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Frontiers in Bioscience (Landmark... Jan 2024Emerging evidence suggests the biological implications of N6-methyladenosine (m6A) in carcinogenesis. Herein, we systematically analyzed the role of m6A modification in...
OBJECTIVE
Emerging evidence suggests the biological implications of N6-methyladenosine (m6A) in carcinogenesis. Herein, we systematically analyzed the role of m6A modification in renal cell carcinoma (RCC) progression.
METHODS
Based on 23 m6A regulators, unsupervised clustering analyses were conducted to determine m6A modification subtypes across 893 RCC specimens in the Cancer Genome Atlas (TCGA) cohort. By performing principal component analysis (PCA) analysis, m6A scoring system was developed for evaluating m6A modification patterns of individual RCC patients. The activity of signaling pathways was assessed by gene-set variation analysis (GSVA) algorithm. The single-sample gene set enrichment analysis (ssGSEA) algorithm was applied for quantifying the infiltration levels of immune cells and the activity of cancer immunity cycle. Drug responses were estimated by genomics of drug sensitivity in cancer (GDSC), the Cancer Therapeutics Response Portal (CTRP) and Preservice Research Institute for Science and Mathematics (PRISM) database.
RESULTS
Five m6A modification subtypes were characterized by different survival outcomes, oxidative stress, cancer stemness, infiltrations of immune cells, activity of cancer immunity cycle, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression and microsatellite instability (MSI) levels. According to m6A score, RCC patients were categorized into high and low m6A score groups. Patients with high m6A score displayed a prominent survival advantage, and the prognostic value of m6A score was confirmed in two anti-PD-1/PD-L1 immunotherapy cohorts. m6A score was significantly linked to oxidative stress-related genes, and high m6A score indicated the higher sensitivity to axitinib, pazopanib and sorafenib and the lower sensitivity to sunitinib.
CONCLUSION
This study analyzed the extensive regulatory mechanisms of m6A modification on oxidative stress, the tumor microenvironment, and immunity. Quantifying m6A scores may enhance immunotherapeutic effects and assist in developing more effective agents.
Topics: Humans; Carcinoma, Renal Cell; B7-H1 Antigen; Tumor Microenvironment; Kidney Neoplasms; Methylation
PubMed: 38287827
DOI: 10.31083/j.fbl2901033 -
Drugs - Real World Outcomes Jun 2024The tyrosine kinase inhibitors cabozantinib and axitinib have been widely used in England to treat advanced renal cell carcinoma following prior vascular endothelial...
BACKGROUND AND OBJECTIVE
The tyrosine kinase inhibitors cabozantinib and axitinib have been widely used in England to treat advanced renal cell carcinoma following prior vascular endothelial growth factor-targeted therapy, but data on real-world usage remain limited. Our objective was to describe the real-world treatment patterns and outcomes of patients with advanced renal cell carcinoma who received second-line or later-line (≥ 2L) cabozantinib or axitinib after vascular endothelial growth factor-targeted therapy in clinical practice in England.
METHODS
This retrospective cohort study used clinical practice data (collected 2011-20) from the English Cancer Analysis System database. Patient characteristics, treatment sequence and duration, and overall survival (time from initiation of cabozantinib/axitinib treatment to death) were evaluated.
RESULTS
Data from 1485 eligible adults with advanced renal cell carcinoma were analyzed: 440 received ≥ 2L cabozantinib (2L for 88.6% of them); 1045 received ≥ 2L axitinib (2L for 89.5%). The most common first-line treatments were sunitinib (2L cabozantinib subcohort, 48%; 2L axitinib subcohort, 46%) and pazopanib (46% and 54%, respectively); nivolumab was the most common third-line treatment (18% and 19%, respectively). Median (interquartile range) 2L therapy duration was 5.52 (2.73-11.74) months for cabozantinib and 4.60 (1.45-12.36) months for axitinib. Following adjustment for potential confounders using inverse probability weighting, overall survival (median [interquartile range]) was longer for ≥ 2L cabozantinib (11.2 [5.7-28.0] months) than for ≥ 2L axitinib (10.4 [4.7-22.0] months; log-rank p = 0.0034).
