Lenvatinib in hepatocellular carcinoma: Resistance mechanisms and strategies for improved efficacy

Liver International, Год журнала: 2024, Номер 44(8), С. 1808 - 1831

Опубликована: Май 3, 2024

Hepatocellular carcinoma (HCC), one of the most prevalent and destructive causes cancer-related deaths worldwide, approximately 70% patients with HCC exhibit advanced disease at diagnosis, limiting potential for radical treatment. For such patients, lenvatinib, a long-awaited alternative to sorafenib first-line targeted therapy, has become key Unfortunately, despite some progress, prognosis remains poor because drug resistance development. However, molecular mechanisms underlying lenvatinib ways relief in are largely unknown lack systematic summary; thus, this review not only aims explore factors contributing HCC, but more importantly, summary methods conquer or mitigate resistance. The results suggest that abnormal activation pathways, transport, epigenetics, tumour microenvironment, cancer stem cells, regulated cell death, epithelial-mesenchymal transition, other involved development subsequent progression. To improve therapeutic outcomes inhibiting acquired resistance, combined therapies, nano-delivery carriers may be possible approaches.

Язык: Английский

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Tumor Microenvironment Composition and Related Therapy in Hepatocellular Carcinoma

Journal of Hepatocellular Carcinoma, Год журнала: 2023, Номер Volume 10, С. 2083 - 2099

Опубликована: Ноя. 1, 2023

Globally, primary liver cancer is the third leading cause of death, and hepatocellular carcinoma (HCC) accounts for 75%-95%. The tumor microenvironment (TME), composed extracellular matrix, helper cells, immune cytokines, chemokines, growth factors, promotes escape, invasion, metastasis HCC. Tumor postoperative recurrence are main threats to long-term prognosis TME-related therapies increasingly recognized as effective treatments. Molecular-targeted therapy, immunotherapy, their combined therapy approaches. Immunotherapy, represented by checkpoint inhibitors (ICIs), targeted highlighted tyrosine kinase (TKIs), have greatly improved This review focuses on TME compositions emerging therapeutic approaches in

Язык: Английский

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γδ T Cells: A Game Changer in the Future of Hepatocellular Carcinoma Immunotherapy

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(3), С. 1381 - 1381

Опубликована: Янв. 23, 2024

Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment options and poor prognosis for advanced-stage patients. Recent advancements in cancer immunotherapy have generated significant interest exploring novel approaches to combat HCC. One such approach involves the unique versatile subset of T cells known as γδ cells. represent distinct lymphocytes that differ from conventional αβ terms antigen recognition effector functions. They play crucial role immunosurveillance against various malignancies, including studies demonstrated can directly recognize target HCC cells, making them an attractive candidate immunotherapy. In this article, we aimed explore exerted by context We investigate strategies designed maximize therapeutic effectiveness these examine challenges opportunities inherent applying research findings clinical practice. The potential bring about revolutionary shift capitalizing on attributes offers considerable promise enhancing patient outcomes, warranting further investigation.

Язык: Английский

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Insights into lenvatinib resistance: mechanisms, potential biomarkers, and strategies to enhance sensitivity

Medical Oncology, Год журнала: 2024, Номер 41(3)

Опубликована: Фев. 21, 2024

Язык: Английский

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Applications of single-cell multi-omics in liver cancer

JHEP Reports, Год журнала: 2024, Номер 6(7), С. 101094 - 101094

Опубликована: Апрель 15, 2024

Primary liver cancer, more specifically hepatocellular carcinoma (HCC), remains a significant global health problem associated with increasing incidence and mortality. Clinical, biological, molecular heterogeneity are well-known hallmarks of cancer HCC is considered one the most heterogeneous tumour types, displaying substantial inter-patient, intertumoural intratumoural variability. This plays pivotal role in hepatocarcinogenesis, metastasis, relapse drug response or resistance. Unimodal single-cell sequencing techniques have already revolutionised our understanding different layers hierarchy microenvironment HCC. By highlighting cellular intricate interactions among immune stromal cells before during treatment, these contributed to deeper comprehension clonality, hematogenous spreading mechanisms action checkpoint inhibitors. However, major questions remain be elucidated, identification biomarkers predicting resistance immunotherapy-based regimens representing an important unmet clinical need. Although application multi-omics research has been limited thus far, revolution individualised care for patients will only possible by integrating various unimodal methods into methodologies at resolution. In this review, we highlight established explore their biological impact on research, while casting glance future dynamic rapidly evolving field.

Язык: Английский

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New insights into the mechanism of resistance to lenvatinib and strategies for lenvatinib sensitization in hepatocellular carcinoma

Drug Discovery Today, Год журнала: 2024, Номер 29(8), С. 104069 - 104069

Опубликована: Авг. 1, 2024

Язык: Английский

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Peripheral Lymphocytes in Primary Liver Cancers: Elevated NK and CD8+ T Cells and Dysregulated Selenium Metabolism

Biomolecules, Год журнала: 2024, Номер 14(2), С. 222 - 222

Опубликована: Фев. 14, 2024

Peripheral blood lymphocytes (PBLs), which play a pivotal role in orchestrating the immune system, garner minimal attention hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The impact of primary liver cancers on PBLs remains unexplored. In this study, flow cytometry facilitated quantification cell populations, while transcriptome was executed utilizing 10× single-cell sequencing technology. Additionally, pertinent cases were curated from GEO database. Subsequent bioinformatics statistical analyses conducted R (4.2.1) software. Elevated counts NK cells CD8+ T observed both ICC HCC when compared to benign disease (BLD). multivariate Cox model, emerged as independent risk factors for recurrence-free survival. Single-cell uncovered downregulation TGFβ signaling tumor-derived cells. Pathway enrichment analysis, based differential expression profiling, highlighted aberrations selenium metabolism. Proteomic analysis preoperative postoperative peripheral samples patients undergoing tumor resection revealed significant upregulation SELENBP1 SEPP1. Primary cancer has definite PBLs, manifested by alterations cellular quantities selenoprotein

