Wnt-TCF7-SOX9 axis promotes cholangiocarcinoma proliferation and pemigatinib resistance in a FGF7-FGFR2 autocrine pathway

Oncogene, Год журнала: 2022, Номер 41(20), С. 2885 - 2896

Опубликована: Апрель 15, 2022

Язык: Английский

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Precision Medicine in Biliary Tract Cancer

Journal of Clinical Oncology, Год журнала: 2022, Номер 40(24), С. 2716 - 2734

Опубликована: Июль 15, 2022

Precision medicine has become a dominant theme in the treatment of biliary tract cancers (BTCs). Although prognosis remains poor, technologies for improved molecular characterization along with US Food and Drug Administration approval several targeted therapies have changed therapeutic landscape advanced BTC. The hallmark BTC oncogenesis is chronic inflammation liver regardless anatomical subtype. Subtypes correspond to distinct characteristics, making molecularly heterogenous collection tumors. Collectively, up 40% BTCs harbor potentially targetable abnormality, National Comprehensive Cancer Network guidelines recommend profiling all patients Use circulating tumor DNA, immunohistochemistry, next-generation sequencing continues expand utility biomarker-driven management monitoring Improving outcomes using biomarker-agnostic nontargetable tumors also priority, combinational strategies such as immune checkpoint inhibition plus chemotherapy hold promise this subgroup patients.

Язык: Английский

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Resistance of Lenvatinib in Hepatocellular Carcinoma

Current Cancer Drug Targets, Год журнала: 2022, Номер 22(11), С. 865 - 878

Опубликована: Апрель 30, 2022

Lenvatinib is a multikinase inhibitor which mainly hinders liver cancer proliferation by inhibiting angiogenesis. In 2018, was approved for the first-line treatment of patients with advanced hepatocellular carcinoma [HCC] in United States, European Union, Japan, and China. has been established as sorafenib replacement drug higher objective response rate [ORR], longer progression-free survival [PFS], time to progression [TTP]. resistance during become increasingly common recent years. Accordingly, it necessary determine factors associated explore solutions. this review, we sought mechanisms methods reduce summarized achievements treatment.

Язык: Английский

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New drug approvals for 2022: Synthesis and clinical applications

Medicinal Research Reviews, Год журнала: 2023, Номер 43(6), С. 2352 - 2391

Опубликована: Май 21, 2023

Abstract The U.S. Food and Drug Administration has approved a total of 37 new drugs in 2022, which are composed 20 chemical entities 17 biologics. In particular, entities, including small molecule drugs, 1 radiotherapy, 2 diagnostic agents, provide privileged scaffolds, breakthrough clinical benefits, mechanism action for the discovery more potent candidates. structure‐based drug development with clear targets fragment‐based scaffolds have always been important modules field discovery, could easily bypass patent protection bring about improved biological activity. Therefore, we summarized relevant valuable information application, action, synthesis newly 2022. We hope this timely comprehensive review creative elegant inspiration on synthetic methodologies novel extended indications.

Язык: Английский

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Practical guidelines for molecular testing of cholangiocarcinoma in clinical practice: Italian experts’ position paper

Critical Reviews in Oncology/Hematology, Год журнала: 2024, Номер 194, С. 104224 - 104224

Опубликована: Янв. 10, 2024

Biliary tract cancers (BTCs) represent a spectrum of malignancies associated with dismal prognosis. Recent genomic profiling studies have provided deeper understanding the complex and heterogenous molecular landscape BTCs, identifying several actionable genetic alterations, expanding treatment options. Due to high number complexity alterations which require testing, next-generation sequencing (NGS) is currently preferred approach over conventional methods (i.e., immunohistochemistry, fluorescence in-situ hybridization PCR) for BTCs should be performed upfront in all BTC patients. However, sampling often yields low tumor cellularity tissue, hampering NGS analysis. Future perspectives overcome this obstacle include liquid biopsy optimization protocols. In position paper, authors discuss current histopathologic, molecular, therapeutic provide critical overview available testing diagnostics, propose practical diagnostic algorithm samples.

Язык: Английский

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Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Май 3, 2024

Abstract Background Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity crosstalk of tumor microenvironment remain incompletely understood. Methods To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify construct cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network important receptor-ligand complexes using single-cell transcriptomics analysis Adjacent normal tissue. Results Through intersection TCGA DEGs WGCNA module genes, 784 differential genes related CAFs were obtained. After series regression analyses, score was generated integrating expressions EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, their corresponding coefficients. In TCGA-CHOL, GSE89748, 107,943 cohorts, high group showed unfavorable survival prognosis ( p < 0.001, = 0.0074, 0.028, respectively). Additionally, drugs have been predicted be more sensitive high-risk 0.05). Subsequent dimension reduction clustering, thirteen clusters identified atlas. Cell-cell interaction unveiled significant enhancement signal transduction in tissues, particularly from cells via diverse pathways. Moreover, SCENIC indicated that HOXA5, WT1, LHX2 are fibroblast specific motifs. Conclusions This study reveals key role - oncocytes remodeling immunosuppressive intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation downstream signaling pathways such as PI3K-AKT Notch tumor, thus initiating tumorigenesis. Targeted aimed at disrupting fibroblasts-tumor cell interaction, along with enrichment pathways, show potential mitigating facilitates progression.