CONCLUSIONS
The Cancer Analysis System database is a valuable research resource providing extensive real-world clinical data. Real-world overall survival was longer with ≥ 2L cabozantinib than with axitinib.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT04637204; registered November 2020.
PubMed: 38265633
DOI: 10.1007/s40801-023-00415-w -
Pharmaceuticals (Basel, Switzerland) Jan 2024Tumour-associated angiogenesis play key roles in tumour growth and cancer metastasis. Consequently, several anti-angiogenic drugs such as sunitinib and axitinib have...
Tumour-associated angiogenesis play key roles in tumour growth and cancer metastasis. Consequently, several anti-angiogenic drugs such as sunitinib and axitinib have been approved for use as anti-cancer therapies. However, the majority of these drugs target the vascular endothelial growth factor A (VEGFA)/VEGF receptor 2 (VEGFR2) pathway and have shown mixed outcome, largely due to development of resistances and increased tumour aggressiveness. In this study, we used the zebrafish model to screen for novel anti-angiogenic molecules from a library of compounds derived from natural products. From this, we identified canthin-6-one, an indole alkaloid, which inhibited zebrafish intersegmental vessel (ISV) and sub-intestinal vessel development. Further characterisation revealed that treatment of canthin-6-one reduced ISV endothelial cell number and inhibited proliferation of human umbilical vein endothelial cells (HUVECs), suggesting that canthin-6-one inhibits endothelial cell proliferation. Of note, canthin-6-one did not inhibit VEGFA-induced phosphorylation of VEGFR2 in HUVECs and downstream phosphorylation of extracellular signal-regulated kinase (Erk) in leading ISV endothelial cells in zebrafish, suggesting that canthin-6-one inhibits angiogenesis independent of the VEGFA/VEGFR2 pathway. Importantly, we found that canthin-6-one impairs tumour-associated angiogenesis in a zebrafish B16F10 melanoma cell xenograft model and synergises with VEGFR inhibitor sunitinib malate to inhibit developmental angiogenesis. In summary, we showed that canthin-6-one exhibits anti-angiogenic properties in both developmental and pathological contexts in zebrafish, independent of the VEGFA/VEGFR2 pathway and demonstrate that canthin-6-one may hold value for further development as a novel anti-angiogenic drug.
PubMed: 38256941
DOI: 10.3390/ph17010108 -
Heliyon Jan 2024Clear cell renal cell carcinoma (ccRCC) represents a frequent subtype of kidney cancer, with the prognosis remaining poor for individuals with metastatic disease. Given...
Clear cell renal cell carcinoma (ccRCC) represents a frequent subtype of kidney cancer, with the prognosis remaining poor for individuals with metastatic disease. Given its resistance to both radiation and chemotherapy, targeted therapies and immunotherapies have emerged as critical for effective ccRCC treatment. Within this context, the SNARE protein STX4, which is associated with malignant cancer cell migration, provides a promising focus. The underlying mechanism, however, requires further illumination. Furthermore, the influence of STX4 on the ccRCC tumor microenvironment remains to be determined. In our research, we utilized multiple databases and immunohistochemical staining to confirm differential STX4 expression and its prognostic implications. We evaluated the potential tumor-promoting function of STX4 in ccRCC cell lines through molecular studies. Additionally, we conducted functional enrichment analysis to delve deeper into the underlying mechanisms and performed immune infiltration and drug sensitivity analyses to assess the potential of STX4 as a prognostic biomarker and therapeutic target. Our study reveals that STX4 contributes to cancer progression by enhancing AKT expression and stimulating the activation of VEGF signaling pathways. Additionally, STX4 further fosters CD8 T-cell infiltration and diminishes the percentage of CAFs and M2-TAMs. Our findings suggest that patients presenting higher STX4 levels may exhibit enhanced responsiveness to immunotherapy and higher sensitivity to the medications axitinib and everolimus. Finally, we propose STX4 expression assessment as a novel approach to predict patient response to respective immunotherapies and targeted treatments, hence potentially improving patient outcomes.
