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Therapie Apr 2024In 2017, the Continuum+ platform was launched to provide a monitoring solution to home-based cancer care patients: AKO@dom monitoring. This platform also offers the...
In 2017, the Continuum+ platform was launched to provide a monitoring solution to home-based cancer care patients: AKO@dom monitoring. This platform also offers the follow-up of adverse drug reactions (ADRs) via direct notification to regional centers of pharmacovigilance (RCPVs). According to previous studies, the AKO@dom monitoring has successfully maintained treatment at the maximum effective dosage, managing ADRs and patient satisfaction. However, on the pharmacovigilance side, opinions are more divided. Due to the launch of the AKO@dom-PICTO experimentation in December 2021, in which our RCPV takes part, and to provide more data on pharmacovigilance, we decided to conduct a descriptive analysis of cases reported to our RCPV via the Continuum+ platform between 2019 and 2022. During these three years, we analyzed 1070 events, corresponding to 37 patients. Patients were primarily women (74.8%) aged around seventy with breast cancer. The most used drugs were tyrosine kinase inhibitors: palbociclib (29.7%), axitinib (16.2%), and cabozantinib (13.2%). Patients had an average of 8 ADRs, including one serious and/or unexpected ADR. Although the Continuum+ platform makes it possible to considerably limit under-reporting in pharmacovigilance, it has shortcomings. The lack of medical elements and context in notifications is a massive problem for analyzing pharmacovigilance reports. Improved access to the platform's medical information for RCPVs and pharmacovigilance training for healthcare professionals would make Continuum+ a helpful tool in pharmacovigilance.
PubMed: 38658232
DOI: 10.1016/j.therap.2024.04.001 -
ACS Applied Materials & Interfaces May 2024Antiangiogenic therapy is an effective way to disrupt nutrient supply and starve tumors, but it is restricted by poor efficacy and negative feedback-induced tumor...
Antiangiogenic therapy is an effective way to disrupt nutrient supply and starve tumors, but it is restricted by poor efficacy and negative feedback-induced tumor relapse. In this study, a neuropilin-1 (NRP-1)-targeted nanomedicine (designated as FPPT@Axi) is reported for spatiotemporal tumor suppression by combining photodynamic therapy (PDT) with antiangiogenesis. In brief, FPPT@Axi is prepared by utilizing an NRP-1-targeting chimeric peptide (Fmoc-K(PpIX)-PEG-TKPRR) to encapsulate the antiangiogenic drug Axitinib (Axi). Importantly, the NRP-1-mediated targeting property enables FPPT@Axi to selectively concentrate at vascular endothelial and breast cancer cells, facilitating the production of reactive oxygen species (ROS) for specific vascular disruption and enhanced cell apoptosis under light stimulation. Moreover, the codelivered Axi can further inhibit vascular endothelial growth factor receptor (VEGFR) to impair the negative feedback of PDT-induced tumor neovascularization. Consequently, FPPT@Axi spatiotemporally restrains the tumor growth through blocking angiogenesis, destroying tumor vessels, and inducing tumor apoptosis. Such an NRP-1-mediated targeting codelivery system sheds light on constructing an appealing candidate with translational potential by using clinically approved PDT and chemotherapy.
Topics: Neuropilin-1; Photochemotherapy; Humans; Animals; Mice; Angiogenesis Inhibitors; Neovascularization, Pathologic; Female; Axitinib; Nanomedicine; Apoptosis; Human Umbilical Vein Endothelial Cells; Breast Neoplasms; Mice, Inbred BALB C; Cell Line, Tumor; Photosensitizing Agents; Reactive Oxygen Species; Mice, Nude
PubMed: 38651381
DOI: 10.1021/acsami.4c03886 -
Nature Communications Apr 2024N-Glycosylated heterocycles play important roles in biological systems and drug development. The synthesis of these compounds heavily relies on ionic N-glycosylation,...
