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Neoplasia (New York, N.Y.) Oct 2022Sunitinib is an effective treatment for patients with metastatic Renal Cell Carcinoma (mRCC) but ultimately resistance occurs. The aim of this study was to investigate...
Sunitinib is an effective treatment for patients with metastatic Renal Cell Carcinoma (mRCC) but ultimately resistance occurs. The aim of this study was to investigate sunitinib resistance in RCCs and to develop therapeutic combination strategies with targeted radioimmunotherapy (RIT). We studied two RCC models, analyzed Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) and AXL/MET expression and performed therapy studies in Balb/c mice combining sunitinib and [Lu]Lu-cG250 RIT (6.5 MBq/10 μg), specifically targeting RCC cells. pAXL and pMET were expressed in sunitinib-resistant SK-RC-52 and absent in sunitinib-sensitive NU12. NGS evaluation showed that expression of VEGFA, VEGFB, VEGFD, PGF and VEGFR1,2,3 was higher and expression of VEGFC and PDGFA was lower in NU12 than in SK-RC-52. Therapy studies combining sunitinib with [Lu]Lu-cG250 RIT showed that the best response in mice with "resistant" SK-RC-52 tumors was observed with two cycles of Sunitinib and Lu]Lu-cG250 RIT, probably due to increased vascular permeability by sunitinib treatment. In the "sensitive" NU12 model, two cycles of [Lu]Lu-cG250 RIT and two cycles of combination treatment were equally effective. Enhanced therapeutic efficacy was achieved when two agents ([Lu]Lu-cG250 RIT and sunitinib) that on their own did not induce satisfactory response levels, are combined. Our findings provide a promising new therapeutic strategy for patients with advanced RCC.
Topics: Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Kidney Neoplasms; Mice; Mice, Nude; Radioimmunotherapy; Sunitinib; Vascular Endothelial Growth Factor A
PubMed: 35878454
DOI: 10.1016/j.neo.2022.100826 -
Cancer Medicine Oct 2022Sunitinib is one of the first-line targeted drugs for metastatic renal cell carcinoma (RCC) with dual effects of antiangiogensis and proapoptosis. Sam68 (Src-associated...
Sunitinib is one of the first-line targeted drugs for metastatic renal cell carcinoma (RCC) with dual effects of antiangiogensis and proapoptosis. Sam68 (Src-associated in mitosis, 68 KDa), is found being involved in cell apoptosis. This article reveals that Sam68 impacts the sensitivity to sunitinib by mediating the apoptosis of RCC cells. Immunohistochemical staining indicated that the Sam68 expression levels in sunitinib sensitive tumor tissues were markedly higher than those in sunitinib resistant tumor tissues. Sunitinib induced RCC cell apoptosis in a concentration-dependent manner and inhibited the expression of total and phosphorylated Sam68 (p-Sam68). Downregulation of Sam68 expression inhibited RCC cell apoptosis induced by sunitinib. While upregulation of Sam68 expression could enhance apoptosis induced by sunitinib. Xenograft models showed that tumors in the Sam68-knockdown group did not shrink as much as those in the control group after treatment with sunitinib for 4 weeks. Together, our results suggest that Sam68 expression is associated with the sensitivity of ccRCC patients to sunitinib. Sam68 may promote cell apoptosis induced by sunitinib, and the Sam68 expression level may be a biomarker for predicting sunitinib sensitivity in ccRCC patients.
Topics: Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Kidney Neoplasms; Sunitinib
PubMed: 35476809
DOI: 10.1002/cam4.4743 -
Neurotherapeutics : the Journal of the... Apr 2021Limited therapeutic efficacy of temozolomide (TMZ) against glioblastomas highlights the importance of exploring new drugs for clinical therapy. Sunitinib, a...
