Dynamic epigenetic changes to VHL occurs with sunitinib in metastatic clear cell renal cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE67700 | GEO | 2016/03/17
SECONDARY ACCESSION(S): PRJNA280722
REPOSITORIES: GEO
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Project description:BackgroundGenetic intratumoral heterogeneity (ITH) hinders biomarker development in metastatic clear cell renal cancer (mccRCC). Epigenetic relative to genetic ITH or the presence of consistent epigenetic changes following targeted therapy in mccRCC have not been evaluated. The aim of this study was to determine methylome/genetic ITH and to evaluate specific epigenetic and genetic changes associated with sunitinib therapy.Patients and methodsMulti-region DNA sampling performed on sequential frozen pairs of primary tumor tissue from 14 metastatic ccRCC patients, in the Upfront Sunitinib (SU011248) Therapy Followed by Surgery in Patients with Metastatic Renal Cancer: a Pilot Phase II Study (SuMR; ClinicalTrials.gov identifier: NCT01024205), at presentation (biopsy) and after 3-cycles of 50mg sunitinib (nephrectomy). Untreated biopsy and nephrectomy samples before and after renal artery ligation were controls. Ion Proton sequencing of 48 key ccRCC genes, and MethylCap-seq DNA methylation analysis was performed, data was analysed using the statistical computing environment R.ResultsUnsupervised hierarchical clustering revealed complete methylome clustering of biopsy and three nephrectomy samples for each patient (14/14 patients). For mutational status, untreated biopsy and all treated nephrectomy samples clustered together in 8/13 (61.5%) patients. The only methylation target significantly altered following sunitinib therapy was VHL promoter region 7896829 which was hypermethylated with treatment (FDR=0.077, P<0.001) and consistent for all patients (pre-treatment 50% patients had VHL mutations, 14% patients VHL hypermethylation). Renal artery ligation did not affect this result. No significant differences in driver or private mutation count was found with sunitinib treatment.ConclusionsDemonstration of relative methylome homogeneity and consistent VHL hypermethylation, after sunitinib, may overcome the hurdle of ITH present at other molecular levels for biomarker research.
| S-EPMC5041900 | biostudies-literature
Project description:BackgroundRecently, we developed an apoptotic assay for expanding the monitoring capabilities of the circulating tumour cells (CTC) test during therapy. An automated platform for computing CTCs was integrated with a mAb (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 in early apoptosis; we showed that live CTCs were associated with progression, consistent with enhanced cell migration and invasion. The test was first applied here to mRCC.MethodsLive/apoptotic CTCs changes were measured in mRCC patients receiving first-line Sunitinib and compared with circulating endothelial cell (CEC) levels.ResultsThe presence of EpCAM-positive, live CTCs predicts progression in individual mRCC patient, being associated with distant metastasis under first-line Sunitinib. Synchronous detection of CTCs and CEC levels discloses for the first time an association between their dynamic changes and outcome: a rapid increase of the CEC number as early as the first cycle of therapy is associated with CTC decrease in non-progressed patients, whereas a delayed response of CECs is related to higher CTC values in the progressed group indicating treatment failure.ConclusionWe demonstrated that a delayed response to antiangiogenic treatment indicated by persistent detection of CECs correlates with persistent live CTCs and more aggressive disease.
| S-EPMC3494437 | biostudies-literature
Project description:Sunitinib is a protein tyrosine kinase-inhibitor targeting VEGFR, c-kit and PDGFR. It has been approved for the treatment of metastatic renal-cell carcinoma and gastrointestinal stromal tumors. Although it has been shown to prolong disease-free and overall survival in renal-cell carcinoma patients, only 70% of the treated population receive a clinical benefit (CB) from the treatment. Markers that could predict clinical benefit to sunitinib would be an important aid in monitoring and following their treatment. We assessed the outcome and plasma proangiogenic factors in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib in our institution.We have treated 42 patients with metastatic clear-cell renal carcinoma with sunitinib. Plasma concentrations of VEGF-A, sVEGFR2 and PDGF were determined by ELISA.At the time of analysis 39 patients were evaluable for response and 30 patients had obtained a clinical benefit (CB). Median progression-free survival was 268 days (8.93 months) and median overall survival was 487 days (16.23 months). Interestingly, disease stabilization or objective response resulted in comparable overall survival. Most treatment-related adverse events were of mild-to-moderate intensity with one treatment-related death. Plasma sVEGFR2 and PDGF levels had no predictive value. Fold-increase in plasma VEGF was significantly lower in patients that obtained a CB as compared to patients that progressed after two cycles of treatment. Plasma VEGF did not increase in patients with initial CB at the time of progression.Sunitinib showed substantial activity in mRCC. Disease stabilization or objective response resulted in comparable overall survival and both outcomes should be considered positive. Fold-increase in plasma VEGF predicts for CB and could be a candidate marker. Progression after initial CB is not associated with elevated plasma VEGF, implying a different mechanism of resistance.