N-Glycosylated heterocycles play important roles in biological systems and drug development. The synthesis of these compounds heavily relies on ionic N-glycosylation, which is usually constrained by factors such as labile glycosyl donors, precious metal catalysts, and stringent conditions. Herein, we report a dehydroxylative radical method for synthesizing N-glycosides by leveraging copper metallaphotoredox catalysis, in which stable and readily available 1-hydroxy carbohydrates are activated for direct N-glycosylation. Our method employs inexpensive photo- and copper- catalysts and can tolerate some extent of water. The reaction exhibits a broad substrate scope, encompassing 76 examples, and demonstrates high stereoselectivity, favoring 1,2-trans selectivity for furanoses and α-selectivity for pyranoses. It also exhibits high site-selectivity for substrates containing multiple N-atoms. The synthetic utility is showcased through the late-stage functionalization of bioactive compounds and pharmaceuticals like Olaparib, Axitinib, and Metaxalone. Mechanistic studies prove the presence of glycosyl radicals and the importance of copper metallaphotoredox catalysis.
PubMed: 38649350
DOI: 10.1038/s41467-024-47711-9 -
Cancer Research and Treatment Apr 2024In this study, we evaluated 66 patients diagnosed with adenoid cystic carcinoma (ACC) enrolled in two Korean Cancer Study Group trials to investigate the response and...
Analysis of Response and Progression Patterns of Tyrosine Kinase Inhibitors in Recurrent or Metastatic Adenoid Cystic Carcinoma: A Post Hoc Analysis of Two KCSG Phase II Trials.
PURPOSE
In this study, we evaluated 66 patients diagnosed with adenoid cystic carcinoma (ACC) enrolled in two Korean Cancer Study Group trials to investigate the response and progression patterns in recurrent and/or metastatic ACC treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs).
MATERIALS AND METHODS
We evaluated 66 patients diagnosed with ACC who were enrolled in the Korean Cancer Study Group trials. The tumor measurements, clinical data, treatment outcomes, and progression patterns of therapy were analyzed.
RESULTS
In the 66 patients (53 receiving axitinib and 13 receiving nintedanib), the disease control rate was 61%, and 3 patients achieved partial response. The median follow-up, median progression-free survival (PFS), overall survival, and 6-month PFS rate were 27.6, 12.4, and 18.1 months and 62.1%, respectively. Among 42 patients who experienced progression, 27 (64.3%) showed target lesion progression. Bone metastasis was an independent poor prognostic factor.
CONCLUSION
Overall, most patients demonstrated stable disease with prolonged PFS; however, prominent target lesion progression occurred in some patients. Thus, PFS may capture VEGFR-TKI efficacy better than the objective response rate.
PubMed: 38637966
DOI: 10.4143/crt.2024.008 -
Current Drug Discovery Technologies 2024VEGFR-2 tyrosine kinase inhibitors are receiving a lot of attention as prospective anticancer medications in the current drug discovery process.
BACKGROUND
VEGFR-2 tyrosine kinase inhibitors are receiving a lot of attention as prospective anticancer medications in the current drug discovery process.
OBJECTIVE
This work aims to explore the PubChem library for novel VEGFR-2 kinase inhibitors. 1H-Indazole-containing drug AXITINIB, or AG-013736 (FDA approved), is chosen as a rational molecule for drug design. This scaffold proved its efficiency in treating cancer and other diseases as well.
METHODS
The present study used the virtual screening of the database, protein preparation, grid creation, and molecular docking analyses.
RESULTS
The protein was validated on different parameters like the Ramachandran plot, the ERRAT score, and the ProSA score. The Ramachandran plot revealed that 92.1% of the amino acid residues were located in the most favorable region; this was complemented by an ERRAT score (overall quality factor) of 96.24 percent and a ProSA (Z score) of -9.24 percent. The Lipinski rule of five was used as an additional filter for screening molecules. The docking results showed values of binding affinity between -14.08 and -12.34 kcal/mol. The molecule C1 showed the highest docking value of -14.08 Kcal/mol with the maximum number of strong H-bonds by -NH of pyridine to amino acid Cys104 (4.22Å), -NH of indazole to Glu108 (4.72), and Glu70 to bridge H of -NH. These interactions are similar to Axitinib docking interactions like Glu70, Cys104, and Glu102. The docking studies revealed that pi-alkyl bonds are formed with unsubstituted pyridine, whereas important H-bonds are observed with different substitutions around -NH. Based on potential findings, we designed new molecules, and molecular docking studies were performed on the same protein along with ADMET studies. The designed molecules (M1-M4) also showed comparable docking results similar to Axitinib, along with a synthetic accessibility score of less than 4.5.