Limited therapeutic efficacy of temozolomide (TMZ) against glioblastomas highlights the importance of exploring new drugs for clinical therapy. Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, is currently being tested as therapy for glioblastomas. Unfortunately, sunitinib still has insufficient activity to cure glioblastomas. Our aim was to determine the molecular mechanisms counteracting sunitinib drug sensitivity and find potential adjuvant drugs for glioblastoma therapy. Through in vitro experiments, transcriptome screening by RNA sequencing, and in silico analyses, we found that sunitinib induced glioma apoptotic death, and downregulated genes were enriched in oncogenic genes of glioblastoma. Meanwhile, sunitinib-upregulated genes were highly associated with the protective autophagy process. Blockade of autophagy significantly enhanced sunitinib's cytotoxicity. Growth arrest and DNA damage-inducible protein (GADD) 34 was identified as a candidate involved in sunitinib-promoted autophagy through activating p38-mitogen-activated protein kinase (MAPK) signaling. Higher GADD34 levels predicted poor survival of glioblastoma patients and induced autophagy formation in desensitizing sunitinib cytotoxicity. Guanabenz, an alpha2-selective adrenergic agonist and GADD34 functional inhibitor, was identified to enhance the efficacy of sunitinib by targeting GADD34-induced protective autophagy in glioblastoma cells, TMZ-resistant cells, hypoxic cultured cells, sphere-forming cells, and colony formation abilities. A better combined treatment effect with sunitinib and guanabenz was also observed by using xenograft mice. Taken together, the sunitinib therapy combined with guanabenz in the inhibition of GADD34-enhanced protective autophagy may provide a new therapeutic strategy for glioblastoma.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Antineoplastic Agents, Alkylating; Autophagy; Brain Neoplasms; Cell Line, Tumor; Computer Simulation; Drug Resistance, Neoplasm; Drug Therapy, Combination; Gene Expression Profiling; Glioblastoma; Guanabenz; Humans; Mice; Molecular Targeted Therapy; Neoplasm Transplantation; Protein Kinase Inhibitors; Protein Phosphatase 1; RNA-Seq; Sunitinib; Temozolomide; Up-Regulation
PubMed: 33410111
DOI: 10.1007/s13311-020-00961-z -
Biochemical Pharmacology Aug 2023Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis, proliferation and migration of vascular endothelial cells. It is well known that...
Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis, proliferation and migration of vascular endothelial cells. It is well known that cardiovascular safety liability for a wide range of small molecule tyrosine kinase inhibitors (TKIs) can result from interference with the VEGFR2 signalling system. In this study we have developed a ligand-binding assay using a fluorescent analogue of sunitinib (sunitinib-red) and full length VEGFR2 tagged on its C-terminus with the bioluminescent protein nanoluciferase to monitor ligand-binding to VEGFR2 using bioluminescence resonance energy transfer (BRET). This NanoBRET assay is a proximity-based assay (requiring the fluorescent and bioluminescent components to be within 10 nm of each other) that can monitor the binding of ligands to the kinase domain of VEGFR2. Sunitinib-red was not membrane permeable but was able to monitor the binding affinity and kinetics of a range of TKIs in cell lysates. Kinetic studies showed that sunitinib-red bound rapidly to VEGFR2 at 25 °C and that cediranib had slower binding kinetics with an average residence time of 111 min. Comparison between the log K values for inhibition of binding of sunitinib-red and log IC values for attenuation of VEGFa-stimulated NFAT responses showed very similar values for compounds that inhibited sunitinib-red binding. However, two compounds that failed to inhibit sunitinib-red binding (dasatinib and entospletinib) were still able to attenuate VEGFR2-mediated NFAT signalling through inhibition of downstream signalling events. These results suggest that these compounds may still exhibit cardiovascular liabilities as a result of interference with downstream VEGFR2 signalling.
Topics: Sunitinib; Vascular Endothelial Growth Factor A; Tyrosine Kinase Inhibitors; Endothelial Cells; Ligands; Kinetics; Protein Kinase Inhibitors; Vascular Endothelial Growth Factor Receptor-2
PubMed: 37406966
DOI: 10.1016/j.bcp.2023.115672 -
Health Technology Assessment... Jan 2018Several therapies have recently been approved for use in the NHS for pretreated advanced or metastatic renal cell carcinoma (amRCC), but there is a lack of comparative... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Several therapies have recently been approved for use in the NHS for pretreated advanced or metastatic renal cell carcinoma (amRCC), but there is a lack of comparative evidence to guide decisions between them.
