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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 -
Urologic Oncology Feb 2024Deciding on the optimal second-line (2L) treatment for metastatic clear-cell renal cell carcinoma (ccRCC) remains challenging due to the limited information comparing... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Deciding on the optimal second-line (2L) treatment for metastatic clear-cell renal cell carcinoma (ccRCC) remains challenging due to the limited information comparing each of the available options and the influence of the newly expanding first-line (1L) agents.
PATIENTS AND METHODS
We identified phase II/III randomized controlled trials (RCTs) evaluating 2L treatments in metastatic ccRCC. This Network Meta-analysis (NMA) evaluates the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and severe adverse events (SAE). We used normal likelihood model to incorporate log hazard ratios (HRs), odds ratios (OR), and 95%-confidence-intervals (CI). Treatment p-scores were used for ranking. Data was analyzed in a fixed-effects model using the netmeta package in R v.1.5-0.
RESULTS
All therapies demonstrated some benefits over placebo. Lenvatinib + everolimus ranked first for OS (HR = 0.44; 95%CI = 0.24-0.82; p-score = 0.92), PFS (HR = 0.13; 95%CI = 0.07-0.24, p-score = 0.98), and ORR (OR = 35.95; 95%CI = 11.55-111.87; p-score = 0.93) compared to placebo, though with a higher SAE (OR = 5.27; p-score = 0.23). Cabozantinib ranked second for OS (HR = 0.57, p-score = 0.80), PFS (HR = 0.19; p-score = 0.86), and ORR (OR = 27.24, p-score = 0.84). Nivolumab was third for ORR (p-score = 0.79), fourth for OS (p-score = 0.69), fifth for PFS (p-score = 0.61), and last for SAE (p-score = 0.83). Lenvatinib monotherapy ranked worst SAE (OR = 5.89, p-score = 0.17) and third for OS and PFS. The latest drug, tivozanib, was sixth for PFS, OS, and ORR. The NMA matrix revealed no differential OS benefit between cabozantinib, lenvatinib + everolimus, and nivolumab. Other regimens had no significant OS benefit when compared to placebo.
CONCLUSION
Based on OS and PFS, the lenvtatinib + everolimus combination yielded superior, followed by cabozantinib and Lenvatinib monotherapies; all were limited by a worse SAE profile. Nivolumab and pazopanib had the lowest odds of SAEs.
Topics: Humans; Carcinoma, Renal Cell; Antineoplastic Agents; Everolimus; Nivolumab; Kidney Neoplasms; Network Meta-Analysis; Anilides; Phenylurea Compounds; Pyridines; Quinolines
PubMed: 38216444
DOI: 10.1016/j.urolonc.2023.12.002 -
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 -
Current Opinion in Oncology Jul 2024This article discusses the evolving approaches to desmoid tumors management, shedding light on recent developments. (Review)
Review
PURPOSE OF REVIEW
This article discusses the evolving approaches to desmoid tumors management, shedding light on recent developments.
RECENT FINDINGS
Active surveillance has become the primary approach for managing primary peripheral desmoid tumors. This strategy was initially based on evidence from retrospective studies. Roughly 50% of cases managed with active surveillance show spontaneous stabilization or regression. Recent prospective trials conducted in Italy, The Netherlands, and France (2022-2023) confirm the efficacy of active surveillance, revealing 3-year progression-free survival rates ranging from 53.4 to 58%. For the patients under active surveillance, decisions regarding treatment are based on significant tumor growth or progressive symptoms. Moreover, three contemporary randomized trials investigated medical treatments for progressive or recurrent desmoid tumors. Sorafenib, pazopanib, and nirogacestat demonstrated clinical activity, as evidenced by favorable progression-free survival and objective response rates.
SUMMARY
Active surveillance has solidified its position as the primary management approach for desmoid tumors, validated by three robust prospective studies. Three recent randomized trials explored medical treatment for progressive or recurrent desmoid tumors, revealing promising clinical activities.
Topics: Humans; Fibromatosis, Aggressive; Watchful Waiting; Randomized Controlled Trials as Topic; Sorafenib; Indazoles; Pyrimidines; Sulfonamides
PubMed: 38726846
DOI: 10.1097/CCO.0000000000001049 -
Drug Metabolism and Pharmacokinetics Apr 2024Pazopanib exhibits pH-dependent solubility and its absorption depends primarily on the stomach pH. Significant decrease of pazopanib absorption by coadministration with...