Язык: Английский

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Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma

Current Treatment Options in Oncology, Год журнала: 2024, Номер 25(1), С. 127 - 160

Опубликована: Янв. 1, 2024

Biliary tract cancers are molecularly and anatomically diverse which include intrahepatic cholangiocarcinoma, extrahepatic (perihilar distal) gallbladder cancer. While recognized as distinct entities, the rarer incidence of these combined with diagnostic challenges in classifying anatomic origin has resulted clinical trials guideline recommended strategies being generalized patients all types biliary In this review, we delve into unique aspects, subtype-specific trial outcomes, multidisciplinary management cholangiocarcinoma. When resectable, definitive surgery followed by adjuvant chemotherapy (sometimes selective radiation/chemoradiation) is current standard care. Due to high recurrence rates, there growing interest use upfront/neoadjuvant therapy improve surgical outcomes downstage who may not initially be resectable. Select perihilar cholangiocarcinoma successfully treated novel approaches such liver transplant. advanced disease setting, combination gemcitabine cisplatin remains base for systemic was recently improved upon addition immune checkpoint blockade doublet reported TOPAZ-1 KEYNOTE-966 trials. Second-line all-comer treatments remain limited both options efficacy, so participation should strongly considered. With increased molecular testing, detection actionable mutations opportunities receive indicated targeted therapies on rise most significant driver survival stage disease. Though currently reserved second or later line, future looking at moving earlier treatment settings immunotherapy. cross-disciplinary surgical, medical, radiation oncology, patient-centered care also collaboration endoscopists, palliative specialists, nutritionists global patient outcomes.

Язык: Английский

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Safety Profile and Adverse Event Management for Futibatinib, An Irreversible FGFR1–4 Inhibitor: Pooled Safety Analysis of 469 Patients

Clinical Cancer Research, Год журнала: 2024, Номер 30(8), С. 1466 - 1477

Опубликована: Фев. 8, 2024

Abstract Purpose: Futibatinib, a covalently-binding inhibitor of fibroblast growth factor receptor (FGFR)1-4 gained approval for the treatment refractory, advanced intrahepatic cholangiocarcinoma (iCCA) harboring an FGFR2 fusion/other rearrangement. An integrated analysis was performed to evaluate safety and provide guidance on management futibatinib-associated adverse events (AEs) in patients with unresectable/metastatic tumors, including iCCA. Patients Methods: Data from three global phase I or II studies futibatinib (NCT02052778; JapicCTI-142552) were pooled. AEs graded per NCI CTCAE v4.03, where applicable. Safety analyzed receiving any starting dose (overall population) those approved 20 mg once every day. Results: In total, 469 one 33 known tumor types analyzed, 318 who received clinical interest (AECI; grade/grade ≥3) overall population included hyperphosphatemia (82%/19%), nail disorders (27%/1%), hepatic (27%/11%), stomatitis (19%/3%), palmar-plantar erythrodysesthesia syndrome (PPES; 13%/3%), rash (9%/0%), retinal (8%/0%), cataract (4%/1%). Median time onset grade ≥3 AECIs ranged 9 days (hyperphosphatemia) 125 (cataract). Grade hyperphosphatemia, AEs, PPES, resolved ≤2 within median 7, 8, 28 days, respectively. Discontinuations due treatment-related rare (2%), no deaths occurred. AE phosphate-lowering medication adjustments. Conclusions: Futibatinib showed consistent manageable profile across various types. mostly reversible appropriate management.

Язык: Английский

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Changing Landscape of Systemic Therapy in Biliary Tract Cancer

Cancers, Год журнала: 2022, Номер 14(9), С. 2137 - 2137

Опубликована: Апрель 25, 2022

Biliary tract cancers (BTC) are often diagnosed at advanced stages and have a grave outcome due to limited systemic options. Gemcitabine cisplatin combination (GC) has been the first-line standard for more than decade. Second-line chemotherapy (CT) options limited. Targeted therapy or TT (fibroblast growth factor 2 inhibitors FGFR2, isocitrate dehydrogenase 1 IDH-1, neurotrophic tyrosine receptor kinase NTRK gene fusions inhibitors) had reasonable success, but <5% of total BTC patients eligible them. The use immune checkpoint (ICI) such as pembrolizumab is restricted microsatellite instability high (MSI-H) in first line. success TOPAZ-1 trial (GC plus durvalumab) promising, with numerous trials underway that might soon bring targeted (pemigatinib infrigatinib) ICI combinations (with CT stable cancers) Newer targets newer agents established being investigated, this may change management landscape coming years from traditional individualized (TT) ICI-centered combinations. latter group occupy major space paucity targetable mutations greater toxicity profile.

Язык: Английский

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Role of molecular genetics in the clinical management of cholangiocarcinoma

ESMO Open, Год журнала: 2022, Номер 7(3), С. 100505 - 100505

Опубликована: Июнь 1, 2022

The incidence of cholangiocarcinoma (CCA) has steadily increased during the past 20 years, and mortality is increasing. majority patients with CCA have advanced or metastatic disease at diagnosis, treatment options for unresectable are limited, resulting in poor prognosis. However, recent identification targetable genomic alterations expanded eligible patients. Given importance early accurate diagnosis optimizing patient outcomes, this review discusses best practices a focus on categorizing molecular genetics available targeted therapies. Imaging staging CCAs discussed, as well recommended biopsy collection techniques, profiling methodologies, which become increasingly important biomarker data accumulate. Approved agents targeting actionable specifically include ivosidenib tumors harboring IDH1 mutations, infigratinib pemigatinib those FGFR2 fusions. Other currently under development indication shown promising results, presented here.

Язык: Английский

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