OBJECTIVE
To evaluate the clinical effectiveness and cost-effectiveness of axitinib (Inlyta, Pfizer Inc., NY, USA), cabozantinib (Cabometyx, Ipsen, Slough, UK), everolimus (Afinitor, Novartis, Basel, Switzerland), nivolumab (Opdivo, Bristol-Myers Squibb, NY, USA), sunitinib (Sutent, Pfizer, Inc., NY, USA) and best supportive care (BSC) for people with amRCC who were previously treated with vascular endothelial growth factor (VEGF)-targeted therapy.
DATA SOURCES
A systematic review and mixed-treatment comparison (MTC) of randomised controlled trials (RCTs) and non-RCTs. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were objective response rates (ORRs), adverse events (AEs) and health-related quality of life (HRQoL). MEDLINE, EMBASE and The Cochrane Library were searched from inception to January and June 2016 for RCTs and non-RCTs, respectively. Two reviewers abstracted data and performed critical appraisals.
REVIEW METHODS
A fixed-effects MTC was conducted for OS, PFS [hazard ratios (HRs)] and ORR (odds ratios), and all were presented with 95% credible intervals (CrIs). The RCT data formed the primary analyses, with non-RCTs and studies rated as being at a high risk of bias included in sensitivity analyses (SAs). HRQoL and AE data were summarised narratively. A partitioned survival model with health states for pre progression, post progression and death was developed to perform a cost-utility analysis. Survival curves were fitted to the PFS and OS results from the MTC. A systematic review of HRQoL was undertaken to identify sources of health state utility values.
RESULTS
Four RCTs ( = 2618) and eight non-RCTs ( = 1526) were included. The results show that cabozantinib has longer PFS than everolimus (HR 0.51, 95% CrI 0.41 to 0.63) and both treatments are better than BSC. Both cabozantinib (HR 0.66, 95% CrI 0.53 to 0.82) and nivolumab (HR 0.73, 95% CrI 0.60 to 0.89) have longer OS than everolimus. SAs were consistent with the primary analyses. The economic analysis, using drug list prices, shows that everolimus may be more cost-effective than BSC with an incremental cost-effectiveness ratio (ICER) of £45,000 per quality-adjusted life-year (QALY), as it is likely to be considered an end-of-life treatment. Cabozantinib has an ICER of £126,000 per QALY compared with everolimus and is unlikely to be cost-effective. Nivolumab was dominated by cabozantinib (i.e. more costly and less effective) and axitinib was dominated by everolimus.
LIMITATIONS
Treatment comparisons were limited by the small number of RCTs. However, the key limitation of the analysis is the absence of the drug prices paid by the NHS, which was a limitation that could not be avoided owing to the confidentiality of discounts given to the NHS.
CONCLUSIONS
The RCT evidence suggests that cabozantinib is likely to be the most effective for PFS and OS, closely followed by nivolumab. All treatments appear to delay disease progression and prolong survival compared with BSC, although the results are heterogeneous. The economic analysis shows that at list price everolimus could be recommended as the other drugs are much more expensive with insufficient incremental benefit. The applicability of these findings to the NHS is somewhat limited because existing confidential patient access schemes could not be used in the analysis. Future work using the discounted prices at which these drugs are provided to the NHS would better inform estimates of their relative cost-effectiveness.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42016042384.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Clinical Trials as Topic; Cost-Benefit Analysis; Everolimus; Humans; Kidney Neoplasms; Models, Econometric; Nivolumab; Pyridines; Quality-Adjusted Life Years; Sunitinib; Technology Assessment, Biomedical; Vascular Endothelial Growth Factor A
PubMed: 29393024
DOI: 10.3310/hta22060 -
BMC Cancer Jun 2022Tyrosine kinase inhibitors (TKIs), such as sunitinib, are used for cancer treatment, but may also affect platelet count and function with possible hemostatic...
Quantitative and qualitative changes in platelet traits of sunitinib-treated patients with renal cell carcinoma in relation to circulating sunitinib levels: a proof-of-concept study.
BACKGROUND
Tyrosine kinase inhibitors (TKIs), such as sunitinib, are used for cancer treatment, but may also affect platelet count and function with possible hemostatic consequences. Here, we investigated whether patient treatment with the TKI sunitinib affected quantitative and qualitative platelet traits as a function of the sunitinib level and the occurrence of bleeding.
