Pediatric low-grade glioma in the era of molecular diagnostics

Acta Neuropathologica Communications, Journal Year: 2020, Volume and Issue: 8(1)

Published: March 12, 2020

Abstract Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which currently assigned World Health Organisation grades I II. They differ substantially from their adult counterparts both underlying genetic alterations infrequency with they transform to higher tumors. Nonetheless, low glioma therapeutic challenge due heterogeneity clinical behavior – particular, those incomplete surgical resection often suffer repeat progressions resultant morbidity and, some cases, mortality. The identification up-regulation RAS–mitogen-activated protein kinase (RAS/MAPK) pathway as near universal feature these has led development targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help further define fall under umbrella pediatric-type low-grade glioma. In doing so discuss specific drivers pediatric effectively test for them, newest agents utility treating this disease, propose risk-based stratification system that considers parameters aid clinicians making treatment decisions.

Language: Английский

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Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance

British Journal of Cancer, Journal Year: 2020, Volume and Issue: 124(5), P. 880 - 892

Published: Dec. 3, 2020

Abstract Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% urothelial carcinoma intrahepatic cholangiocarcinoma. We begin review by highlighting the diversity FGFR genomic alterations identified cancers current challenges associated with development clinical-grade molecular diagnostic tests accurately detect these tissue blood patients. The past decade has seen significant advancements FGFR-targeted therapies, which include selective, non-selective covalent small-molecule inhibitors, as well monoclonal antibodies against receptors. describe expanding landscape anti-FGFR therapies that being assessed early phase randomised controlled clinical trials, such erdafitinib pemigatinib, approved Food Drug Administration for treatment FGFR3 -mutated FGFR2 -fusion cholangiocarcinoma, respectively. However, despite initial sensitivity inhibition, acquired drug resistance leading cancer progression develops most This phenomenon underscores need clearly delineate tumour-intrinsic tumour-extrinsic mechanisms facilitate second-generation inhibitors novel strategies beyond on targeted therapy.

Language: Английский

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MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma

Cancers, Journal Year: 2021, Volume and Issue: 13(12), P. 3026 - 3026

Published: June 17, 2021

Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic clinical researchers. The activated more than 50% of human cases; however, activating mutations RAS RAF genes are rarely found HCC, which genetic events leading to activation other cancers. This suggests that there an alternative mechanism behind HCC. Here, we will review recent advances understanding cellular molecular mechanisms involved discuss potential therapeutic strategies targeting context

Language: Английский

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PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 9, 2022

Abstract PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such cancer, immune disorders, viral infections, neurodegenerative diseases, but also provide unique chemical knockdown tools biological research catalytic, reversible, rapid manner. In 2019, our group published review article “PROTACs: great opportunities academia industry” journal, summarizing representative compounds reported before end 2019. past 2 years, entire field protein experienced development, including large increase number papers on small-molecule degraders have entered will enter stage. addition PROTAC molecular glue technology, other technologies are developing rapidly. this article, we mainly summarize related targets 2020–2021 present researchers exciting developments degradation. The problems need solved briefly introduced.

Language: Английский

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Recent advances in systemic therapy for hepatocellular carcinoma

Biomarker Research, Journal Year: 2022, Volume and Issue: 10(1)

Published: Jan. 9, 2022

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors in world. Therapeutic options for advanced HCC are limited. Systemic treatment, especially with conventional cytotoxic drugs, usually ineffective. For more than a decade, sorafenib has been only systemic drug that proven to be clinically effective treating HCC. However, over past three years, rapid progress molecular targeted therapies dramatically changed treatment landscape Immune checkpoint now being incorporated into therapies, their combination therapy emerging as tool enhance immune response. In this review, we summarize development agents immunotherapies

Language: Английский

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Epithelial‐to‐mesenchymal transition in oral squamous cell carcinoma: Challenges and opportunities

International Journal of Cancer, Journal Year: 2020, Volume and Issue: 148(7), P. 1548 - 1561

Published: Oct. 22, 2020

Oral squamous cell carcinoma (OSCC) is the most common malignancy representing 90% of all forms oral cancer worldwide. Although great efforts have been made in past decades, 5-year survival rate OSCC patients no more than 60% due to tumor metastasis and subsequent recurrence. The from primary site a complex process known as epithelial-to-mesenchymal transition (EMT). During EMT, epithelial cells gradually acquire structural functional characteristics mesenchymal cells, leading upregulation migration promotion dissemination. Therefore, EMT attracted broad attention its close relationship with invasion metastasis. present review, an extensive description current research on role this type provided, including diverse markers, regulatory networks crucial EMT-inducing transcription factors OSCC. Moreover, brief summary was regarding application EMT-correlated indexes prognostic analysis patients, potential therapeutic approaches against difficulties development effective anti-EMT treatment are discussed. Our aim provide novel insights develop new strategies combat by targeting EMT.

