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Journal of Cancer Research and Clinical... Aug 2023Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in...
Pazopanib with Topotecan weekly for patients with platinum-resistant or intermediate-sensitive recurrent ovarian cancer: results of a multicentre, open label phase I/II study (TOPAZ).
PURPOSE
Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC).
METHODS
Patients (≥ 18 years) with first or second recurrence were enrolled in this multicentre open-label trial. Phase I analysed Topotecan 4 mg/m (day 1, 8, 15, ever 28 days) for six cycles to identify the maximum tolerated dose (MTD) of Pazopanib added in a dose-escalating scheme with 400 mg starting dose. The phase II analysed safety and efficacy aspects. For all patients with clinical remission a maintenance with Pazopanib until progression was allowed. This trial is registered with ClinicalTrials.gov, number NCT01600573.
RESULTS
Between June 2012 and February 2017, 11 patients were enrolled in the phase I, and 50 patients in the phase II study. The MTD of Pazopanib was determined by 400 mg/daily. Haematological and liver toxicities determined the dose limiting toxicities (DLT) and the most common grade 3-4 adverse events: leucopenia (25%), neutropenia (22%), thrombocytopenia (19%), accumulation of cholestatic (20%) and hepatocellular damage (15%), which often caused dose modifications, but no new life-threatening events. Overall response was 16% and clinical benefit rate 68%. Median progression-free survival (PFS) was 3.5 months (95% CI 2.0-5.0). Due to early progression only 20% of the patients were able to start with maintenance treatment.
CONCLUSION
The combination of pazopanib and weekly topotecan is feasible, resulting in a manageable haematological and liver toxicity, but despite its encouraging response rate, was not associated with a significant survival benefit.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Leukopenia; Neoplasm Recurrence, Local; Ovarian Neoplasms; Platinum; Topotecan
PubMed: 37000264
DOI: 10.1007/s00432-023-04647-9 -
Scientific Reports Mar 2024To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs)... (Observational Study)
Observational Study
To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs) related to various MKIs treated for renal cell carcinoma. We analyzed spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS) in an observational and retrospective manner. Selecting electrolyte disorders' adverse events to multikinase inhibitors (axitinib, cabozantinib, lenvatinib, pazopanib, sunitinib, and sorafenib). We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms to analyze suspected adverse reactions of electrolyte disorders induced by MKIs (which were treated for renal cell carcinoma) between January 2004 and December 2022. As of December 2022, 2772 MKIs (which were treated for renal cell carcinoma) ICSRs were related to electrolyte disorders AEs. In general, there were more AEs cases in males, except lenvatinib and 71.8% of the cases were submitted from North America. ICSRs in this study, the age group most frequently affected by electrolyte disorders AEs was individuals aged 45-64 years for axitinib, cabozantinib, pazopanib, and sunitinib, whereas electrolyte disorders AEs were more common in older patients (65-74 years) for sorafenib and lenvatinib. For all EDs documented in ICSRs (excluding missing data), the most common adverse outcome was hospitalization(1429/2674, 53.4%), and the most serious outcome was death/life-threat(281/2674, 10.5%). The prevalence of mortality was highest for sunitinib-related EDs (145/616, 23.5%), excluding missing data (n = 68), followed by cabozantinib-related EDs (20/237, 8.4%), excluding missing data (n = 1). The distribution of time-to-onset of Each drug-related ICSRs was not all the same, and the difference was statistically significant (P = 0.001). With the criteria of ROR, the six MKIs were all significantly associated with electrolyte disorders AEs, the strongest association was the association between cabozantinib and hypermagnesaemia. MKIs have been reported to have significant electrolyte disorders AEs. Patients and physicians need to recognize and monitor these potentially fatal adverse events.