CONCLUSION
The docking method employed in this work opens up new possibilities for the design and synthesis of novel compounds that can act as VEGFR-2 tyrosine kinase inhibitors and treat cancer.
Topics: Antineoplastic Agents; Axitinib; Molecular Docking Simulation; Prospective Studies; Protein Kinase Inhibitors; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Drug Design
PubMed: 38629172
DOI: 10.2174/0115701638255384230920040154 -
Minerva Urology and Nephrology Jun 2024
Complete response of metastatic RCC with caval vein thrombus following treatment with pembrolizumab and axitinib: is it possible to extend the indications for systemic therapy?
Topics: Humans; Axitinib; Antibodies, Monoclonal, Humanized; Kidney Neoplasms; Carcinoma, Renal Cell; Venous Thrombosis; Vena Cava, Inferior; Male; Middle Aged; Female; Aged
PubMed: 38618704
DOI: 10.23736/S2724-6051.24.05821-X -
Heliyon Apr 2024Clear cell renal cell carcinoma (ccRCC) presents challenges in early diagnosis and effective treatment. In this study, we aimed to establish a prognostic model based on...
Clear cell renal cell carcinoma (ccRCC) presents challenges in early diagnosis and effective treatment. In this study, we aimed to establish a prognostic model based on G2M checkpoint-related genes and identify associated clusters in ccRCC through clinical bioinformatic analysis and experimental validation. Utilizing a single-cell RNA dataset (GSE159115) and bulk-sequencing data from The Cancer Genome Atlas (TCGA) database, we analyzed the G2M checkpoint pathway in ccRCC. Differential expression analysis identified 45 genes associated with the G2M checkpoint, leading to the construction of a predictive model with four key genes (E2F2, GTSE1, RAD54L, and UBE2C). The model demonstrated reliable predictive ability for 1-, 3-, and 5-year overall survival, with AUC values of 0.794, 0.790, and 0.794, respectively. Patients in the high-risk group exhibited a worse prognosis, accompanied by significant differences in immune cell infiltration, immune function, TIDE and IPS scores, and drug sensitivities. Two clusters of ccRCC were identified using the "ConsensusClusterPlus" package, cluster 1 exhibited a worse survival rate and was resistant to chemotherapeutic drugs of Axitinib, Erlotinib, Pazopanib, Sunitinib, and Temsirolimus, but not Sorafenib. Targeted experiments on RAD54L, a gene involved in DNA repair processes, revealed its crucial role in inhibiting proliferation, invasion, and migration in 786-O cells. In conclusion, our study offers valuable insights into the molecular mechanisms underlying ccRCC, identifying potential prognostic genes and molecular subtypes associated with the G2M checkpoint. These findings hold promise for guiding personalized treatment strategies in the management of ccRCC.
