells, stromal soluble factors, plays a pivotal role modulating behavior treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, AI-driven diagnostics transforming research, offering precise personalized approaches treatment. Immunotherapy, particularly checkpoint inhibitors mRNA vaccines, has revolutionized therapy enhancing body’s response. Despite these advances, mechanisms remain challenge, underscoring need combined therapies ongoing achieve durable comprehensive overview aims highlight current state transformative impacts advancements clinical practice.

Language: Английский

Citations

7
Circulating Tumor Cells: Origin, Role, Current Applications, and Future Perspectives for Personalized Medicine DOI Creative Commons

Maria Cristina Rapanotti,

Tonia Cenci, Maria Giovanna Scioli

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(9), P. 2137 - 2137

Published: Sept. 20, 2024

Circulating tumor cells (CTCs) currently represent a revolutionary tool offering unique insights for the evaluation of cancer progression, metastasis, and response to therapies. Indeed, CTCs, upon detachment from primary tumors, enter bloodstream acquire great potential their use personalized management. In this review, we describe current understanding advances in clinical employment CTCs. Although considered rare fleeting, CTCs are now recognized as key players favoring development metastasis disease recurrence, particularly malignant melanoma, lung, breast, colorectal patients. To date, advancements technology several successful approaches, also including immunomagnetic enrichment allow reliable reproducible detection characterization Those innovative methodologies improved isolation, quantification, blood patients, providing extremely useful evidence new into nature tumor, its epithelial/mesenchymal profile, resistance therapy. fact, addition prognostic predictive value, could serve valuable instrument real-time monitoring treatment facilitating timely interventions thus improving patient outcomes. However, despite potential, challenges hinder widespread utility CTCs: (i) CTCs’ rarity heterogeneity pose technical limitations isolation characterization, well significant hurdles implementation; (ii) it is mandatory standardize CTC methods, optimize sample processing techniques, integrate them with existing diagnostic modalities; (iii) need such single-cell analysis platforms, enhance sensitivity specificity detection, thereby integration routine practice. conclusion, extraordinary diagnostics therapeutics, unprecedented opportunities medicine precision oncology. Moreover, ability provide biology, response, progression underlines application improve patients’ outcomes advance our biology.

Language: Английский

Citations

4
The Clinical Relevance of Epithelial-to-Mesenchymal Transition Hallmarks: A Cut-Off-Based Approach in Healthy and Cancerous Cell Lines DOI Open Access

Maria Cristina Rapanotti,

Elisa Cugini,

Maria Giovanna Scioli

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3617 - 3617

Published: April 11, 2025

The atypical activation of the epithelial-to-mesenchymal transition represents one main mechanisms driving cancer cell dissemination. It enables epithelial cells to detach from primary tumor mass and gain survival advantages in bloodstream, significantly contributing spread circulating cells. Notably, is not a binary process but rather leads formation wide range subpopulations characterized by simultaneous expression both mesenchymal markers. Therefore, analyzing modulation EMT hallmarks during conversion healthy metastatic cells, which acquire stem characteristics, particular interest. This study investigates panel transition-related genes lines, derived various tissues, including lung, colon, pancreas, skin, neuro-ectoderm, with aim identifying potential cut-off values for assessing aggressiveness. Interestingly, we found that levels CDH1, encodes marker E-cadherin, CDH5, encoding vascular endothelial cadherin, transition-transcription factor ZEB1, effectively distinguished Additionally, our data suggest tissue-specific signature markers progression. Overall, results underscore importance investigating as identify most suitable acting indicators disease aggressiveness therapeutic responsiveness.

Language: Английский

Citations

0
Methionine enkephalin inhibited cervical cancer migration as well as invasion and activated CD11b+ NCR1+ NKs of tumor microenvironment DOI
Na Qu, Yiming Meng, Jingbo Zhai

et al.

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 124, P. 110967 - 110967

Published: Sept. 21, 2023

Language: Английский

Citations

2
Logic-based modeling and drug repurposing for the prediction of novel therapeutic targets and combination regimens against E2F1-driven melanoma progression DOI Creative Commons
Nivedita Singh,

Faiz M. Khan,

Lakshmi Bala

et al.

BMC Chemistry, Journal Year: 2023, Volume and Issue: 17(1)

Published: Nov. 22, 2023

Abstract Melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 activation downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation E2F1-governed GRNs holds potential prevent metastasis however, these entail complex feedback feedforward motifs among various layers, which make it difficult identify druggable components. To this end, computational approaches such as mathematical modeling virtual screening are important tools unveil dynamics signaling critical components that could be further explored targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells reconstruct core network underlying melanoma. Using logic-based in silico perturbation experiments network, identified simultaneous Protein kinase B (AKT1) oncoprotein murine double minute 2 (MDM2) drastically reduces EMT structures two protein signatures, strategies were performed FDA-approved drug library. Furthermore, combining repurposing computer-aided design techniques, followed molecular simulation analysis, potent drugs (Tadalafil Finasteride) can efficiently inhibit AKT1 MDM2 proteins. We propose considered for development management Graphical abstract

Language: Английский

Citations

2