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Expert Review of Anticancer Therapy Jun 2022Immune checkpoint inhibitors (ICIs) have made an appearance in clinical practice, and the treatment outcome of metastatic renal cell cancer (mRCC) has dramatically... (Review)
Review
INTRODUCTION
Immune checkpoint inhibitors (ICIs) have made an appearance in clinical practice, and the treatment outcome of metastatic renal cell cancer (mRCC) has dramatically improved as a result. Currently, most patients are treated with a combination of ICIs or a combination of ICI and tyrosine kinase inhibitors (TKIs). These new therapeutic tools need to be organized and summarized in order to realize and advance personalized therapy for mRCC.
AREA COVERED
In this review, the characteristics of five regimens (nivolumab plus ipilimumab, pembrolizumab plus axitinib, avelumab plus axitinib, and nivolumab plus cabozantinib and pembrolizumab plus lenvatinib) are briefly elucidated and their efficacies and safety profiles are compared. For ICI-unfit patients, the current choices are examined. In addition, the potential second-line regimens after these combination therapies are introduced as sequential treatment. Finally, in the future direction section, ongoing clinical trials are also introduced.
EXPERT OPINION
ICIs are rapidly being introduced for the treatment of mRCC. Currently, most patients are treated with a combination of ICIs or a combination of ICI and TKIs. In order to develop optimal personalized treatment for our patients, it is necessary for the physicians who treat mRCC patients to possess in-depth knowledge of these new therapeutic tools.
Topics: Axitinib; Carcinoma, Renal Cell; Humans; Immune Checkpoint Inhibitors; Kidney Neoplasms; Nivolumab; Precision Medicine
PubMed: 35531636
DOI: 10.1080/14737140.2022.2075347 -
Drug Design, Development and Therapy 2022To evaluate the effect of axitinib on buspirone metabolism in vitro and in vivo.
OBJECTIVE
To evaluate the effect of axitinib on buspirone metabolism in vitro and in vivo.
METHODS
A microsome incubation assay was performed to study the effect and mechanism of axitinib on buspirone metabolizing. In vivo, buspirone was administered with or without axitinib to Sprague-Dawley rats. Plasma samples were collected and subjected to ultra-performance liquid chromatography-tandem mass spectrometry.
RESULTS
In both human liver microsomes (HLMs) and rat liver microsomes (RLMs), axitinib (100 μM) decreased buspirone hydroxylation and N-dealkylation by >85%. Axitinib inhibited buspirone hydroxylation and N-dealkylation, with an IC of 15.76 and 9.74 for RLMs, and 10.63 and 9.902 for HLMs. Axitinib showed noncompetitive inhibition of both 6'-hydroxylation and N-dealkylation. Moreover, coadministration of axitinib and buspirone led to an increase in the maximum plasma concentration (C ) and area under the plasma concentration-time curve (AUC) of buspirone by 4.3- and 5.3-fold, respectively, compared with the control group.
CONCLUSION
Axitinib inhibited buspirone metabolism in vivo and in vitro, which increases the risk of the side effects of buspirone in the clinic. When coadministered with axitinib, a lower dosage of buspirone should be defined to avoid a toxic response. Axitinib is suspected to function as an inhibitor of CYP3A4.
Topics: Animals; Axitinib; Buspirone; Cytochrome P-450 CYP3A; Microsomes, Liver; Rats; Rats, Sprague-Dawley
PubMed: 35795848
DOI: 10.2147/DDDT.S359451 -
Stem Cell Research & Therapy Nov 2023Kidney organoids derived from human pluripotent stem cells (HiPSCs) hold huge applications for drug screening, disease modeling, and cell transplanting therapy. However,...
BACKGROUND
Kidney organoids derived from human pluripotent stem cells (HiPSCs) hold huge applications for drug screening, disease modeling, and cell transplanting therapy. However, these applications are limited since kidney organoid cannot maintain complete morphology and function like human kidney. Kidney organoids are not well differentiated since the core of the organoid lacked oxygen, nutrition, and vasculature, which creates essential niches. Hypoxia-inducible factor-1 α (HIF-1α) serves as a critical regulator in vascularization and cell survival under hypoxia environment. Less is known about the role of HIF-1α in kidney organoids in this regard. This study tried to investigate the effect of HIF-1α in kidney organoid vascularization and related disease modeling.
METHODS
For the vascularization study, kidney organoids were generated from human induced pluripotent stem cells. We overexpressed HIF-1α via plasmid transfection or treated DMOG (Dimethyloxallyl Glycine, an agent for HIF-1α stabilization and accumulation) in kidney progenitor cells to detect the endothelium. For the disease modeling study, we treated kidney organoid with cisplatin under hypoxia environment, with additional HIF-1α transfection.