Pazopanib exhibits pH-dependent solubility and its absorption depends primarily on the stomach pH. Significant decrease of pazopanib absorption by coadministration with proton pump inhibitors in clinical situation need to be overcome. Thus, the purpose of this study is firstly to investigate the effect of acidic beverages and sodium citrate buffer on the solubility of pazopanib and secondly to examine the effect of sodium citrate buffer on pazopanib absorption in a rat model with esomeprazole-mediated gastric acid suppression. Pazopanib solubility decreased with increasing pH of sodium citrate buffer in vitro. Interestingly, its solubility in some acidic beverages was significantly lower than that in sodium citrate buffer of the same pH. The AUC of pazopanib administered in tap water to rats treated with esomeprazole (ESP rats) was 66 % lower than that in the control rats treated with saline. However, AUC was 4.8 times higher in ESP rats that received pazopanib with sodium citrate buffer (pH 2.3) compared to ESP rats that received pazopanib with tap water. Our results indicate that the drug-drug interactions between pazopanib and proton pump inhibitors can be overcome, at least in part, by suspending pazopanib in sodium citrate buffer.
Topics: Rats; Animals; Proton Pump Inhibitors; Esomeprazole; Sodium Citrate; Solubility; Gastric Acid; Sodium; Water; Hydrogen-Ion Concentration; Indazoles; Pyrimidines; Sulfonamides
PubMed: 38447327
DOI: 10.1016/j.dmpk.2024.100995 -
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 -
Cureus Sep 2023Anticancer agents are responsible for a majority of adverse drug reactions (ADRs) in cancer patients. ADR reporting with anticancer drugs is very rare in India due to...
INTRODUCTION
Anticancer agents are responsible for a majority of adverse drug reactions (ADRs) in cancer patients. ADR reporting with anticancer drugs is very rare in India due to the lack of awareness and knowledge about the Pharmacovigilance Programme of India. Hence, this study was done to assess the pattern of ADRs with anticancer agents in cancer patients and to increase awareness about ADR monitoring among healthcare professionals.
MATERIALS AND METHODS
This is an observational, retrospective and non-interventional study conducted in an ADR monitoring centre (AMC) in Govt. Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, North India. Voluntarily reported ADR forms with anticancer drugs as suspected drugs over a period of seven years from January 2016 to December 2022 were analyzed. Various parameters were analyzed, which include demographic details of the patients, type of ADR, department reporting ADR and suspected drug. Causality assessment, severity assessment and preventability assessment were done according to the World Health Organization Uppsala Monitoring Centre (WHO-UMC) scale, modified Hartwig and Siegel scale and modified Schumock and Thornton scale, respectively.
RESULTS
The maximum numbers of ADRs were reported in the age group of 41-60 years (68.29%) and in females (59.75%). The maximum number of ADRs was reported with the use of taxanes (docetaxel and paclitaxel) (24.39%), targeted drugs (geftinib, imatinib, bortezomib, bevacizumab, rituximab and pazopanib) (24.39%) and platinum co-ordination complexes (cisplatin, oxaliplatin and carboplatin) (17.07%). Majority of the ADRs reported were shivering and ADRs on the skin. Majority of the ADRs were probable (64.70%), mild in nature (85.29%), definitely preventable (45.58%) and probably preventable (45.58%).
CONCLUSION
ADR monitoring is needed to increase the outcome of anticancer drug treatment in cancer patients. The quality of treatment in cancer patients can be improved through the timely management of these ADRs. It is a need of the present era to inform healthcare professionals about the Pharmacovigilance Programme to increase the reporting of ADRs due to anticancer drugs.
PubMed: 37822427
DOI: 10.7759/cureus.44984 -
Nature Reviews. Rheumatology May 2024
Topics: Pyrimidines; Indazoles; Sulfonamides; Humans; Osteoarthritis; Nanoparticles; Angiogenesis Inhibitors
PubMed: 38503892
DOI: 10.1038/s41584-024-01104-w -
The Journal of Dermatology Jul 2023Cutaneous angiosarcoma (CAS) is a rare and highly aggressive type of vascular tumor. Although chemoradiotherapy with taxanes is recognized as a first-line therapy for...
Cutaneous angiosarcoma (CAS) is a rare and highly aggressive type of vascular tumor. Although chemoradiotherapy with taxanes is recognized as a first-line therapy for CAS, second-line therapy for CAS remains controversial. From the above findings, the efficacy and safety profiles of taxane-switch (change paclitaxel to docetaxel or vise), eribulin methylate, and pazopanib regimens in second-line chemotherapy were evaluated retrospectively in 50 Japanese taxane-resistant CAS patients. Although there was no significant difference in progression-free survival (P = 0.3528) among the regimens, the incidence of all adverse events (AEs) (P = 0.0386), as well as severe G3 or more AEs (P = 0.0477) was significantly higher in the eribulin methylate group and pazopanib group than in the taxane-switch group. The present data suggest that switching to another taxane should be considered for the treatment of taxane-resistant CAS in second-line therapy based on the safety profiles.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; East Asian People; Hemangiosarcoma; Paclitaxel; Retrospective Studies; Skin Neoplasms; Taxoids
PubMed: 36938650
DOI: 10.1111/1346-8138.16786