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Omics : a Journal of Integrative Biology Feb 2024High-grade gliomas (HGGs) are extremely aggressive primary brain tumors with high mortality rates. Despite notable progress achieved by clinical research and biomarkers...
High-grade gliomas (HGGs) are extremely aggressive primary brain tumors with high mortality rates. Despite notable progress achieved by clinical research and biomarkers emerging from proteomics studies, efficacious drugs and therapeutic targets are limited. This study used targeted proteomics, molecular docking, and simulation-based drug repurposing to identify potential drug candidates for HGGs. Importantly, we performed multiple reaction monitoring (MRM) on differentially expressed proteins with putative roles in the development and progression of HGGs based on our previous work and the published literature. Furthermore, molecular docking-based drug repurposing was performed with a customized library of FDA-approved drugs to identify multitarget-directed ligands. The top drug candidates such as Pazopanib, Icotinib, Entrectinib, Regorafenib, and Cabozantinib were explored for their drug-likeness properties using the SwissADME. Pazopanib exhibited binding affinities with a maximum number of proteins and was considered for molecular dynamic simulations and cell toxicity assays. HGG cell lines showed enhanced cytotoxicity and cell proliferation inhibition with Pazopanib and Temozolomide combinatorial treatment compared to Temozolomide alone. To the best of our knowledge, this is the first study combining MRM with molecular docking and simulation-based drug repurposing to identify potential drug candidates for HGG. While the present study identified five multitarget-directed potential drug candidates, future clinical studies in larger cohorts are crucial to evaluate the efficacy of these molecular candidates. The research strategy and methodology used in the present study offer new avenues for innovation in drug discovery and development which may prove useful, particularly for cancers with low cure rates.
Topics: Humans; Temozolomide; Molecular Docking Simulation; Drug Repositioning; Glioma; Indazoles; Pyrimidines; Sulfonamides
PubMed: 38320249
DOI: 10.1089/omi.2023.0256 -
Computers in Biology and Medicine Mar 2024Tyrosine kinase inhibitors (TKIs) are highly efficient small-molecule anticancer drugs. Despite the specificity and efficacy of TKIs, they can produce off-target...
Tyrosine kinase inhibitors (TKIs) are highly efficient small-molecule anticancer drugs. Despite the specificity and efficacy of TKIs, they can produce off-target effects, leading to severe liver toxicity, and even some of them are labeled as black box hepatotoxicity. Thus, we focused on representative TKIs associated with severe hepatic adverse events, namely lapatinib, pazopanib, regorafenib, and sunitinib as objections of study, then integrated drug side-effect data from United State Food and Drug Administration (U.S. FDA) and network pharmacology to elucidate mechanism underlying TKI-induced liver injury. Based on network pharmacology, we constructed a specific comorbidity module of high risk of serious adverse effects and created drug-disease networks. Enrichment analysis of the networks revealed the depletion of all-trans-retinoic acid and the involvement of down-regulation of the HSP70 family-mediated endoplasmic reticulum (ER) stress as key factors in TKI-induced liver injury. These results were further verified by transcription data. Based on the target prediction results of drugs and reactive metabolites, we also shed light on the association between toxic metabolites and severe hepatic adverse reactions, and thinking HSPA8, HSPA1A, CYP1A1, CYP1A2 and CYP3A4 were potential therapeutic or preventive targets against TKI-induced liver injury. In conclusion, our research provides comprehensive insights into the mechanism underlying severe liver injury caused by TKIs, offering a better understanding of how to enhance patient safety and treatment efficacy.
Topics: United States; Humans; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Chemical and Drug Induced Liver Injury, Chronic; Network Pharmacology; Chemical and Drug Induced Liver Injury
PubMed: 38308871
DOI: 10.1016/j.compbiomed.2024.108040 -
Clinical Genitourinary Cancer Apr 2024Although in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI)...
BACKGROUND
Although in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI) has been ascertained, in those with favorable risk data are ambiguous. Herein, we investigated the impact of number and type of metastatic site in patients with favorable risk to contribute to the best therapeutic choice.
MATERIAL AND METHODS
Multicenter data regarding patients with favorable risk mRCC carcinoma receiving first-line TKIs, sunitinib or pazopanib, were retrospectively collected. We divided our population into 2 groups based on the number of metastatic sites and analyzed its impact on tumor response and efficacy outcome. The Kaplan-Meier method was used to estimate efficacy outcomes and the log-rank test to examine differences between subgroups.