RESULT
HIF-1α overexpression elicited kidney organoid vascularization. The endothelial cells and angiotool analysis parameters were increased in HIF-1α plasmid-transfected and DMOG-treated organoids. These angiogenesis processes were partially blocked by VEGFR inhibitors, semaxanib or axitinib. Cisplatin-induced kidney injury (Cleaved caspase 3) was protected by HIF-1α through the upregulation of CD31 and SOD2.
CONCLUSION
We demonstrated that HIF-1α elicited the process of kidney organoid vascularization and protected against cisplatin-induced kidney organoid injury in hypoxia environment.
Topics: Organoids; Kidney; Multipotent Stem Cells; Hypoxia-Inducible Factor 1, alpha Subunit; Humans; Models, Biological; Plasmids; Gene Expression; Stem Cells; Receptors, Vascular Endothelial Growth Factor; Angiogenesis Inhibitors; Angiogenesis; Axitinib; Cells, Cultured; Cisplatin; Cell Hypoxia; Kidney Diseases
PubMed: 37981699
DOI: 10.1186/s13287-023-03528-9 -
Expert Review of Anticancer Therapy May 2020: The incidence of advanced renal cell carcinoma (RCC) is increasing. Over the last 10 years targeted therapies have led to improved efficacy outcomes for renal... (Comparative Study)
Comparative Study Review
: The incidence of advanced renal cell carcinoma (RCC) is increasing. Over the last 10 years targeted therapies have led to improved efficacy outcomes for renal carcinoma, including longer survival. However, the majority of patients develop disease progression within a year of initiation of first-line therapy. Recently a number of new regimens have been investigated including the combination of immune checkpoint inhibitors with VEGF inhibitors.: In this review, we assess the efficacy and safety of avelumab/axitinib in treatment-naïve patients with metastatic RCC and compare this combination to other current and emerging treatment regimens. In the Javelin 101 phase III registration trial, avelumab/axitinib demonstrated superior response rates and progression-free survival compared to sunitinib. However, after follow-up of 11.6 months, there was no significant difference in overall survival (OS). Avelumab/axitinib showed a tolerable safety profile. Adverse events were manageable and were in line with expected toxicities from the single agents.: Avelumab/axitinib has shown impressive efficacy and a tolerable safety profile in metastatic RCC. The future role of this treatment combination in the rapidly evolving landscape of novel combinations in this disease will have to be defined.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Disease Progression; Humans; Kidney Neoplasms; Progression-Free Survival; Survival Rate; Treatment Outcome
PubMed: 32293937
DOI: 10.1080/14737140.2020.1756780 -
Future Medicinal Chemistry Nov 2023Pyrazole or 1-pyrazole, a five-membered 1,2-diazole, is found in several approved drugs and some bioactive natural products. A myriad number of derivatives of this small... (Review)
Review
Pyrazole or 1-pyrazole, a five-membered 1,2-diazole, is found in several approved drugs and some bioactive natural products. A myriad number of derivatives of this small molecule have been reported in clinical and preclinical studies for the potential treatment of several diseases. The number of drugs containing a pyrazole nucleus has increased significantly in the last 10 years. Some of the best-selling drugs in this class are ibrutinib, ruxolitinib, axitinib, niraparib and baricitinib, and are used to treat different types of cancers; lenacapavir to treat HIV; riociguat to treat pulmonary hypertension; and sildenafil to treat erectile dysfunction. Several aniline-derived pyrazole compounds have been reported as potent antibacterial agents with selective activity against methicillin-resistant and vancomycin-resistant enterococci. Here, we discuss the pyrazole-derived drugs reported up to September 2023.
Topics: Male; Humans; Methicillin-Resistant Staphylococcus aureus; Anti-Bacterial Agents; Pyrazoles; Drug Discovery; Microbial Sensitivity Tests
PubMed: 37933613
DOI: 10.4155/fmc-2023-0207 -
Oncotarget 2022GZ17-6.02 is undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in renal carcinoma cells and to...
