Sunitinib efficacy with minimal toxicity in patient-derived organoid models of retinoblastoma
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PROVIDER: PRJNA832801 | ENA |
REPOSITORIES: ENA
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Project description:Background. Recurrence or persistence of retinoblastoma (RB) is common following chemoreduction and often be managed with intra-arterial/ intravitreal chemotherapy. However, no/minimal response to local chemotherapy has been documented, with enucleation needed for tumor control. Otherwise, the globe is preserved with effective tumor control but at the cost of vision due to retinal toxicity. The aim of this study was to discover novel drug with improved antitumor activity and retinal safety profiles for RB via drug reprofiling in patient-derived tumor organoids. Methods. Five tumor organoid lines were fully characterized using CGH/SNP array and whole exome sequencing and used as a model to test 133 FDA-approved compounds using two-step screening processes. RNA sequencing was conducted to generate drug signature in conjunction with cell cycle and apoptotic assays. An ability of candidate drug to restrict proliferative tumor cone were examined together with retinal toxicity testing in human ESC-derived retinal organoids, in comparison with clinically used drugs by immunostaining. Results. Sunitinib was identified as high cytotoxic agent for the classical RB1-deficient and novel MYCN-amplified RBs. Gene signature indicated that anti-tumoral activity of sunitinib was associated with MAPK activity. Additionally, sunitinib was more effective to suppress proliferative tumor cones and had less retinal toxicity compared with melphalan and topotecan. Conclusions. Sunitinib may be a “universal” drug for all subtypes of RB. With high efficacy and low retinal toxicity, sunitinib is potential agent used in local chemotherapy for treating RB.
2023-02-08 | GSE201740 | GEO
Project description:To gain insights into the mechanisms of dihydroberberine, sunitinib and dihydroberberine plus sunitinib on inhibition to A549 cells, we have employed whole genome microarray expression profiling as a discovery platform to identify different genes between dihydroberberine, sunitinib and dihydroberberine plus sunitinib-treated sample and control.
2015-06-26 | GSE70282 | GEO
Project description:Background Sunitinib is a small molecule tyrosine kinase inhibitor approved for the treatment of diverse cancers. Despite widespread clinical approval the associated cardiovascular toxicity sequelae are of concern; high grade toxicities may lead to dose reduction, interruption or discontinuation. Thus, an effective strategy for the early detection of cardiac damage in the context of sunitinib treatment is warranted. Although yet to be fully elucidated, molecular pathways and kinases implicate include those related to cardiac energy metabolism. We hypothesised that plasticity in cardiac metabolism could represent a novel early marker of cardiotoxicity. Methods and Results Female Balb/CJ mice (n = 36) or Sprague-Dawley rat (n = 12) models were treated with sunitinib. Physiological parameters were measured. An hypothesis driven cardiac positron emission tomography (PET) approach was implemented to investigate alterations in myocardial glucose, fatty acid and oxidative metabolism. Following treatment, blood pressure increased, whilst left ventricular ejection fraction decreased in both models. Increased myocardial glucose uptake after 48 hours indicated early perturbations in glucose metabolism. Myocardial fatty acid metabolism appeared increased as a result of sunitinib treatment indicated by PET but electron microscopy revealed significantly increased storage of lipids in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top cardiac signalling pathways perturbed by sunitinib treatment. [11C]Acetate-PET data suggested a decrease in myocardial perfusion following 5 days of treatment. Conclusions Data implicates sunitinib as a mediator of compromised myocardial energy metabolism. Increased reliance on glycolysis, increases in myocardial lipid deposition and perturbed mitochondrial function may ultimately result in a fundamental energy crisis manifesting as compromised cardiac function, the long term effects of which are unknown. Our data support the utility of an hypothesis driven PET approach to monitor cardiac metabolic pathway remodelling in response to sunitinib, which may ultimately have clinical utility as a novel safety imaging biomarker strategy.
2017-01-03 | PXD001888 | Pride
Project description:Sunitinib is a receptor tyrosine kinase (RTK) inhibitor that is widely used for treatment of various types of cancer. Vascular toxicity represents a debilitating side-effect of sunitinib which impends its application in some patients. Study of sunitinib has been primarily focused on transcriptional control, and there is an important gap in our understanding of its impact on translation. To interrogate the role of mRNA translation in mediating the effect of sunitinib on endothelial cells (ECs) we performed ribosome footprinting.
2024-08-01 | GSE181278 | GEO
Project description:To gain insights into the mechanisms of dihydroberberine, sunitinib and dihydroberberine plus sunitinib on inhibition to A549 cells, we have employed whole genome microarray expression profiling as a discovery platform to identify different genes between dihydroberberine, sunitinib and dihydroberberine plus sunitinib-treated sample and control. A549 cells were cultivated in the absence or presence of 25?mol/L dihydroberberine, 2?mol/L sunitinib, 25?mol/L dihydroberberine plus 2?mol/L sunitinib for 48 h, followed by the Agilent Whole Human Genome Oligo Microarray
2015-06-26 | E-GEOD-70282 | biostudies-arrayexpress
Project description:Persistent or recurrent retinoblastoma (RB) is associated with the presence of vitreous or/and subretinal seeds in advanced RB and represents a major cause of therapeutic failure. This necessitates the development of novel therapies and thus requires a model of advanced RB for testing candidate therapeutics. To this aim, we established and characterized a three-dimensional, self-organizing organoid model derived from chemotherapy-naïve tumors. The responses of organoids to drugs were determined and compared to relate organoid model to advanced RB, in terms of drug sensitivities. We found that organoids had histological features resembling retinal tumors and seeds and retained DNA copy-number alterations as well as gene expression profile and protein expression of the parental tissue. Cone signal circuitry (M/L+ cells) and glial tumor microenvironment (GFAP+ cells) were primarily present in organoids. Topotecan alone or the combined drug regimen of topotecan and melphalan effectively targeted proliferative tumor cones (RXRg+ Ki67+) in organoids after 24-h drug exposure, blocking mitotic entry. In contrast, methotrexate showed the least efficacy against tumor cells. The drug responses of organoids were consistent with those of tumor cells in advanced disease. Patient-derived organoids enable the creation of a faithful model to use in examining novel therapeutics for RB.
2018-10-23 | GSE120710 | GEO
Project description:Sunitinib resistance creates a major clinical challenge for the treatment of advanced clear cell renal cell carcinoma (ccRCC) and functional and metabolic changes linked to sunitinib resistance are not fully understood. We sought to characterize the molecular and metabolic changes induced by the development of sunitinib resistance in ccRCC by developing and characterizing the transcriptome of two human ccRCC cell lines resistant to sunitinib.
2024-04-17 | GSE216494 | GEO
Project description:A multiple receptor tyrosine kinase inhibitor, sunitinib, is a first-line therapy for clear cell renal cell carcinoma (CCRCC). Unfortunately, it has the major challenges of low initial response rate and resistance after about one year of treatment. Here we evaluated a microRNA (miRNA) and its target responsible for sunitinib resistance. Using miRNA profiling, we identified miR-96-5p upregulation in tumors from sunitinib-resistant CCRCC patients
2021-12-03 | GSE189331 | GEO
Project description:A three-dimensional organoid model recapitulates tumorigenic aspects and drug responses of advanced human retinoblastoma
| PRJNA494224 | ENA
Project description:To investigate the function FUS in the regulation of sunitinib-resistance， we used lentiviral transduction to knock down FUS expression in the sunitinib-resistant RCC cells.
2023-03-31 | GSE226245 | GEO