| S-EPMC2662874 | biostudies-other
Project description:Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). Despite sunitinib's clinical efficacy, patients eventually develop drug resistance and disease progression. Herein, we tested the hypothesis whether initial sunitinib resistance may be transient and could be overcome by dose increase. In selected patients initially treated with 50 mg sunitinib and presenting with minimal toxicities, sunitinib dose was escalated to 62.5 mg and/or 75 mg at the time of tumor progression. Mice bearing two different patient-derived ccRCC xenografts (PDX) were treated 5 days per week with a dose-escalation schema (40-60-80 mg/kg sunitinib). Tumor tissues were collected before dose increments for immunohistochemistry analyses and drug levels. Selected intrapatient sunitinib dose escalation was safe and several patients had added progression-free survival. In parallel, our preclinical results showed that PDXs, although initially responsive to sunitinib at 40 mg/kg, eventually developed resistance. When the dose was incrementally increased, again we observed tumor response to sunitinib. A resistant phenotype was associated with transient increase of tumor vasculature despite intratumor sunitinib accumulation at higher dose. In addition, we observed associated changes in the expression of the methyltransferase EZH2 and histone marks at the time of resistance. Furthermore, specific EZH2 inhibition resulted in increased in vitro antitumor effect of sunitinib. Overall, our results suggest that initial sunitinib-induced resistance may be overcome, in part, by increasing the dose, and highlight the potential role of epigenetic changes associated with sunitinib resistance that can represent new targets for therapeutic intervention.
| S-EPMC4326587 | biostudies-literature
Project description:BackgroundSunitinib has become mainstay first line treatment for patients with metastatic renal clear cell carcinoma (mRCC). Still, useful predictive markers of response are lacking and urgently needed for clinical decision making.MethodsIn the present study we investigated the predictive value of standard serum markers as well as clinical markers, including C-reactive protein (CRP), Neutrophil to Lymphocyte ratio (NLR) and early hypertension (eHTN) in an unselected prospective patient population treated with sunitinib for mRCC. Forty-six patients were enrolled in a prospective single-arm study of predictive markers for sunitinib response. Response rates according to RECIST 1.1 were used as primary end-point. Secondary objectives were to evaluate prognostic value of the candidate markers with regard to progression free survival (PFS) and overall survival (OS). In addition, toxicity rates and quality of life was recorded.ResultsMedian PFS and OS was 9.1 months and 15.0 months, respectively. Of 38 patients evaluable for response, 1 patient had complete response (CR), 7 had partial response (PR), 18 had stable disease (SD) and 12 had progressive disease (PD). Normal CRP at baseline was significantly associated with objective response (CR + PR) (p = 0.01). Normal CRP was also significantly associated with improved PFS and OS (Log rank, p = 0.05 and <0.01, respectively). Early hypertension, NLR and IMDC risk score were not significantly associated with response rates or survival.ConclusionBaseline CRP was a significant predictive factor of sunitinib response and a prognostic factor of survival. Baseline CRP might be a useful biomarker in the treatment planning of mRCC. Due to the relatively small sample size, our results need to be confirmed in larger studies.
| S-EPMC5580299 | biostudies-literature
Project description:BACKGROUND: Sunitinib is widely used as first-line treatment for metastatic clear cell renal cancer (MCRC). No reports are known of treatment after sunitinib failure. As irinotecan, cisplatin, and mitomycin-C (IPM) chemotherapy has been reported to influence MCRC after progression on cytokine therapy, we report on the outcome of 11 patients treated with IPM after sunitinib failure. PATIENTS AND METHODS: Eleven patients with progression of disease on sunitinib therapy were treated with 4, monthly cycles of monthly IPM. RESULTS: Nine out of 11 patients progressed during IPM therapy. The median time to progression was 1.4 months (95% CI: 0.7-2.1 months), while the overall survival was 4.2 months (95% CI: 0.9-2.3). Overall 10 patients have died of progressive renal cancer. One patient had a radiological response to therapy and remains progression free 11 months after treatment. Four of the 10 patients required a dose reduction for grade 3 or 4 toxicities. CONCLUSIONS: IPM alone does not appear to benefit patients with MCRC who previously progressed during sunitinib therapy. The median progression-free survival and overall survival for these patients is short.
