The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer

Annals of Oncology, Journal Year: 2022, Volume and Issue: 33(12), P. 1269 - 1283

Published: Sept. 9, 2022

Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for genomic profiling that overcomes many limitations traditional tissue-based analysis. We examined cfDNA as a tool to inform patients with BTC and generate novel insights into tumor biology.We analyzed next-generation sequencing data 2068 samples from 1671 generated Guardant360. carried out annotation on multi-institutional subset (n = 225) assess intra-patient cfDNA-tumor concordance the association variant allele fraction (VAF) outcomes.Genetic alterations were detected in 84% patients, targetable 44% patients. Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, BRAF V600E clonal majority cases, affirming these early driver events BTC. Concordance between tissue mutation detection was high IDH1 mutations (87%) (100%), low FGFR2 fusions (18%). uncovered putative mechanisms resistance targeted therapies, including cysteine residue (FGFR2 C492F) which covalent FGFR inhibitors bind. High pre-treatment VAF associated poor prognosis shorter response chemotherapy therapy. Finally, we report frequency promising targets currently under investigation other solid tumors, KRAS G12C (1.0%), G12D (5.1%), PIK3CA (6.8%), ERBB2 amplifications (4.9%).These findings largest most comprehensive study date highlight utility current this disease. Characterization oncogenic drivers therapeutic will drug development efforts reduce mortality

Language: Английский

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FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(4), P. 312 - 329

Published: Feb. 29, 2024

Language: Английский

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Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Sept. 16, 2024

Abstract Histone post-translational modifications (HPTMs), as one of the core mechanisms epigenetic regulation, are garnering increasing attention due to their close association with onset and progression diseases potential targeted therapeutic agents. Advances in high-throughput molecular tools abundance bioinformatics data have led discovery novel HPTMs which similarly affect gene expression, metabolism, chromatin structure. Furthermore, a growing body research has demonstrated that histone also play crucial roles development various diseases, including cancers, cardiovascular infectious psychiatric disorders, reproductive system diseases. This review defines nine modifications: lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, 2-hydroxybutyrylation. It comprehensively introduces modification processes these HPTMs, transcription, replication, DNA repair recombination, structure, well involvement promoting occurrence clinical applications targets biomarkers. Moreover, this provides detailed overview HPTM inhibitors targeting emerging strategies treatment multiple while offering insights into future prospects challenges. Additionally, we briefly introduce techniques field research.

Language: Английский

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The role of fibroblast growth factor receptor (FGFR) protein-tyrosine kinase inhibitors in the treatment of cancers including those of the urinary bladder

Pharmacological Research, Journal Year: 2019, Volume and Issue: 151, P. 104567 - 104567

Published: Nov. 23, 2019

Language: Английский

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The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

Cancers, Journal Year: 2020, Volume and Issue: 12(10), P. 3029 - 3029

Published: Oct. 18, 2020

One of the major challenges in treatment breast cancer is heterogeneous nature disease. With multiple subtypes identified, there an unmet clinical need for development therapies particularly less tractable subtypes. Several transduction mechanisms are involved progression cancer, therefore making assessment molecular landscape that characterizes each patient intricate. Over last decade, numerous studies have focused on tyrosine kinase inhibitors (TKIs) to target main pathways dysregulated however their effectiveness often limited either by resistance treatments or appearance adverse effects. In this context, fibroblast growth factor/fibroblast factor receptor (FGF/FGFR) system represents emerging pathway and therapeutic be fully investigated among diverse anti-cancer settings cancer. Here, we recapitulated previous dealing with FGFR aberrations, such as gene amplification, point mutations, chromosomal translocations occur Furthermore, alterations FGF/FGFR signaling across different been described. Next, discussed functional interplay between axis important components tumor microenvironment. Lastly, pointed out usefulness inhibitors, revealed preclinical models

Language: Английский

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Diagnostic, Predictive, and Prognostic Biomarkers in Non-Small Cell Lung Cancer (NSCLC) Management

Journal of Personalized Medicine, Journal Year: 2021, Volume and Issue: 11(11), P. 1102 - 1102

Published: Oct. 27, 2021

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite growing efforts for its early detection by screening populations at risk, majority lung patients are still diagnosed in an advanced stage. The management has dramatically improved last decade and no longer based on “one-fits-all” paradigm or general histological classification non-small cell versus small cancer. Emerging options targeted therapies immunotherapies have shifted to a more personalized treatment approach, significantly influencing clinical course outcome disease. Molecular biomarkers emerged as valuable tools prognosis prediction therapy response. In this review, we discuss relevant used tumors, from diagnosis prognosis. We also promising new biomarkers, focusing most abundant type

Language: Английский

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Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review

Frontiers in Chemistry, Journal Year: 2022, Volume and Issue: 10

Published: April 14, 2022

Targeted therapy is a groundbreaking innovation for cancer treatment. Among the receptor tyrosine kinases, fibroblast growth factor receptors (FGFRs) garnered substantial attention as promising therapeutic targets due to their fundamental biological functions and frequently observed abnormality in tumors. In past 2 decades, several generations of FGFR kinase inhibitors have been developed. This review starts by introducing basis FGF/FGFR signaling. It then gives detailed description different types small-molecule according modes action, followed systematic overview small-molecule-based therapies modalities. ends with our perspectives development novel inhibitors.

Language: Английский

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Bio-scaffold for bone tissue engineering with focus on bacterial cellulose, biological materials for hydroxyapatite synthesis and growth factors

European Polymer Journal, Journal Year: 2023, Volume and Issue: 194, P. 112168 - 112168

Published: May 24, 2023

Language: Английский

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HDAC3 is critical in tumor development and therapeutic resistance in Kras -mutant non–small cell lung cancer

Science Advances, Journal Year: 2023, Volume and Issue: 9(11)

Published: March 17, 2023

HDAC3 is one of the main targets histone deacetylase (HDAC) inhibitors in clinical development as cancer therapies, yet vivo role solid tumors unknown. We identified a critical for Kras -mutant lung cancer. Using genetically engineered mouse models (GEMMs), we found that required tumor growth vivo. was to direct and enhance transcription effects lineage factor NKX2-1 mediate expression common set target genes. FGFR1 previously unidentified HDAC3. Leveraging this, an HDAC3-dependent transcriptional cassette becomes hyperactivated Kras/LKB1 cells develop resistance MEK inhibitor trametinib, this can be reversed by treatment with HDAC1/HDAC3 entinostat. combination entinostat plus trametinib elicits therapeutic benefit GEMM.

Language: Английский

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The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

Molecules, Journal Year: 2023, Volume and Issue: 28(14), P. 5359 - 5359

Published: July 12, 2023

The altered activation or overexpression of protein kinases (PKs) is a major subject research in oncology and their inhibition using small molecules, inhibitors (PKI) the best available option for cure cancer. pyrazole ring extensively employed field medicinal chemistry drug development strategies, playing vital role as fundamental framework structure various PKIs. This scaffold holds importance considered privileged based on its synthetic accessibility, drug-like properties, versatile bioisosteric replacement function. It has proven to play key many PKI, such Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, RET. Of 74 molecule PKI approved by US FDA, 8 contain ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, Ruxolitinib. focus this review unfused within clinically tested additional required elements chemical structures. Related important fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, pyrazolo[3,4-d]pyrimidine are beyond work.

Language: Английский

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