Language: Английский

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Futibatinib Is a Novel Irreversible FGFR 1–4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors

Cancer Research, Journal Year: 2020, Volume and Issue: 80(22), P. 4986 - 4997

Published: Sept. 24, 2020

FGFR signaling is deregulated in many human cancers, and considered a valid target FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), structurally novel, irreversible FGFR1-4 inhibitor. Among panel 296 kinases, selectively inhibited with IC50 values 1.4 to 3.7 nmol/L. Futibatinib covalently bound kinase domain, inhibiting phosphorylation and, turn, downstream tumor cell lines. exhibited potent, selective growth inhibition several lines (gastric, lung, multiple myeloma, bladder, endometrial, breast) harboring various genomic aberrations. Oral administration led significant dose-dependent reduction FGFR-driven xenograft models, was associated sustained inhibition, which proportional administered dose. The frequency appearance drug-resistant clones lower than reversible ATP-competitive inhibitor, FGFR2 mutants, including V565I/L gatekeeper greater potency any inhibitors tested (IC50, 1.3-50.6 nmol/L). These results indicate that novel orally available, selective, inhibitor broad spectrum antitumor activity models. findings provide strong rationale for testing patients tumors oncogenically driven by aberrations, phase I III trials ongoing. SIGNIFICANCE: Preclinical characterization futibatinib, an demonstrates potent against cancer supporting clinical evaluation GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/22/4986/F1.large.jpg.

Language: Английский

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Targeting FGFR inhibition in cholangiocarcinoma

Cancer Treatment Reviews, Journal Year: 2021, Volume and Issue: 95, P. 102170 - 102170

Published: Feb. 26, 2021

Cholangiocarcinomas (CCAs) are rare but aggressive tumours of the bile ducts, which often diagnosed at an advanced stage and have poor outcomes on systemic therapy. Somatic alterations with therapeutic implications been identified in almost half CCAs, particular intrahepatic CCA (iCCA), subtype arising from ducts within liver. Among patients CCA, fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements occur exclusively iCCA, where they estimated to be found up 10-15% patients. Clinical trials for selective FGFR kinase inhibitors shown consistent activity these agents previously treated iCCA harbouring alterations. Current show differences their structure, mechanisms target engagement, specificities FGFR1, 2, 3 4 other related kinases. These offer potential improve FGFR-driven impact variations molecular profiles efficacy, safety, acquired resistance mechanisms, patients' health-related quality life remains fully characterized. The most common adverse event associated is hyperphosphatemia, on-target off-tumour effect FGFR1 inhibition, strategies manage this include dose adjustment, chelators, use a low phosphate diet. As targeted enter clinic testing actionable mutations monitoring emergence will essential.

Language: Английский

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FGFR-TKI resistance in cancer: current status and perspectives

Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)

Published: Feb. 10, 2021

Fibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success tumor-targeted therapy. However, resistance to FGFR-TKI become a concern. Here, we review mechanisms cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, gene fusion. In addition, summarize strategies overcome resistance, developing covalent inhibitors, dual-target adopting combination therapy, targeting lysosomes, which will facilitate transition precision medicine individualized treatment.

Language: Английский

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Signaling pathways and targeted therapies in lung squamous cell carcinoma: mechanisms and clinical trials

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Oct. 5, 2022

Lung cancer is the leading cause of cancer-related death across world. Unlike lung adenocarcinoma, patients with squamous cell carcinoma (LSCC) have not benefitted from targeted therapies. Although immunotherapy has significantly improved patients' outcomes, relatively low response rate and severe adverse events hinder clinical application this promising treatment in LSCC. Therefore, it vital importance to a better understanding mechanisms underlying pathogenesis LSCC as well inner connection among different signaling pathways, which will surely provide opportunities for more effective therapeutic interventions In review, new insights were given about classical pathways been proved other types but LSCC, including PI3K pathway, VEGF/VEGFR signaling, CDK4/6 pathway. Other may potentials also discussed, FGFR1 EGFR KEAP1/NRF2 Next, chromosome 3q, harbors two key differentiation markers SOX2 TP63 discussed its related potential targets. We provided some progress epigenetic therapies immune checkpoints blockade (ICB) Subsequently, we outlined combination strategies ICB Finally, prospects challenges exploration novel

Language: Английский

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