Clinical treatment of cholangiocarcinoma: an updated comprehensive review

Annals of Hepatology, Journal Year: 2022, Volume and Issue: 27(5), P. 100737 - 100737

Published: July 7, 2022

Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms the bile ducts and represents second most common hepatic cancer after hepatocellular carcinoma; it sub-classified as intrahepatic cholangiocarcinoma (iCCA) extrahepatic (eCCA), latter comprising both perihilar (pCCA or Klatskin tumor), distal (dCCA). The global incidence CCA has increased worldwide in recent decades. Chronic inflammation biliary epithelium stasis represent main risk factors shared by all sub-types. When feasible, liver resection treatment choice for CCA, followed systemic chemotherapy with capecitabine. Liver transplants option patients very early iCCA, referral centers only. diagnosis often performed at an advanced stage when unresectable. In this setting, gemcitabine cisplatin first option, but prognosis remains poor. order to ameliorate patients’ survival, new drugs have been studied last few years. Target therapies are directed against different molecules, which altered cells. These second-line therapy, alone combination chemotherapy. same immune checkpoints inhibitors targeting programmed death 1 (PD-1), death-ligand (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), proposed, well vaccines adoptive cell therapy (ACT). experimental treatments showed promising results proposed second- third-line treatment, target therapies.

Language: Английский

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RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity acrossFGFR2Alterations and Resistance Mutations

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(9), P. 2012 - 2031

Published: June 4, 2023

Abstract Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting FGFR2 has not been achieved. Although the clinical efficacy pan-FGFR inhibitors (pan-FGFRi) validates driver status in fusion–positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- FGFR4-mediated toxicities (hyperphosphatemia diarrhea, respectively) emergence resistance mutations. RLY-4008 highly selective, irreversible inhibitor designed overcome these limitations. In vitro, demonstrates >250- >5,000-fold selectivity over FGFR1 FGFR4, respectively, targets primary alterations vivo, induces regression xenograft models—including models with mutations that drive progression on current pan-FGFRi—while sparing FGFR4. early testing, induced responses without clinically significant off-isoform FGFR toxicities, confirming potential targeting. Significance: Patients FGFR2-driven derive from pan-FGFRi FGFR1–4-mediated acquired tumor while other FGFRs, suggesting it may have potential. See related commentary Tripathi et al., p. 1964. This article featured Selected Articles Issue, 1949

Language: Английский

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Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(6)

Published: Feb. 1, 2024

Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but toxicity these drugs frequently leads dose reduction or interruption such that maximum efficacy cannot achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition diarrhea due FGFR4 inhibition, as current therapies not selective among FGFRs. Designing has proved difficult with conventional approaches because orthosteric sites FGFR family members observed highly similar X-ray structures. In this study, aided analysis protein dynamics, we designed a selective, covalent inhibitor. key initial step, long-timescale molecular dynamics simulations domains allowed us identify differential motion their P-loops, which located adjacent site. Using insight, were able design binders selectively covalently engage P-loop FGFR2. Our drug discovery efforts culminated development lirafugratinib (RLY-4008), inhibitor shows substantial selectivity over (~250-fold) (~5,000-fold) vitro, causes tumor regression multiple -altered human xenograft models, was recently demonstrated efficacious clinic at doses do induce clinically significant diarrhea.

Language: Английский

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Pemigatinib in previously treated solid tumors with activating FGFR1–FGFR3 alterations: phase 2 FIGHT-207 basket trial

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(6), P. 1645 - 1654

Published: May 6, 2024

Abstract Fibroblast growth factor receptor ( FGFR ) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1–FGFR3 inhibitor, the phase 2 FIGHT-207 basket study of FGFR- altered advanced solid tumors. Primary end points were objective response rate (ORR) cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, 32). Secondary progression-free survival, duration overall survival B, safety. Exploratory included ORR cohort C (kinase potentially pathogenic variants unknown significance, 26) analysis co-alterations associated with resistance response. ORRs for A, 26.5% (13/49), 9.4% (3/32) 3.8% (1/26), respectively. Tumors no approved inhibitors or those not previously confirmed to be sensitive inhibition had responses. In median was 4.5 3.7 months, 7.8 6.9 months 17.5 11.4 Safety consistent previous reports. The most common any-grade treatment-emergent adverse events hyperphosphatemia (84%) stomatitis (53%). TP53 co-mutations lack BAP1 higher rates. FGFR1 – FGFR3 gatekeeper molecular brake mutations led acquired resistance. New therapeutic areas drug failure mechanisms identified across ClinicalTrials.gov identifier: NCT03822117 .