GZ17-6.02 is undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in renal carcinoma cells and to determine whether it interacted with axitinib to enhance tumor cell killing. GZ17-6.02 interacted in an arithmetically greater than additive fashion with axitinib to kill kidney cancer cells. GZ17-6.02 and axitinib cooperated to inactivate ERBB2, c-MET, c-KIT, c-SRC, the AMPK, STAT3, STAT5 and eIF2α and to activate PERK, ULK1 and ATG13. The drugs interacted to increase the expression of FAS-L and to decrease the levels of MCL1, BCL-XL, and HDACs 1-3. The drugs as single agents inactivated the Hippo pathway. GZ17-6.02 and axitinib interacted to enhance autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5, eIF2α, toxic BH3 domain proteins or CD95/FADD significantly reduced drug combination lethality. GZ17-6.02 and axitinib increased the expression of BAK, BIM, Beclin1 and ATG5, effects blocked by knock down of eIF2α. The drugs increased phosphorylation of ULK1 S757 and ATG13 S318 and decreased the phosphorylation of mTORC1 and mTORC2, effects blocked by knock down of AMPKα. Knock down of Beclin1 or ATG5 prevented the drug combination reducing expression of HDACs 1-3 and from enhancing the expression of MHCA. Knock down of HDACs 1-3 enhanced MHCA expression. We conclude that GZ17-6.02 and axitinib interact to kill requiring ER stress signaling, autophagy and death receptor signaling. Autophagic degradation of HDACs played a key role in enhancing MHCA expression and of a potential improved response to checkpoint inhibitory immunotherapy.
Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Autophagy; Axitinib; Beclin-1; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Synergism; Eukaryotic Initiation Factor-2; Humans; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Myeloid Cell Leukemia Sequence 1 Protein; Receptors, Death Domain; STAT5 Transcription Factor
PubMed: 35136485
DOI: 10.18632/oncotarget.28189 -
RSC Advances Aug 2022Axitinib is a potent vascular endothelial growth factor receptor (VEGFR) inhibitor, which has a strong inhibitory effect on the three isoforms of VEGFR 1-3. Having...
Axitinib is a potent vascular endothelial growth factor receptor (VEGFR) inhibitor, which has a strong inhibitory effect on the three isoforms of VEGFR 1-3. Having strong therapeutic efficacy, its broad use is limited by its side effects such as hypertension, proteinuria, cardiovascular damage, and liver and kidney dysfunction. Selenium compounds are broadly reported to have a good protective effect on cardiovascular disease, inflammation, infection, and immune function. In this study, a selenium substitute of axitinib was synthesized, and its anti-renal cell carcinoma activity and side effects were investigated. The results of the study indicated that Se-axitinib had potent antitumor activity on renal cell carcinoma (RCC), alleviated vascular hyperpermeability, and also alleviated axitinib-related side effects including hypertension, liver dysfunction and kidney dysfunction significantly. Therefore, we suggest that Se-axitinib could be a solution to the severe side effects of VEGFR inhibitors and provide evidence to improve the outcome of RCC treatment.
PubMed: 36043080
DOI: 10.1039/d2ra01882a -
ESMO Open Apr 2022In the phase III JAVELIN Renal 101 trial, first-line avelumab plus axitinib demonstrated a progression-free survival (PFS) and objective response rate (ORR) benefit... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the phase III JAVELIN Renal 101 trial, first-line avelumab plus axitinib demonstrated a progression-free survival (PFS) and objective response rate (ORR) benefit versus sunitinib in patients with advanced renal cell carcinoma (aRCC). However, efficacy in elderly patients remains unclear. We report efficacy and safety by age group from the second interim analysis of overall survival (OS).
PATIENTS AND METHODS
PFS and ORR as per blinded independent central review (RECIST 1.1), OS, and safety were assessed in patient groups aged <65, ≥65 to <75, and ≥75 years.
RESULTS
In the avelumab plus axitinib and sunitinib arms, 271/138/33 and 275/128/41 patients aged <65, ≥65 to <75, and ≥75 years, respectively, were randomized. At data cut-off (January 2019), median PFS [95% confidence interval (CI)] with avelumab plus axitinib versus sunitinib in these respective age groups was 11.6 (8.4-19.4) versus 6.9 (5.6-8.4) months [hazard ratio (HR), 0.63; 95% CI 0.501-0.786], 13.8 (11.1-18.0) versus 11.0 (7.8-16.6) months (HR, 0.88; 95% CI 0.627-1.231), and 13.8 [7.0-not estimable (NE)] versus 9.8 (4.3-NE) months (HR, 0.76; 95% CI 0.378-1.511). Median OS (95% CI) in the respective age groups was not reached (NR) (NE-NE) versus 28.6 (25.5-NE) months (HR, 0.74; 95% CI 0.541-1.022), 30.0 (30.0-NE) versus NR (NE-NE) months (HR, 0.89; 95% CI 0.546-1.467), and 25.3 (19.9-NE) versus NR (19.4-NE) months (HR, 0.87; 95% CI 0.359-2.106). ORR (95% CI) in the respective age groups was 49.4% (43.3% to 55.6%) versus 27.3% (22.1% to 32.9%), 60.9% (52.2% to 69.1%) versus 28.9% (21.2% to 37.6%), and 42.4% (25.5% to 60.8%) versus 22.0% (10.6% to 37.6%). In the avelumab plus axitinib arm, grade ≥3 adverse events (AEs) and immune-related AEs occurred in 76.9%/81.2%/72.7% and 45.5%/48.1%/36.4% in the respective age groups.
