Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(4), P. 967 - 990

Published: March 19, 2024

Precision medicine is transforming colorectal cancer treatment through the integration of advanced technologies and biomarkers, enhancing personalized effective disease management. Identification key driver mutations molecular profiling have deepened our comprehension genetic alterations in cancer, facilitating targeted therapy immunotherapy selection. Biomarkers such as microsatellite instability (MSI) DNA mismatch repair deficiency (dMMR) guide decisions, opening avenues for immunotherapy. Emerging liquid biopsies, artificial intelligence, machine learning promise to revolutionize early detection, monitoring, selection precision medicine. Despite these advancements, ethical regulatory challenges, including equitable access data privacy, emphasize importance responsible implementation. The dynamic nature with its tumor heterogeneity clonal evolution, underscores necessity adaptive strategies. future lies potential enhance patient care, clinical outcomes, understanding this intricate disease, marked by ongoing evolution field. current reviews focus on providing in-depth knowledge various diverse approaches utilized against at both biochemical levels.

Language: Английский

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Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Nov. 21, 2024

Metabolic alterations, a hallmark of cancer, enable tumor cells to adapt their environment by modulating glucose, lipid, and amino acid metabolism, which fuels rapid growth contributes treatment resistance. In primary breast metabolic shifts such as the Warburg effect enhanced lipid synthesis are closely linked chemotherapy failure. Similarly, metastatic lesions often display distinct profiles that not only sustain but also confer resistance targeted therapies immunotherapies. The review emphasizes two major aspects: mechanisms driving in both how unique environments sites further complicate treatment. By targeting vulnerabilities at stages, new strategies could improve efficacy existing provide better outcomes for cancer patients.

Language: Английский

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Cancer-associated fibroblasts as therapeutic targets for cancer: advances, challenges, and future prospects

Journal of Biomedical Science, Journal Year: 2025, Volume and Issue: 32(1)

Published: Jan. 9, 2025

Abstract Research into cancer treatment has been mainly focused on developing therapies to directly target cells. Over the past decade, extensive studies have revealed critical roles of tumour microenvironment (TME) in initiation, progression, and drug resistance. Notably, cancer-associated fibroblasts (CAFs) emerged as one primary contributors shaping TME, creating a favourable environment for development. Many preclinical identified promising targets CAFs, demonstrating remarkable efficacy some CAF-targeted treatments models. Encouraged by these compelling findings, therapeutic strategies now advanced clinical evaluation. We aim provide comprehensive review relevant subjects including CAF-related markers targets, their multifaceted roles, current landscape ongoing trials. This knowledge can guide future research CAFs advocate investigations targeting CAFs.

Language: Английский

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N-glycosylation of ephrin B1 modulates its function and confers therapeutic potential in B-cell lymphoma

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108229 - 108229

Published: Jan. 1, 2025

Given the pivotal role of Eph-Ephrin signaling pathway in tumor progression, agonists or antagonists targeting Eph/Ephrin have emerged as promising anticancer strategies. However, implications glycosylation modifications within and their targeted protein therapeutics remain elusive. Here, we identify that N-glycosylation receptor-binding domain (RBD) ephrin B1 (EFNB1) is indispensable for its functional repertoire. Notably, compared to wild-type EFNB1, glycosylation-deficient N139D mutant drastically diminishes sensitivity cells chemotherapeutic agents, suggesting existence both glycosylation-dependent independent effects mediated by EFNB1. Transcriptomic analysis highlights immune response oxidative phosphorylation primary pathways modulated modifications. In coculture systems, EFNB1-RBD-Fc recombinant protein, while inhibiting B-lymphoma cells, also exerts differential impacts on stromal depending status. Furthermore, efficacy glycosylated non-glycosylated influenced endogenous EFNB1 levels cells. Taking together, this study demonstrates complexity multifaceted roles modulating function. These findings underscore need a nuanced understanding patterns Eph/Ephrin-targeted therapies optimize therapeutic potential.

Language: Английский

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Ephrin-Eph signaling: an important regulator of epithelial integrity and barrier function

Tissue Barriers, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

Eph receptor-interacting proteins (ephrin) ligands and their erythropoietin-producing human hepatocellular (Eph) receptors elicit bidirectional signals that regulate cell migration, angiogenesis, neuronal plasticity, other developmental processes in the embryo. In adulthood, ephrin-Eph signaling regulates numerous homeostatic events, including epithelial proliferation differentiation. Epithelial surfaces, those of skin vagina, are lined by layers stratified squamous epithelium (SSE) protect against mechanical stress microbial pathogen invasion. Ephrin-Eph is known to promote cutaneous barrier function regulating expression specialized cell-cell adhesion junctions termed desmosomes, but role this system maintaining integrity vagina less explored. This review summarizes current understanding desmosome considers evidence suggests similarly these vaginal SSE.