Topics: Aged; Humans; Male; Anilides; Axitinib; Bayes Theorem; Carcinoma, Renal Cell; Electrolytes; Indazoles; Kidney Neoplasms; Pharmacovigilance; Phenylurea Compounds; Pyridines; Pyrimidines; Quinolines; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; United States; United States Food and Drug Administration; Female; Middle Aged
PubMed: 38454105
DOI: 10.1038/s41598-024-56335-4 -
Pharmacological Research Mar 2024The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological... (Review)
Review
The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological angiogenesis/lymphangiogenesis and in diseases associated to pathological vessel formation, play multifaceted functions in the central nervous system (CNS). In addition to shaping brain development, by controlling cerebral vasculogenesis and regulating neurogenesis as well as astrocyte differentiation, the VEGFs/VEGFRs axis exerts essential functions in the adult brain both in physiological and pathological contexts. In this article, after describing the physiological VEGFs/VEGFRs functions in the CNS, we focus on the VEGFs/VEGFRs involvement in neurodegenerative diseases by reviewing the current literature on the rather complex VEGFs/VEGFRs contribution to the pathogenic mechanisms of Alzheimer's (AD) and Parkinson's (PD) diseases. Thereafter, based on the outcome of VEGFs/VEGFRs targeting in animal models of AD and PD, we discuss the factual relevance of pharmacological VEGFs/VEGFRs modulation as a novel and potential disease-modifying approach for these neurodegenerative pathologies. Specific VEGFRs targeting, aimed at selective VEGFR-1 inhibition, while preserving VEGFR-2 signal transduction, appears as a promising strategy to hit the molecular mechanisms underlying AD pathology. Moreover, therapeutic VEGFs-based approaches can be proposed for PD treatment, with the aim of fine-tuning their brain levels to amplify neurotrophic/neuroprotective effects while limiting an excessive impact on vascular permeability.
Topics: Animals; Parkinson Disease; Alzheimer Disease; Vascular Endothelial Growth Factor Receptor-1; Central Nervous System; Brain
PubMed: 38336311
DOI: 10.1016/j.phrs.2024.107101 -
Oncogene May 2024Clear cell renal cell carcinoma (ccRCC) presents a unique profile characterized by high levels of angiogenesis and robust vascularization. Understanding the underlying...
Clear cell renal cell carcinoma (ccRCC) presents a unique profile characterized by high levels of angiogenesis and robust vascularization. Understanding the underlying mechanisms driving this heterogeneity is essential for developing effective therapeutic strategies. This study revealed that ubiquitin B (UBB) is downregulated in ccRCC, which adversely affects the survival of ccRCC patients. UBB exerts regulatory control over vascular endothelial growth factor A (VEGFA) by directly interacting with specificity protein 1 (SP1), consequently exerting significant influence on angiogenic processes. Subsequently, we validated that DNA methyltransferase 3 alpha (DNMT3A) is located in the promoter of UBB to epigenetically inhibit UBB transcription. Additionally, we found that an unharmonious UBB/VEGFA ratio mediates pazopanib resistance in ccRCC. These findings underscore the critical involvement of UBB in antiangiogenic therapy and unveil a novel therapeutic strategy for ccRCC.
Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Sp1 Transcription Factor; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Down-Regulation; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Animals; Pyrimidines; Indazoles; DNA Methyltransferase 3A; Sulfonamides; Mice; Ubiquitin; DNA (Cytosine-5-)-Methyltransferases; Drug Resistance, Neoplasm; Promoter Regions, Genetic; Female; Male; Angiogenesis
PubMed: 38467852
DOI: 10.1038/s41388-024-03003-6 -
BMC Medical Genomics Oct 2023The impact of inflammatory response on tumor development and therapeutic response is of significant importance in clear cell renal cell carcinoma (ccRCC). The...
OBJECTIVE
The impact of inflammatory response on tumor development and therapeutic response is of significant importance in clear cell renal cell carcinoma (ccRCC). The customization of specialized prognostication approaches and the exploration of supplementary treatment options hold critical clinical implications in relation to the inflammatory response.