METHODS
Blood was collected from 20 metastatic renal cell carcinoma (mRCC) patients before treatment, and at 2 weeks, 4 weeks and 3 months after sunitinib administration. We measured blood cell counts, platelet aggregation, and concentrations of sunitinib as well as its N-desethyl metabolite in plasma, serum and isolated platelets. Progression of disease (PD) and bleeding were monitored after 3 months.
RESULTS
In sunitinib-treated mRCC patients, concentrations of (N-desethyl-)sunitinib in plasma and serum were highly correlated. In the patients' platelets the active metabolite levels were relatively increased as compared to sunitinib. On average, a sustained reduction in platelet count was observed on-treatment, which was significantly related to the inhibitor levels in plasma/serum. Principal component and correlational analysis showed that the (N-desethyl-)sunitinib levels in plasma/serum were linked to a reduction in both platelet count and collagen-induced platelet aggregation. The reduced aggregation associated in part with reported bleeding, but did not correlate to PD.
CONCLUSION
The sunitinib-induced reduction in quantitative and qualitative platelet traits may reflect the effective sunitinib levels in the patient. These novel results may serve as a proof-of-principle for other TKI-related drugs, where both platelet count and functions are affected, which could be used for therapeutic drug monitoring.
Topics: Antineoplastic Agents; Blood Platelets; Carcinoma, Renal Cell; Humans; Indoles; Kidney Neoplasms; Pyrroles; Sunitinib
PubMed: 35698081
DOI: 10.1186/s12885-022-09676-0 -
Angiogenesis Oct 2015To improve the efficacy of radiotherapy (RTx), there is a growing interest in combining RTx with drugs that inhibit angiogenesis, i.e., the process of neo-vessel... (Review)
Review
To improve the efficacy of radiotherapy (RTx), there is a growing interest in combining RTx with drugs that inhibit angiogenesis, i.e., the process of neo-vessel formation out of preexisting capillaries. A frequently used drug to inhibit angiogenesis is sunitinib (Sutent, SU11248), a receptor tyrosine kinase inhibitor that is currently FDA approved for the treatment of several cancer types. The current review presents an overview of the preclinical studies and clinical trials that combined sunitinib with RTx. We discuss the findings from preclinical and clinical observations with a focus on dose scheduling and commonly reported toxicities. In addition, the effects of combination therapy on tumor response and patient survival are described. Finally, the lessons learned from preclinical and clinical studies are summarized and opportunities and pitfalls for future clinical trials are presented.
Topics: Animals; Chemoradiotherapy; Humans; Indoles; Neoplasms; Neovascularization, Pathologic; Pyrroles; Sunitinib
PubMed: 26202788
DOI: 10.1007/s10456-015-9476-3 -
Journal of the National Comprehensive... Jul 2023Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among adolescents and young adults (AYAs) diagnosed with cancer. The aim of this study was to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among adolescents and young adults (AYAs) diagnosed with cancer. The aim of this study was to assess the incidence and predictors of left ventricular systolic dysfunction (LVSD) and hypertension among AYAs receiving VEGF inhibition compared with non-AYAs.
METHODS
This retrospective analysis used data from the ASSURE trial (ClinicalTrials.gov identifier: NCT00326898), in which participants with nonmetastatic, high-risk, renal cell cancer were randomized to sunitinib, sorafenib, or placebo. The incidence of LVSD (left ventricular ejection fraction decrease >15%) and hypertension (blood pressure ≥140/90 mm Hg) were compared using nonparametric tests. Multivariable logistic regression examined the association between AYA status, LVSD, and hypertension while adjusting for clinical factors.
RESULTS
AYAs represented 7% (103/1,572) of the population. Over a study treatment period of 54 weeks, the incidence of LVSD was not significantly different among AYAs (3%; 95% CI, 0.6%-8.3%) versus non-AYAs (2%; 95% CI, 1.2%-2.7%). The incidence of hypertension was significantly lower among AYAs (18%; 95% CI, 7.5%-33.5%) compared with non-AYAs (46%; 95% CI, 41.9%-50.4%) in the placebo arm. In the sunitinib and sorafenib groups, the incidence of hypertension for AYAs compared with non-AYAs was 29% (95% CI, 15.1%-47.5%) versus 47% (95% CI, 42.3%-51.7%), and 54% (95% CI, 33.9%-72.5%) versus 63% (95% CI, 58.6%-67.7%), respectively. AYA status (odds ratio, 0.48; 95% CI, 0.31-0.75) and female sex (odds ratio, 0.74; 95% CI, 0.59-0.92) were each associated with a lower risk of hypertension.