Язык: Английский

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Lenvatinib and immune-checkpoint inhibitors in hepatocellular carcinoma: mechanistic insights, clinical efficacy, and future perspectives

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Дек. 21, 2024

Lenvatinib is a multi-target tyrosine kinase inhibitor widely used in the treatment of hepatocellular carcinoma (HCC). Its primary mechanism action involves inhibiting signal pathways such as vascular endothelial growth factor receptors (VEGFR) and fibroblast (FGFR), thereby reducing tumor cell proliferation angiogenesis affecting tumor's immune microenvironment. In liver cancer, although lenvatinib monotherapy has shown good clinical effect, problem drug resistance becoming more serious. This may be caused by variety factors, including genetic mutations, signaling pathway remodeling, changes order to overcome resistance, combination other therapeutic strategies gradually become research hotspot, it worth noting that checkpoint inhibitors (ICIs) application prospect. not only enhances anti-tumor response but also helps improve efficacy. However, therapy faces challenges regarding safety tolerability. Therefore, studying mechanisms identifying relevant biomarkers particularly important, aids early diagnosis personalized treatment. article reviews treating efficacy its with inhibitors, causes exploration biomarkers, novel for lenvatinib. We hope provide insights into use scientific settings, offering new cancer.

Язык: Английский

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Targeting TIME in Advanced Hepatocellular Carcinoma: Mechanisms of Drug Resistance and Treatment Strategies

Critical Reviews in Oncology/Hematology, Год журнала: 2025, Номер unknown, С. 104735 - 104735

Опубликована: Апрель 1, 2025

Язык: Английский

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Sustained Antigen Stimulation to Evoke and Study Negative feedback Systems responsible for Self-Tolerance/Tumor Immune Escape and transition to the M2 macrophage

Опубликована: Апрель 18, 2025

Abstract Chronic inflammation plays an obscure role in cancer initiation, with broad references implicating immune exhaustion (IEX) or free radical mediated cell damage. is, however, paradoxically synonymous the term “immune tolerance” which other cases presents itself as a therapeutic limitation to efficacy of tumor therapies particularly those involving microbial -associated molecular patterns (MAMPs) regimens. As “tolerance” remains this day “phenomenon” there is pressing need fully understand every biological aspect apparent negative feedback response, because doing so will serve guide development targeted therapies. In work, we employ rudimentary model, can be adopted it possible provoke through sustained antigen stimulation immunocompetent cells, monitor, define and characterize phenotype evolution using next generation whole transcriptome sequencing + validation studies. This model used study /create vitro “M2” phenotype, involved aggressive tumors synergistic rapid expansion myeloid-derived suppressor cells (MDSCs), dysfunctional CD8+ T cytotoxic (CTL)/ natural killer (NK) cells. Briefly, data shows dominates at 7 11 days, after acute being associated phase specific (time dependent) elevated checkpoints; e.g. PDL1+/MSN, HAVCR2/TIM-3+, SPP1+, C3ar1+, CD73+, IL1RN+, LILRbs+, glycoproteins, integrins etc. Here report on bidirectional changes aligning escape, much centered around loss host defense against viral infection malignancy. Negative rampant induction degradative proteases, SOCS/JAK/STAT/IL-10, CCL2/7 axis tantamount MHC1/2 recognition systems, Type I interferon NOD signaling, antiviral/antibacterial defense, p62/SQSTM also disturbed metabolic signature. The work demonstrates that colloquial terms “tolerance IEX” are somewhat flawed terminology, potent, intentional formidable offense eradicate active arm defense. Truncated /Removed due word count show aligns six distinct chronological differential gene (DEG) expression circumscribe extensive suppression dominate during chronic inflammation. These involve following time dependent patterns: 1) transcripts overexpressed, checkpoint receptors; etc.; 2) overexpressed only chronic; e.g cytokine signaling (SOC3/Jak/Stat), cyto/chemokines (IL-10, CCL2, CCL7), proteases (cathepsins L, D, K, Adam 8, PIM2), adhesives (TSPAN3, QSOX1, PDPN, ITGA5), (PLK2, ADGRE1, CALM1, PCNA, etc.); 3) downregulated severe collective MHC1/II presentation capacity (CD74, H2-Q4, H2-Q6, etc.), (IFN) type systems; 4) only, including OXPHOS/metabolic genes (Aldo A, C, Eno2, Gpi1, (Lyz1, Lyz2, Card19, Ninj1), autophagy-related (p62/SQSTM1). category Tolerance were: 5) induced sharply acute, no longer responsive IFN 1 antiviral response (OAS, BST2, ISG15, ISG20, IRF7, RSAD2/Viperin), TLR2, antibacterial (SAA3, SP140), proinflammatory cytokines (CCL5, TNF, IL1a, IL1b) along IL-1/TLR axis. Last, 6) reverse tolerance, corresponded restored baseline levels maintain mitotic thymosin homeostasis. conclusion, these suggest precipitates feedback, same targets sought today

Язык: Английский

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