PubMed: 38226288
DOI: 10.1016/j.heliyon.2023.e23918 -
BMC Women's Health Jan 2024Both mitophagy and long non-coding RNAs (lncRNAs) play crucial roles in ovarian cancer (OC). We sought to explore the characteristics of mitophagy-related gene (MRG) and...
BACKGROUND
Both mitophagy and long non-coding RNAs (lncRNAs) play crucial roles in ovarian cancer (OC). We sought to explore the characteristics of mitophagy-related gene (MRG) and mitophagy-related lncRNAs (MRL) to facilitate treatment and prognosis of OC.
METHODS
The processed data were extracted from public databases (TCGA, GTEx, GEO and GeneCards). The highly synergistic lncRNA modules and MRLs were identified using weighted gene co-expression network analysis. Using LASSO Cox regression analysis, the MRL-model was first established based on TCGA and then validated with four external GEO datasets. The independent prognostic value of the MRL-model was evaluated by Multivariate Cox regression analysis. Characteristics of functional pathways, somatic mutations, immunity features, and anti-tumor therapy related to the MRL-model were evaluated using abundant algorithms, such as GSEA, ssGSEA, GSVA, maftools, CIBERSORT, xCELL, MCPcounter, ESTIMATE, TIDE, pRRophetic and so on.
RESULTS
We found 52 differentially expressed MRGs and 22 prognostic MRGs in OC. Enrichment analysis revealed that MRGs were involved in mitophagy. Nine prognostic MRLs were identified and eight optimal MRLs combinations were screened to establish the MRL-model. The MRL-model stratified patients into high- and low-risk groups and remained a prognostic factor (P < 0.05) with independent value (P < 0.05) in TCGA and GEO. We observed that OC patients in the high-risk group also had the unfavorable survival in consideration of clinicopathological parameters. The Nomogram was plotted to make the prediction results more intuitive and readable. The two risk groups were enriched in discrepant functional pathways (such as Wnt signaling pathway) and immunity features. Besides, patients in the low-risk group may be more sensitive to immunotherapy (P = 0.01). Several chemotherapeutic drugs (Paclitaxel, Veliparib, Rucaparib, Axitinib, Linsitinib, Saracatinib, Motesanib, Ponatinib, Imatinib and so on) were found with variant sensitivity between the two risk groups. The established ceRNA network indicated the underlying mechanisms of MRLs.
CONCLUSIONS
Our study revealed the roles of MRLs and MRL-model in expression, prognosis, chemotherapy, immunotherapy, and molecular mechanism of OC. Our findings were able to stratify OC patients with high risk, unfavorable prognosis and variant treatment sensitivity, thus improving clinical outcomes for OC patients.
Topics: Female; Humans; RNA, Long Noncoding; Mitophagy; Ovarian Neoplasms; Paclitaxel; Axitinib; Prognosis
PubMed: 38218807
DOI: 10.1186/s12905-023-02864-5 -
Cells Dec 2023Hepatocellular carcinoma (HCC) results in high mortality due to ineffective systemic therapy. Human immortalized cell lines are commonly used to study anti-tumor effects...