CONCLUSIONS
LVSD and hypertension were prevalent among AYAs. CVD among AYAs is only partially explained by cancer therapy. Understanding CVD risk among AYA cancer survivors is important for promoting cardiovascular health in this growing population.
Topics: Adolescent; Female; Young Adult; Humans; Vascular Endothelial Growth Factor A; Retrospective Studies; Sorafenib; Stroke Volume; Sunitinib; Ventricular Function, Left; Hypertension; Cardiovascular Diseases; Kidney Neoplasms
PubMed: 37433436
DOI: 10.6004/jnccn.2023.7018 -
International Journal of Molecular... Oct 2019Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years,... (Review)
Review
Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Biomarkers; Clinical Trials as Topic; Disease Management; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Neoplasm Grading; Neovascularization, Pathologic; Neuroendocrine Tumors; Pancreatic Neoplasms; Sunitinib; Treatment Outcome
PubMed: 31597249
DOI: 10.3390/ijms20194949 -
Health Technology Assessment... Sep 2009The submission's evidence for the clinical effectiveness and cost-effectiveness of sunitinib for the treatment of gastrointestinal stromal tumours (GISTs) is based on a... (Review)
Review
The submission's evidence for the clinical effectiveness and cost-effectiveness of sunitinib for the treatment of gastrointestinal stromal tumours (GISTs) is based on a randomised controlled trial (RCT) comparing sunitinib with placebo for people with unresectable and/or metastatic GIST after failure of imatinib and with Eastern Cooperative Oncology Group (ECOG) progression status 0-1, and an ongoing, non-comparative cohort study of a similar population but with ECOG progression status 0-4. The searches are appropriate and include all relevant studies and the RCT is of high quality. In the RCT sunitinib arm overall survival was 73 median weeks [95% confidence interval (CI) 61 to 83] versus 75 median weeks (95% CI 68 to 84) for the cohort study. However, time to tumour progression in the cohort study was different from that in the RCT sunitinib arm [41 (95% CI 36 to 47) versus 29 (95% CI 22 to 41) median weeks respectively]. Median progression-free survival with sunitinib was 24.6 weeks (95% CI 12.1 to 28.4) versus 6.4 weeks (95% CI 4.4 to 10.0) on placebo (hazard ratio 0.333, 95% CI 0.238 to 0.467, p < 0.001). The manufacturer used a three-state Markov model to model the cost-effectiveness of sunitinib compared with best supportive care for GIST patients; the modelling approach and sources and justification of estimates are reasonable. The base-case incremental cost-effectiveness ratio (ICER) was 27,365 pounds per quality-adjusted life-year (QALY) with the first cycle of sunitinib treatment not costed; when we included the cost of the first treatment cycle we estimated a base-case ICER of 32,636 pounds per QALY. Pfizer's sensitivity analysis produced a range of ICERs from 15,536 pounds per QALY to 59,002 pounds per QALY. Weaknesses of the manufacturer's submission include that the evidence is based on only one published RCT; that 84% of the RCT control population crossed over to the intervention group, giving rise to the use of unusual rank preserved structural failure time (RPSFT) analysis to correct for possible bias; and that a number of errors and omissions were made in the probabilistic sensitivity analysis, meaning that it is not possible to come to firm conclusions about the cost-effectiveness of sunitinib for GIST in this patient population. In conclusion, during the blinded phase of the RCT, overall survival was significantly longer in the sunitinib arm than in the placebo arm (hazard ratio 0.491, 95% CI 0.290 to 0.831, p <0.007). However, intention-to-treat analysis of the entire study showed no statistically significant difference in overall survival for those who received sunitinib (73 weeks) versus those who received placebo (65 weeks) (hazard ratio 0.876, 95% CI 0.679 to 1.129, p = 0.306).
Topics: Antineoplastic Agents; Cost-Benefit Analysis; Drug Industry; Gastrointestinal Stromal Tumors; Humans; Indoles; Pyrroles; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Sunitinib
PubMed: 19804692
DOI: 10.3310/hta13suppl2/10