CONCLUSIONS
First-line avelumab plus axitinib demonstrated favorable efficacy across age groups, including patients aged ≥75 years. OS data were still immature; follow-up is ongoing. The safety profile was generally consistent across age groups.
Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Female; Follow-Up Studies; Humans; Kidney Neoplasms; Male; Sunitinib
PubMed: 35397432
DOI: 10.1016/j.esmoop.2022.100450 -
PloS One 2024Pathological angiogenesis and vascular instability are observed in diabetic retinopathy (DR), diabetic macular edema (DME), and wet age-related macular degeneration... (Comparative Study)
Comparative Study
PURPOSE
Pathological angiogenesis and vascular instability are observed in diabetic retinopathy (DR), diabetic macular edema (DME), and wet age-related macular degeneration (wAMD). Many receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptors (VEGFRs) contribute to angiogenesis, whereas the RTK TIE2 is important for vascular stability. Pan-VEGFR tyrosine kinase inhibitors (TKIs) such as vorolanib, sunitinib, and axitinib are of therapeutic interest over current antibody treatments that target only one or two ligands. This study compared the anti-angiogenic potential of these TKIs.
METHODS
A kinase HotSpot™ assay was conducted to identify TKIs inhibiting RTKs associated with angiogenesis and vascular stability. Half-maximal inhibitory concentration (IC50) for VEGFRs and TIE2 was determined for each TKI. In vitro angiogenesis inhibition was investigated using a human umbilical vein endothelial cell sprouting assay, and in vivo angiogenesis was studied using the chorioallantoic membrane assay. Melanin binding was assessed using a melanin-binding assay. Computer modeling was conducted to understand the TIE2-axitinib complex as well as interactions between vorolanib and VEGFRs.
RESULTS
Vorolanib, sunitinib, and axitinib inhibited RTKs of interest in angiogenesis and exhibited pan-VEGFR inhibition. HotSpot™ assay and TIE2 IC50 values showed that only axitinib potently inhibited TIE2 (up to 89%). All three TKIs effectively inhibited angiogenesis in vitro. In vivo, TKIs were more effective at inhibiting VEGF-induced angiogenesis than the anti-VEGF antibody bevacizumab. Of the three TKIs, only sunitinib bound melanin. TKIs differ in their classification and binding to VEGFRs, which is important because type II inhibitors have greater selectivity than type I TKIs.
CONCLUSIONS
Vorolanib, sunitinib, and axitinib exhibited pan-VEGFR inhibition and inhibited RTKs associated with pathological angiogenesis. Of the three TKIs, only axitinib potently inhibited TIE2 which is an undesired trait as TIE2 is essential for vascular stability. The findings support the use of vorolanib for therapeutic inhibition of angiogenesis observed in DR, DME, and wAMD.
Topics: Axitinib; Humans; Sunitinib; Angiogenesis Inhibitors; Imidazoles; Pyrroles; Indoles; Human Umbilical Vein Endothelial Cells; Receptors, Vascular Endothelial Growth Factor; Indazoles; Animals; Protein Kinase Inhibitors; Receptor, TIE-2; Neovascularization, Pathologic
PubMed: 38833447
DOI: 10.1371/journal.pone.0304782 -
Therapeutic Advances in Medical Oncology 2021The treatment of patients with renal cell carcinoma (RCC) is evolving rapidly, with promising new regimens being developed and approved for patients with advanced... (Review)
Review
The treatment of patients with renal cell carcinoma (RCC) is evolving rapidly, with promising new regimens being developed and approved for patients with advanced disease, particularly the combination of tyrosine kinase inhibitors with immune checkpoint inhibitors. Within the last 6 months, favorable first-line setting results for patients with clear cell RCC have been reported for the combination of cabozantinib plus nivolumab in the phase III CheckMate 9ER study, leading to its regulatory approval, and lenvatinib plus pembrolizumab in the phase III CLEAR study. Additional systemic first-line treatments for clear cell RCC include axitinib plus pembrolizumab, pazopanib, and sunitinib for favorable-risk patients and ipilimumab plus nivolumab, axitinib plus pembrolizumab, axitinib plus avelumab, and cabozantinib for intermediate- or poor-risk patients. In this review of novel approaches for first-line treatment of advanced RCC, we present an overview of current treatment strategies, the basis behind emerging treatment approaches, a summary of key results from the pivotal studies using tyrosine kinase inhibitor and immune checkpoint inhibitor combination therapy, novel treatments and strategies under development, and efforts for identifying biomarkers to guide treatment decisions.
PubMed: 34527080
DOI: 10.1177/17588359211034708