Hepatocellular carcinoma (HCC) results in high mortality due to ineffective systemic therapy. Human immortalized cell lines are commonly used to study anti-tumor effects in the context of new anti-tumor therapies and tumor biology. As immortalized cell lines have limited biological relevance and heterogeneity compared to primary cells, patient-derived tumor tissues, and corresponding immune cells are the gold standards for studying the complexity of individual tumor entities. However, culturing primary HCC cells has a low success rate. Here, we aimed to establish a reproducible approach to preserve the patient-derived liver cancer cells for in vitro and in vivo studies. The underlying study aimed to establish an in vitro pre-screening platform to test treatment options' effectivity and dosage, e.g., for new substances, autologous modified immune cells, or combined therapies in HCC. We initially employed 15 surgical resection specimens from patients with different HCC entities for isolation and preservation. The isolated liver cancer cells from four HCC-diagnosed patients were used for orthotopic transplantation into the healthy liver of immunodeficient mice, allowing them to grow for six months before human liver cancer cells were isolated and cultured. As a result, we generated and characterized four new primary-like liver cancer cell lines. Compared to immortalized HCC cell lines, freshly generated liver cancer cells displayed individual morphologies and heterogeneous protein-level characteristics. We assessed their ability to proliferate, migrate, form spheroids, and react to common medications compared to immortalized HCC cell lines. All four liver cancer cell lines exhibit strong migration and colony-forming characteristics in vitro, comparable to extensively investigated immortalized HCC cell lines. Moreover, the four etiological different liver cancer cell lines displayed differences in the response to 5-FU, Sorafenib, Axitinib, and interferon-alpha treatment, ranking from non-responders to responders depending on the applicated medication. In sum, we generated individual patient-derived liver cancer cell lines suitable for predictive in vitro drug screenings and for xenograft transplantations to realize the in vivo investigation of drug candidates. We overcame the low cultivation success rate of liver cancer cells derived from patients and analyzed their potential to serve a pre-clinical model.
Topics: Humans; Animals; Mice; Carcinoma, Hepatocellular; Drug Evaluation, Preclinical; Liver Neoplasms; Transplantation, Heterologous; Cell Line
PubMed: 38201286
DOI: 10.3390/cells13010082 -
World Journal of Surgical Oncology Jan 2024Head and neck cancer (HNC) is one of the most frequent malignancies in Asian males with a poor prognosis. Apart from well-known prognostic indicators, markers of tumor... (Review)
Review
BACKGROUND
Head and neck cancer (HNC) is one of the most frequent malignancies in Asian males with a poor prognosis. Apart from well-known prognostic indicators, markers of tumor hypoxia can help us predict response to treatment and survival.
METHODS
A review of the literature on the present evidence and potential clinical importance of tumor hypoxia in head and neck cancer was carried out. The data obtained from the literature search is presented as a narrative review.
RESULTS
The literature shows possible associations between prognosis and low tumor oxygenation. Intermediate hypoxia biomarkers like HIF-1, GLUT-1, miRNA, and lactate, can help in predicting the response to therapy and survival as their altered expression is related to prognosis.
CONCLUSIONS
Hypoxia is common in HNC and can be detected by use of biomarkers. The tumors that show expression of hypoxia biomarkers have poor prognosis except for patients with human papilloma virus-associated or VHL-associated cancers. Therapeutic targeting of hypoxia is emerging; however, it is still in its nascent stage, with increasing clinical trials hypoxia is set to emerge as an attractive therapeutic target in HNC.
Topics: Male; Humans; Tumor Hypoxia; Mouth Neoplasms; Hypoxia; Lactic Acid; Biomarkers
PubMed: 38200568
DOI: 10.1186/s12957-023-03284-3 -
Translational Cancer Research Dec 2023Gastric cancer (GC) is one of the most prevalent cancer types that reduce human life expectancy. The current tumor-node-metastasis (TNM) staging system is inadequate in...
BACKGROUND
Gastric cancer (GC) is one of the most prevalent cancer types that reduce human life expectancy. The current tumor-node-metastasis (TNM) staging system is inadequate in identifying higher or lower risk of GC patients because of tumor heterogeneity. Research shows that complement plays a dual role in the tumor development and progression of GC.