METHODS
In the present study, unsupervised clustering was implemented on TCGA-KIRC tumors using transcriptome profiles of inflammatory response genes, which was then validated in two ccRCC datasets (E-MATB-1980 and ICGC) and two immunotherapy datasets (IMvigor210 and Liu et al.) via SubMap and NTP algorithms. Combining co-expression and LASSO analyses, inflammatory response-based scoring system was defined, which was evaluated in pan-cancer.
RESULTS
Three reproducible inflammatory response subtypes (named IR1, IR2 and IR3) were determined and independently verified, each exhibiting distinct molecular, clinical, and immunological characteristics. Among these subtypes, IR2 had the best OS outcomes, followed by IR3 and IR1. In terms of anti-angiogenic agents, sunitinib may be appropriate for IR1 patients, while axitinib and pazopanib may be suitable for IR2 patients, and sorafenib for IR3 patients. Additionally, IR1 patients might benefit from anti-CTLA4 therapy. A scoring system called IRscore was defined for individual ccRCC patients. Patients with high IRscore presented a lower response rate to anti-PD-L1 therapy and worse prognostic outcomes. Pan-cancer analysis demonstrated the immunological features and prognostic relevance of the IRscore.
CONCLUSION
Altogether, characterization of inflammatory response subtypes and IRscore provides a roadmap for patient risk stratification and personalized treatment decisions, not only in ccRCC, but also in pan-cancer.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Precision Medicine; Sorafenib; Axitinib; Prognosis
PubMed: 37885006
DOI: 10.1186/s12920-023-01687-5 -
Cancer Science Oct 2023Sarcomas are malignant mesenchymal tumors that are extremely rare and divergent. Fusion genes are involved in approximately 30% of sarcomas as driver oncogenes; however,...
Sarcomas are malignant mesenchymal tumors that are extremely rare and divergent. Fusion genes are involved in approximately 30% of sarcomas as driver oncogenes; however, their detailed functions are not fully understood. In this study, we determined the functional significance of 59 sarcoma-related fusion genes. The transforming potential and drug sensitivities of these fusion genes were evaluated using a focus formation assay (FFA) and the mixed-all-nominated-in-one (MANO) method, respectively. The transcriptome was also examined using RNA sequencing of 3T3 cells transduced with each fusion gene. Approximately half (28/59, 47%) of the fusion genes exhibited transformation in the FFA assay, which was classified into five types based on the resulting phenotype. The sensitivity to 12 drugs including multityrosine kinase inhibitors was assessed using the MANO method and pazopanib was found to be more effective against cells expressing the COL1A1-PDGFB fusion gene compared with the others. The downstream MAPK/AKT pathway was suppressed at the protein level following pazopanib treatment. The fusion genes were classified into four subgroups by cluster analysis of the gene expression data and gene set enrichment analysis. In summary, the oncogenicity and drug sensitivity of 59 fusion genes were simultaneously evaluated using a high-throughput strategy. Pazopanib was selected as a candidate drug for sarcomas harboring the COL1A1-PDGFB fusion gene. This assessment could be useful as a screening platform and provides a database to evaluate customized therapy for fusion gene-associated sarcomas.
PubMed: 37592448
DOI: 10.1111/cas.15915 -
European Journal of Pharmaceutical... Sep 2023Pazopanib (PZ) is a multikinase inhibitor, which is mainly used in the treatment of soft tissue sarcoma and advanced renal cancer. However, because of its water...
Pazopanib (PZ) is a multikinase inhibitor, which is mainly used in the treatment of soft tissue sarcoma and advanced renal cancer. However, because of its water insolubility, oral bioavailability is poor. At the same time, photo lability and high dose oral administration lead to severe hepatotoxicity, which is limited in clinical application. In this paper, the novel pazopanib-fumarate disodium glycyrrhizinate nanocrystalline micelles are successfully prepared by liquid-assisted ball milling. The prepared cocrystals and nanocrystalline micelle structures are systematically characterized by X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier Transform Infrared Spectrometer (FTIR) analysis. In vitro solubility and dissolution experiments show that the solubility and dissolution of nanocrystalline micelles are significantly improved under different simulated physiological conditions. The accelerated stabilization experiments show that the nanocrystalline micelles have good physical and chemical stability and showed excellent stability in water (Zeta potential was 62.39 mV). In addition, the in vivo bioavailability of nanocrystalline micelles is 3 times higher than that of PZ, and the therapeutic threshold (> 20 μg/mL) is up to 30 h. This new strategy provides a feasible solution to the undesirable properties of PZ.