Language: Английский

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Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma

Frontiers in Medicine, Journal Year: 2022, Volume and Issue: 9

Published: March 31, 2022

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive primary liver malignancy with increasing incidence worldwide. Recently, histopathologic classification of small duct type and large iCCA has been introduced. Both these types tumors exhibit differences in clinicopathological features, mutational profiles, prognosis. Small composed non-mucin-producing cuboidal cells, whereas mucin-producing columnar reflecting different cells origin. Large shows more invasive growth poorer prognosis than iCCA. The background often chronic disease related to hepatitis B or C viral infection, alcoholic non-alcoholic fatty disease/steatohepatitis, contrast that hepatolithiasis fluke infection. Cholangiolocarcinoma a variant naïve-looking forming cords ductule-like structures, better the conventional type. Fibrous tumor stroma, one characteristic features iCCA, contains activated fibroblasts intermixed innate adaptive immune cells. stroma (mature versus immature) are behavior Low tumor-infiltrating lymphocyte density, KRAS alteration, chromosomal instability immune-suppressive microenvironments resistance programmed death 1/ ligand 1 blockade. Data from recent large-scale exome analyses have revealed heterogeneity molecular profiles showing frequent BAP1 , IDH1/2 hotspot mutations FGFR2 fusion, TP53 SMAD4 observed Multi-omics proposed several classifications including inflammation class proliferation class. enriched inflammatory signaling pathways expression cytokines, while oncogenic pathways. Diverse pathologic its associated multi-omics characteristics currently under active investigation, thereby providing insights into precision therapeutics for patients This review provides latest knowledge on ranging microenvironment genomic transcriptomic research.

Language: Английский

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Precision medicine: Ray of hope in overcoming cancer multidrug resistance

Drug Resistance Updates, Journal Year: 2022, Volume and Issue: 65, P. 100889 - 100889

Published: Nov. 10, 2022

Language: Английский

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Clinical management of intrahepatic cholangiocarcinoma: surgical approaches and systemic therapies

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 24, 2024

Intrahepatic cholangiocarcinoma (ICCA) is a rare and aggressive malignant tumor that arises from the biliary tracts in liver. Upfront surgery with adjuvant capecitabine patients resectable disease often standard treatment. Unfortunately, only 20% of present many individuals will develop recurrence or metastatic after curative-intent resection. Patients advanced ICCA require multidisciplinary care combination cytotoxic chemotherapy, targeted therapy, and/or locoregional therapies. Gemcitabine plus cisplatin currently first line therapy for ICCA. In recent years, efforts have been focused to more effective most commonly FGFR IDH inhibitors Despite these efforts, still carries poor prognosis. We herein review current clinical management focusing on surgical technique systemic

Language: Английский

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Deep immune profiling of intrahepatic cholangiocarcinoma with CODEX multiplexed imaging

Hepatology Communications, Journal Year: 2025, Volume and Issue: 9(3)

Published: Feb. 19, 2025

Background: Intrahepatic cholangiocarcinoma (iCCA) may be genomically subclassified by the presence of potentially actionable molecular aberrations, which pathogenic alterations in isocitrate dehydrogenase (IDH)1 and fibroblast growth factor receptor (FGFR)2 are most frequently observed. The impact these on tumor immune microenvironment remains incompletely understood. Methods: We performed a high-parameter spatial phenotyping iCCA samples with FGFR2 or IDH1 FGFR2/IDH1 wild-type controls at single-cell level using CO-Detection indEXing. Results: A total 24 tumors were examined. Tumors characterized fewer CD8+ T cells “M2-like” macrophages but higher levels polymorphonuclear myeloid-derived suppressor as compared to tumors. Spatial relationships between multiple other cell types (including cells, CD4+, cells) enriched alterations. mutations had trend toward more fibroblasts closer proximity CD4+ structural components subtypes. Conclusions: iCCAs fusions/rearrangements have distinct immunophenotypes. Tailoring immunotherapeutic approaches specific subsets could improve treatment outcomes across divergent molecularly defined

Language: Английский

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The Application of Inorganic Nanoparticles in Molecular Targeted Cancer Therapy: EGFR Targeting

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: July 12, 2021

Epidermal growth factor receptor (EGFR) is an anticancer drug target for a number of cancers, such as non-small cell lung cancer. However, unsatisfying treatment effects, terrible side-effects, and development resistance are current insurmountable challenges EGFR targeting treatments cancers. With the advancement nanotechnology, increasing inorganic nanomaterials applied in EGFR-mediated therapy to improve those limitations further potentiate efficacy molecular targeted cancer therapy. Given their facile preparation, easy modification, biosecurity, nanoparticles (iNPs) have been extensively explored date. This review presents overview application some typical metal nonmetallic EGFR-targeted therapy, then discusses summarizes relevant advantages. Moreover, we also highlight future perspectives regarding remaining issues. We hope these discussions inspire research on iNPs.

Language: Английский

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Long Non-coding RNA DANCR in Cancer: Roles, Mechanisms, and Implications

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Oct. 15, 2021

Long non-coding RNA (lncRNA) DANCR (also known as ANCR)—differentiation antagonizing non-protein coding RNA, was first reported in 2012 to suppress differentiation of epithelial cells. Emerging evidence demonstrates that is a cancer-associated lncRNA abnormally expressed many cancers (e.g., lung cancer, gastric breast hepatocellular carcinoma). Increasing studies suggest the dysregulation plays critical roles cancer cell proliferation, apoptosis, migration, invasion, and chemoresistance vitro tumor growth metastasis vivo . Mechanistic analyses show can serve miRNA sponges, stabilize mRNAs, interact with proteins. Recent research reveals be detected body fluids such serum, plasma, exosomes, providing quick convenient method for monitor. Thus used promising diagnostic prognostic biomarker therapeutic target various types cancer. This review focuses on role mechanism progression an emphasis clinical significance human cancers.

Language: Английский

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