Language: Английский

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Cellular Responses Induced by NCT-503 Treatment on Triple-Negative Breast Cancer Cell Lines: A Proteomics Approach

Biomedicines, Journal Year: 2024, Volume and Issue: 12(5), P. 1087 - 1087

Published: May 14, 2024

Breast cancer (BC) remains one of the leading causes mortality among women, with triple-negative breast (TNBC) standing out for its aggressive nature and limited treatment options. Metabolic reprogramming, cancer’s hallmarks, underscores importance targeting metabolic vulnerabilities therapeutic intervention. This study aimed to investigate impact de novo serine biosynthetic pathway (SSP) inhibition, specifically phosphoglycerate dehydrogenase (PHGDH) NCT-503, on three TNBC cell lines: MDA-MB-231, MDA-MB-468 Hs 578T. First, MS-based proteomics was used confirm distinct expression PHGDH other SSP enzymes using intracellular proteome profiles untreated cells. Furthermore, characterize response lines inhibitor, both in vitro assays label-free, bottom-up were employed. NCT-503 exhibited significant cytotoxic effects all lines, being most susceptible (IC50 20.2 ± 2.8 µM), while MDA-MB-231 578T showed higher, comparable IC50s. Notably, differentially expressed proteins (DEPs) induced by mostly line-specific, terms secreted proteins. Through overrepresentation Reactome GSEA analysis, modifications associated cycle pathways observed MDA-MBs following treatment. Distinctive dysregulation signaling seen extracellular matrix organization characterizing highlighted through treatment-induced Lastly, an analysis conducted DEPs that greater abundance groups evaluate potential chemo-sensitizing properties druggability these promising targets.

Language: Английский

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Diversity of Intercellular Communication Modes: A Cancer Biology Perspective

Cells, Journal Year: 2024, Volume and Issue: 13(6), P. 495 - 495

Published: March 12, 2024

From the moment a cell is on path to malignant transformation, its interaction with other cells from microenvironment becomes altered. The flow of molecular information at heart cellular and systemic fate in tumors, various processes participate conveying key or certain cancer cells. For instance, loss tight junction molecules part signal sent so that they are no longer bound primary tumors thus free travel metastasize. Upon targeting single by therapeutic drug, gap junctions able communicate death by-standing discovery importance novel modes cell–cell communication such as different types extracellular vesicles tunneling nanotubes changing way scientists look these processes. However, all actively involved contexts same time recruited fulfill specific tasks? What does multiplicity mean for overall progression disease? Here, we extend an open invitation think about significance questions, rather than engage elusive attempt systematic repertory mechanisms play.

Language: Английский

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Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(15), P. 12534 - 12552

Published: July 19, 2024

Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here we have optimized 2-aminopyrimidine-based macrocycles to use these as chemical tools the ephrin kinase family. Starting with promiscuous macrocyclic inhibitor,

Language: Английский

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The influence of endothelial metabolic reprogramming on the tumor microenvironment

Oncogene, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 20, 2024

Abstract Endothelial cells (ECs) that line blood vessels act as gatekeepers and shape the metabolic environment of every organ system. In normal conditions, endothelial are relatively quiescent with organ-specific expression signatures profiles. cancer, ECs metabolically reprogrammed to promote formation new fuel tumor growth metastasis. addition EC’s role on cells, tortuous vasculature contributes an immunosuppressive by limiting T lymphocyte infiltration activity while also promoting recruitment other accessory pro-angiogenic immune cells. These elements aid in metastatic spreading cancer contribute therapeutic resistance. The concept restoring a more stabilized concert immunotherapy is emerging potential approach overcoming barriers treatment. This review summarizes metabolism their regulation nutrient uptake delivery, impact shaping microenvironment anti-tumor immunity. We highlight approaches target harness response. Appreciating integration state levels crosstalk among TME may provide avenues for intervention.

Language: Английский

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Inhibition of EphB4 Receptor Signaling by Ephrin-B2-Competitive and Non-Competitive DARPins Prevents Angiogenesis

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

The receptor tyrosine kinase EphB4 is involved in tumor angiogenesis, proliferation, and metastasis. Designed ankyrin repeat proteins (DARPins) binding to the extracellular domain were identified from a combinatorial library using phage display. Surface plasmon resonance (SPR) allowed us distinguish between DARPins that either compete with ligand ephrin-B2 for common site or target different epitope. all prevent ligand-induced phosphorylation impair tube formation by endothelial cells vitro. competitive DARPin AB1 was additionally shown inhibit vascular growth factor (VEGF) fibroblast (FGF)-induced angiogenesis vivo. In summary, we have isolated exert antiangiogenic effects specifically may potentially lead new cancer therapeutics.

Language: Английский

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