RESULTS
A total of 107 patients with a median age of 69 years were included in the final analysis. Patients with 1 metastatic site, compared with patients with > 1 site, had a significantly longer overall survival (OS) (not reached vs. 66 months) and a trend, although not statistically significant, of better progression-free survival (PFS) (31 vs. 17 months). In patients with 1 metastatic site, liver involvement was correlated with worse PFS and OS at the univariate analysis (P = .01) and was confirmed as independent poor prognostic factor for PFS at multivariate analysis.
CONCLUSION
In conclusion, we reported a longer OS in favorable risk mRCC patients receiving TKI with only 1 metastatic site. Nevertheless, in patients with a single metastatic site, hepatic involvement correlated with worse PFS compared to other metastatic sites.
Topics: Humans; Aged; Carcinoma, Renal Cell; Sunitinib; Retrospective Studies; Kidney Neoplasms; Disease-Free Survival; Protein Kinase Inhibitors; Indazoles; Pyrimidines; Sulfonamides
PubMed: 38296678
DOI: 10.1016/j.clgc.2024.01.006 -
Frontiers in Pharmacology 2023Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma...
Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib's angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.
PubMed: 38293667
DOI: 10.3389/fphar.2023.1281067 -
Oxford Medical Case Reports Jan 2024The treatment landscape of advanced kidney cancer has radically changed over the years. Targeting tumor angiogenesis from historical cytokines to multi-tyrosine kinase...
The treatment landscape of advanced kidney cancer has radically changed over the years. Targeting tumor angiogenesis from historical cytokines to multi-tyrosine kinase inhibitors and recently the advent of immunotherapy resulted in a radical improvement in survival but presented substantial challenges in terms of toxicity management. In countries where the access to immune checkpoints inhibitors is still very limited, tyrosine-kinase inhibitors remain the optimal choice. The toxicity profile of these agents can influence both the clinician and the patient's preference for one molecule over another. This report describes the case of a young man treated with Pazopanib in a first-line setting for stage IV renal carcinoma who developed trismus under treatment. The occurrence of this off-target toxicity has made the patient ineligible for anti-angiogenic drugs. Although side effects of tyrosine kinase inhibitors seem manageable and reversible, some less known and unusual effects may evolve into severe and irreversible complications.
PubMed: 38292153
DOI: 10.1093/omcr/omad146 -
Therapeutic Advances in Medical Oncology 2024Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin,...
BACKGROUND AND OBJECTIVES
Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin, achieved an overall response rate (ORR) of less than 10%. This fact potentially hinders the options for fast symptomatic relief or surgical rescue. The combination of trabectedin plus low-dose radiation therapy (T-XRT) demonstrated a response rate of 60% in phase I/II trial, while real-life data achieved 32.5% ORR, probably due to a more relaxed timing between treatments. These results were obtained in progressing and advanced STS. In this study, the merged databases (trial plus real life) have been analyzed, with a special focus on leiomyosarcoma patients.
DESIGN AND METHODS
As responses were seen in a wide range of sarcoma histologies (11), this study planned to analyze whether leiomyosarcoma, the largest subtype with 26 cases (30.6%) in this series, exhibited a better clinical outcome with this therapeutic strategy. In addition, four advanced and progressing leiomyosarcoma patients, all with extraordinarily long progression-free survival of over 18 months, were collected.
RESULTS
A total of 847 cycles of trabectedin were administered to 85 patients, with the median number of cycles per patient being 7 (1-45+). A trend toward a longer progression-free survival (PFS) was observed in leiomyosarcoma patients with median PFS (mPFS) of 9.9 months [95% confidence interval (CI): 1.1-18.7] 5.6 months (95% CI: 3.2-7.9) for the remaining histologies, = 0.25. When leiomyosarcoma and liposarcoma were grouped, this difference reached statistical significance, probably due to the special sensitivity of myxoid liposarcoma. The mPFS for L-sarcomas was 12.7 months (95% CI: 7-18.5) 4.3 months (95% CI: 3.3-5.3) for the remaining histologies, = 0.001. Cases with long-lasting disease control are detected among leiomyosarcoma patients.