METHODS
We downloaded GC data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A complement-related risk signature was constructed through bioinformatics analysis. Subsequently, the predictive ability of this signature was validated with GSE84437 dataset, and a nomogram integrating risk score and common clinical factors was established. Besides, we evaluated the association of risk score with the immune and stromal cell infiltration in TCGA. Furthermore, immunotherapy response prediction and drug susceptibility analysis were conducted to access the ability of the risk signature in predicting the therapeutic effect.
RESULTS
A complement-related gene (CRG) signature, based on six genes (, , , , , and ), was established. In both the training and validation sets, the overall survival of GC patients in the high-risk group was lower than that of the low-risk group, and the nomogram to predict the 1-, 2-, and 3-year survival rates of GC patients was developed. In addition, CIBERSORT algorithm showed the high-risk patients had higher levels of immune cell infiltration than low-risk patients, and the ESTIMATE results implied that the high-risk group had more stromal component in tumor microenvironment. Besides, compared to the low-risk group, there were higher expressions of most immune checkpoint genes and HLA genes in the high-risk group, and the high-risk patients showed higher sensitivity to the chemotherapy and targeted drugs (axitinib, dasatinib, pazopanib, saracatinib, sunitinib and temsirolimus).
CONCLUSIONS
The novel CRG signature may act as a reliable, efficient tool for prognostic prediction and treatment guidance in future clinical practice.
PubMed: 38192986
DOI: 10.21037/tcr-23-628 -
Oncology Letters Feb 2024Immune checkpoint inhibitor (ICI) therapies have broadened the armamentarium for metastatic renal cell carcinoma (mRCC). As the ICI therapy spreads in the clinical...
Immune checkpoint inhibitor (ICI) therapies have broadened the armamentarium for metastatic renal cell carcinoma (mRCC). As the ICI therapy spreads in the clinical settings, immune-related adverse events are more of a concern for clinicians. The present study reports three cases of mRCC treated with pembrolizumab plus axitinib and diagnosed hypopituitarism based on clinical symptoms and hormonal profile. Acute methylprednisolone infusion therapy was necessary in one case because of severe adrenal hypofunction; however, the clinical symptoms of the other two cases were controlled with oral corticosteroid therapy. To the best of our knowledge, there is no report of pembrolizumab plus axitinib related hypopituitarism in the treatment of mRCC. The present cases suggests that hypopituitarism after pembrolizumab plus axitinib treatment for mRCC can be handled with steroid therapy even after the development of hypopituitarism.
PubMed: 38192652
DOI: 10.3892/ol.2023.14199 -
Case Reports in Oncology 2024Immune checkpoint inhibitors (ICIs)-based combinations have improved survival outcomes of advanced renal cell carcinoma (RCC) patients and are currently recommended as...
Pathological Complete Response to Pembrolizumab plus Axitinib Combination following Serious Immune-Related Adverse Events in an Advanced Renal Cell Carcinoma Patient with a History of Rheumatoid Arthritis.
Immune checkpoint inhibitors (ICIs)-based combinations have improved survival outcomes of advanced renal cell carcinoma (RCC) patients and are currently recommended as first-line treatment options. Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD) of unknown etiology characterized by a chronic inflammatory process involving joints and extra-articular organs. Patients with AD are usually excluded from large randomized clinical trials investigating immunotherapeutic drugs. Therefore, little is known about clinical outcomes of patients with a history of RA treated with ICIs in real-world practice. In the present study, we report the clinical outcome of an advanced RCC patient with a history of RA treated with pembrolizumab in combination with axitinib. The patient experienced serious immune-related adverse events (irAEs) and achieved pathological complete response following only one ICI administration. Our case report shows that ICI-based combinations can be administered efficaciously in advanced RCC patients with a history of AD. However, a close monitoring of these patients is required, given the risk of irAEs and clinical exacerbations of symptoms associated with the preexisting AD. Moreover, prospective clinical data are needed to assess the hypothesis of a correlation between the onset of irAEs and AD flares and responses and survival outcomes to ICIs.
PubMed: 38188482
DOI: 10.1159/000535460