| S-EPMC2994212 | biostudies-other
Project description:Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell cancer, characterized by the highest mortality rate among other RCC subtypes due to the occurrence of metastasis and drug resistance following surgery. The Von Hippel‑Lindau tumor suppressor (VHL)‑hypoxia‑inducible factor 1 subunit α (HIF1A)/hypoxia‑inducible factor 2α (HIF2A)‑vascular endothelial growth factor A (VEGFA) protein axis is involved in the development and progression of ccRCC, whereas sunitinib, a tyrosine kinase inhibitor, blocks the binding of VEGFA to its receptor. The aim of the present study was to examine the possible association of the gene expression of VHL, HIF1A, HIF2A, VEGFA and tumor protein P53 (P53) in cancer tissue with the outcome of ccRCC patients who were treated with sunitinib as first‑line therapy following nephrectomy. A total of 36 ccRCC patients were enrolled, 11 of whom were administered sunitinib post‑operatively. Tumor and control samples were collected, and mRNA and protein levels were assessed by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively. High mRNA and protein expression levels of HIF2A and VEGFA were found to be associated with shorter overall survival (OS) and progression‑free survival (PFS) rates, as well as with unfavorable risk factors of cancer recurrence and mortality. Resistance to sunitinib was also observed; the OS and PFS rates were shorter (median OS and PFS: 12 and 6 months, respectively, vs. undetermined). Sunitinib resistance was associated with high HIF2A and VEGFA protein levels (b=0.57 and b=0.69 for OS and PFS, respectively; P<0.001). Taken together, the findings of this study suggest that the protein levels of HIF2A and VEGFA in tumor tissue may serve as independent prognostic factors in ccRCC. ccRCC patients with increased intratumoral HIF2A and VEGFA protein levels, and unaltered VHL protein levels, are not likely to benefit from sunitinib treatment following nephrectomy; however, this hypothesis requires verification by large‑scale replication studies.
| S-EPMC6615924 | biostudies-literature
Project description:Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL+) cells. Renal tumors with either VHL+ or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL+ cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL-) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.
| S-EPMC10110583 | biostudies-literature
Project description:Cytosine5-hyxymethylation (5hmC)which is a new epigenetic modification form plays important roles in the development and progression of tumors. In the present study, we observed that levels of 5hmC in the promoter region of Von Hippel-Lindau (VHL) were lower in 97 samples of renal clear cell carcinoma tissue than in matched adjacent benign tissues. Moreover, when the cancer tissue samples were divided based on pathological staging, VHL expression and the level of 5hmC in the VHL promoter were both lower in pathological grade III tumors than in grades I or II. Correspondingly, expression of TET1, which catalyzes the formation of 5hmC, was also lower in grade III renal clear cell carcinomas than in grade I or II disease. These findings suggest the 5hmC level on VHL is a key determinant of the gene's expression and may participate in the occurrence and development of renal clear cell carcinoma. Thus the 5hmC level may be a useful indicator for early diagnosis and appropriate treatment of renal clear cell carcinoma.
| S-EPMC5609960 | biostudies-literature
Project description:BackgroundSunitinib and everolimus are standard first-line and second-line therapies, respectively, in clear cell renal cell carcinoma (ccRCC).ObjectiveTo conduct a randomized phase 2 trial comparing sunitinib and everolimus in non-clear cell RCC (non-ccRCC).Design, setting, and participantsPatients with metastatic, non-ccRCC, or ccRCC with >20% sarcomatoid features (ccSRCC) were randomized to receive sunitinib or everolimus with crossover at disease progression.Outcome measurement and statistical analysisPrimary end point was progression-free survival (PFS) in first-line therapy; 108 patients were needed to show improvement in median PFS (mPFS) from 12 wk with sunitinib to 20 wk with everolimus.Results and limitationsInterim analysis of 68 patients (papillary [27], chromophobe [12], unclassified [10], translocation [7], ccSRCC [12]) prompted early trial closure. The mPFS in first-line therapy was 6.1 mo with sunitinib and 4.1 mo with everolimus (p=0.6); median overall survival (mOS) was not reached with sunitinib and was 10.5 mo with everolimus, respectively (p=0.014). At final analysis, mOS was 16.2 and 14.9 mo with sunitinib and everolimus, respectively (p=0.18). There were four partial responses (PRs) in first-line therapy (sunitinib: 3 of 33 [9%]; everolimus, 1 of 35 [2.8%]) and four PRs in second-line therapy (sunitinib: 2 of 21 [9.5%]; everolimus, 2 of 23 [8.6%]), with mPFS of 1.8 mo and 2.8 mo, respectively. In patients without sarcomatoid features in their tumors (n=49), mOS was 31.6 mo with sunitinib and 10.5 mo with everolimus (p=0.075). Genomic profiling of a chromophobe RCC from a patient with a PR to first-line everolimus revealed a somatic TSC2 mutation.ConclusionsIn this trial, everolimus was not superior to sunitinib. Both agents demonstrated modest efficacy, underscoring the need for better therapies in non-ccRCC.Patient summaryThis randomized phase 2 trial provides the first head-to-head comparison of everolimus and sunitinib in patients with metastatic non-clear cell renal cell carcinoma (non-ccRCC). The observed very modest efficacy underscores the need to develop more effective therapies for non-ccRCC.
| S-EPMC4879109 | biostudies-literature