Topics: Micelles; Fumarates; Solubility; Calorimetry, Differential Scanning; Glycyrrhetinic Acid; Water; X-Ray Diffraction; Biological Availability; Spectroscopy, Fourier Transform Infrared
PubMed: 37459902
DOI: 10.1016/j.ejps.2023.106530 -
Oncoscience 2023Pazopanib is a multi-kinase inhibitor that is currently approved for treatment of advanced renal cell carcinoma and chemotherapy-refractory soft tissue sarcoma. In this...
Pazopanib is a multi-kinase inhibitor that is currently approved for treatment of advanced renal cell carcinoma and chemotherapy-refractory soft tissue sarcoma. In this case report, we discuss the case of a patient with a fusion positive bone sarcoma who had exceptional tumor control through using pazopanib and surgery for an overall duration exceeding 5 years. We also review the literature on translocation-associated sarcomas and use of pazopanib in bone sarcomas.
PubMed: 37736255
DOI: 10.18632/oncoscience.587 -
Kidney Research and Clinical Practice Jul 2023Mounting evidence indicates that melatonin has possible activity against different tumors. Pazopanib is an anticancer drug used to treat renal cell carcinoma (RCC). This...
Melatonin acts synergistically with pazopanib against renal cell carcinoma cells through p38 mitogen-activated protein kinase-mediated mitochondrial and autophagic apoptosis.
BACKGROUND
Mounting evidence indicates that melatonin has possible activity against different tumors. Pazopanib is an anticancer drug used to treat renal cell carcinoma (RCC). This study tested the anticancer activity of melatonin combined with pazopanib on RCC cells and explored the underlying mechanistic pathways of its action.
METHODS
The 786-O and A-498 human RCC cell lines were used as cell models. Cell viability and tumorigenesis were detected with the MTT and colony formation assays, respectively. Apoptosis and autophagy were assessed using TUNEL, annexin V/propidium iodide, and acridine orange staining with flow cytometry. The expression of cellular signaling proteins was investigated with western blotting. The in vivo growth of tumors derived from RCC cells was evaluated using a xenograft mouse model.
RESULTS
Together, melatonin and pazopanib reduced cell viability and colony formation and promoted the apoptosis of RCC cells. Furthermore, the combination of melatonin and pazopanib triggered more mitochondrial, caspase-mediated, and LC3-II-mediated autophagic apoptosis than melatonin or pazopanib alone. The combination also induced higher activation of the p38 mitogen-activated protein kinase (p38MAPK) in the promotion of autophagy and apoptosis by RCC cells than melatonin or pazopanib alone. Finally, tumor xenograft experiments confirmed that melatonin and pazopanib cooperatively inhibited RCC growth in vivo and predicted a possible interaction between melatonin/pazopanib and LC3-II.
CONCLUSION
The combination of melatonin and pazopanib inhibits the growth of RCC cells by inducing p38MAPK-mediated mitochondrial and autophagic apoptosis. Therefore, melatonin might be a potential adjuvant that could act synergistically with pazopanib for RCC treatment.
PubMed: 37165617
DOI: 10.23876/j.krcp.22.114 -
Nature Communications Jan 2024We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic...
We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (9 [19.1%]), elevated aspartate aminotransferase (7 [14.9%]), alanine aminotransferase (5 [10.6%]), and thrombocytopenia (4 [8.5%]). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20 B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20 B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile.
Topics: Humans; Neoplasm Recurrence, Local; Sarcoma; Soft Tissue Neoplasms; Antibodies, Monoclonal; Indazoles; Pyrimidines; Sulfonamides
PubMed: 38263321
DOI: 10.1038/s41467-024-44875-2