PubMed: 38617927
DOI: 10.1016/j.heliyon.2024.e29289 -
Pharmacological Research May 2024Kidney cancers comprise about 3% of all new malignancies in the United States. Renal cell carcinomas (RCCs) are the most common type of renal malignancy making up about... (Review)
Review
Kidney cancers comprise about 3% of all new malignancies in the United States. Renal cell carcinomas (RCCs) are the most common type of renal malignancy making up about 85% of kidney cancer cases. Signs and symptoms of renal cell carcinomas can result from local tumor growth, paraneoplastic syndromes, or distant metastases. The classic triad of presentation with flank pain, hematuria, and a palpable abdominal mass occurs in fewer than 10% of patients. Most diagnoses result from incidental imaging findings (ultrasonography or abdominal CT imaging) performed for another reason. Localized disease is treated by partial nephrectomy, total nephrectomy, or ablation (tumor destruction with heat or cold). When the tumors have metastasized, systemic therapy with protein-tyrosine kinase antagonists including sorafenib, sunitinib, pazopanib, and tivozanib that target vascular endothelial, platelet-derived, fibroblast, hepatocyte, and stem cell factor growth factor receptors (VEGFR, PDGFR, FGFR, MET, and Kit) were prescribed after 2005. The monoclonal antibody immune checkpoint inhibitor nivolumab (targeting programed cell death protein 1, PD1) was approved for the treatment of RCCs in 2015. It is usually used now in combination with ipilimumab (targeting CTLA-4) or cabozantinib (a multikinase blocker). Other combination therapies include pembrolizumab (targeting PD1) and axitinib (a VEGFR and PDGFR blocker) or lenvatinib (a multikinase inhibitor). Since the KEYNOTE-426 clinical trial, the use of immune checkpoint inhibitors in combination with protein-tyrosine kinase inhibitors is now the standard of care for most patients with metastatic renal cell carcinomas and monotherapies are used only in those individuals who cannot receive or tolerate immune checkpoint inhibitors.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38614375
DOI: 10.1016/j.phrs.2024.107181 -
Expert Opinion on Pharmacotherapy Apr 2024Increasing evidence from preclinical and clinical studies suggests the role of vascular endothelial growth factor (VEGF) signaling in melanoma progression, response to... (Review)
Review
INTRODUCTION
Increasing evidence from preclinical and clinical studies suggests the role of vascular endothelial growth factor (VEGF) signaling in melanoma progression, response to therapy, and overall survival. Moreover, the discovery of the potential involvement of the VEGF pathway in resistance to immunotherapy has led to new clinical trials with VEGFR inhibitors.
AREAS COVERED
We have reviewed recent literature, mainly published within the last 5 years, on VEGFR-targeted treatments for advanced melanoma, including mucosal, acral, and uveal melanoma. The VEGFR inhibitors were used as a single therapy or combined with either immunotherapy or chemotherapy, and they were employed in treatment for KIT-mutated cutaneous melanoma and for patients with brain metastases.
EXPERT OPINION
Trials involving monotherapy have been unsuccessful in demonstrating meaningful efficacy. Despite some activity, the combination of VEGFR-targeting tyrosine kinase inhibitors (TKIs) with immune checkpoint inhibitors (ICI) in patients with ICI-resistant melanoma, the combination did not significantly improve outcomes compared to anti-PD-1 monotherapy in the first-line settings. On the contrary, some patients with mucosal, acral or -mutant melanoma may benefit from TKI-based therapies. Further studies focused on biomarker discovery and randomized trials are necessary to better understand the role of VEGFR1-3 as a therapeutic target in melanoma.
Topics: Humans; Melanoma; Protein Kinase Inhibitors; Skin Neoplasms; Immune Checkpoint Inhibitors; Animals; Antineoplastic Agents; Receptors, Vascular Endothelial Growth Factor; Immunotherapy; Drug Resistance, Neoplasm; Tyrosine Kinase Inhibitors
PubMed: 38607407
DOI: 10.1080/14656566.2024.2342403 -
Annals of Medicine and Surgery (2012) Apr 2024Renal cell carcinoma, a common kidney tumour which is often incidentally discovered on imaging, can manifest with atypical symptoms. Renal cell carcinoma with rhabdoid...
INTRODUCTION
Renal cell carcinoma, a common kidney tumour which is often incidentally discovered on imaging, can manifest with atypical symptoms. Renal cell carcinoma with rhabdoid features is a rare occurrence and even rarer in case of adults. Renal cell carcinoma has the tendency to form thrombus that can migrate to renal vein, inferior vena cava and even right atrium.
CASE PRESENTATION
The authors report a case of an 81-year-old male with rhabdoid renal cell carcinoma presenting with persistent cough for 6-7 months. with tumour thrombus extending into the renal vein and hepatic inferior vena cava. The patient was found feeble for the surgery and hence was treated on anticancer drugs pembrolizumab and axitinib.
CONCLUSION
Renal cell carcinoma has the tendency to form tumour thrombus in renal vein and inferior vena cava. Prognosis without surgical intervention in these conditions is very poor.
PubMed: 38576908
DOI: 10.1097/MS9.0000000000001923