CONCLUSION
Even when extraordinarily long-lasting responses do exist among leiomyosarcoma patients treated with T-XR, we were unable to demonstrate a significant difference favoring leiomyosarcoma patients in clinical outcomes.
PubMed: 38288156
DOI: 10.1177/17588359231225044 -
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 -
Cancer Cell International Jan 2024Pyroptosis, an inflammatory form of programmed cell death, has been implicated in the pathogenesis and progression of several cancers. However, the significance of...
BACKGROUND
Pyroptosis, an inflammatory form of programmed cell death, has been implicated in the pathogenesis and progression of several cancers. However, the significance of pyroptosis-related genes (PRGs) in papillary thyroid cancer (PTC) remains unclear.
METHODS
Transcriptome and clinical data of PTC patients were obtained from The Cancer Genome Atlas. The expression patterns of PRGs were identified by consensus clustering. A prognostic model for predicting the thyroid cancer-free interval (TCFi) employed five machine learning methods. Enrichment and immune-related analyses were performed to elucidate the role of pyroptosis. The responses to radioactive iodine (RAI), immune checkpoint inhibitors (ICIs), molecular targeted therapy (MTT), and chemotherapy (CTx) were predicted based on pyroptosis-derived features. Additionally, the expression of prognostic PRGs was validated via six external datasets, 16 cell lines, and 20 pairs of clinical samples.
RESULTS
PTC patients were classified into three PyroClusters, C1 exhibited BRFA-like tumors with the highest invasiveness and the worst prognosis, C2 presented RAS-like tumors, and C3 was characterized by gene fusion. Nine PRGs (CXCL8, GJA1, H2BC8, IFI27, PRDM1, PYCARD, SEZ6L2, SIGLEC15, TRAF6) were filtered out to construct a PyroScore prognostic model. A derived nomogram demonstrated superior predictive performance than four clinical staging systems. A strong correlation between pyroptosis and tumor immune microenvironment (TIME) remodeling was observed in mechanistic analyses. Patients with a high PyroScore exhibited "hot" tumor immunophenotypes and had a poorer prognosis but could benefit more from ICIs and CTx (such as paclitaxel). Patients with a low PyroScore were more sensitive to RAI and MTT (such as pazopanib and sorafenib).
CONCLUSIONS
PyroScore model can effectively predict TCFi in patients with PTC. Dysregulated expression of PRGs is associated with the TIME modeling. Pyroptosis features have potential significance for developing novel therapeutic strategies for PTC patients.
PubMed: 38287330
DOI: 10.1186/s12935-024-03229-0 -
Cancer Immunology, Immunotherapy : CII Jan 2024Osteosarcoma (OS) represents a profoundly invasive malignancy of the skeletal system. T cell exhaustion (Tex) is known to facilitate immunosuppression and tumor...
Osteosarcoma (OS) represents a profoundly invasive malignancy of the skeletal system. T cell exhaustion (Tex) is known to facilitate immunosuppression and tumor progression, but its role in OS remains unclear. In this study, single-cell RNA sequencing data was employed to identify exhausted T cells within the tumor immune microenvironment (TIME) of OS. We found that exhausted T cells exhibited substantial infiltration in OS samples. Pseudotime trajectory analysis revealed a progressive increase in the expression of various Tex marker genes, including PDCD1, CTLA4, LAG3, ENTPD1, and HAVCR2 in OS. GSVA showed that apoptosis, fatty acid metabolism, xenobiotic metabolism, and the interferon pathway were significantly activated in exhausted T cells in OS. Subsequently, a prognostic model was constructed using two Tex-specific genes, MYC and FCGR2B, which exhibited exceptional prognostic accuracy in two independent cohorts. Drug sensitivity analysis revealed that OS patients with a low Tex risk were responsive to Dasatinib and Pazopanib. Finally, immunohistochemistry verified that MYC and FCGR2B were significantly upregulated in OS tissues compared with adjacent tissues. This study investigates the role of Tex within the TIME of OS, and offers novel insights into the mechanisms underlying disease progression as well as the potential treatment strategies for OS.
Topics: Humans; T-Cell Exhaustion; Transcriptome; Osteosarcoma; Apoptosis; Bone Neoplasms; Tumor Microenvironment; Prognosis
PubMed: 38280005
DOI: 10.1007/s00262-023-03585-2 -
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