Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma.

Although clear cell renal cell carcinoma (ccRCC) has been shown to result in widespread aberrant cytosine methylation and loss of 5-hydroxymethylcytosine (5hmC), the prognostic impact and therapeutic targeting of this epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was strongly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression-free survival after resection of nonmetastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of ten eleven translocation (TET) enzymes, but to their functional inactivation by l-2-hydroxyglutarate (L2HG), which was overexpressed due to the deletion and underexpression of L2HG dehydrogenase (L2HGDH). Ascorbic acid (AA) reduced methylation and restored genome-wide 5hmC levels via TET activation. Fluorescence quenching of the recombinant TET-2 protein was unaffected by L2HG in the presence of AA. Pharmacologic AA treatment led to reduced growth of ccRCC in vitro and reduced tumor growth in vivo, with increased intratumoral 5hmC. These data demonstrate that reduced 5hmC is associated with reduced survival in ccRCC and provide a preclinical rationale for exploring the therapeutic potential of high-dose AA in ccRCC.

Preclinical impact of high dose intermittent antiangiogenic tyrosine kinase inhibitor pazopanib in intrinsically resistant tumor models.

Antiangiogenic tyrosine kinase inhibitors (TKIs) target vascular endothelial growth factor receptors and other receptor tyrosine kinases. As a result of toxicity, the clinical failures or the modest benefits associated with antiangiogenic TKI therapy may be related in some cases to suboptimal drug dosing and scheduling, thereby facilitating resistance. Most antiangiogenic TKIs, including pazopanib, are administered on a continuous daily basis. Here, instead, we evaluated the impact of increasing the dose and administering the drug intermittently. The rationale is that using such protocols, antitumor efficacy could be enhanced by direct tumor cell targeting effects in addition to inhibiting tumor angiogenesis. To test this, we employed two human tumor xenograft models, both of which manifest intrinsic resistance to pazopanib when it is administered continuously: the VHL-wildtype SN12-PM6-1 renal cell carcinoma (RCC) and the metastatic MDA-MB-231/LM2-4 variant breast cancer cell line, when treated as distant metastases. We evaluated four different doses and schedules of pazopanib in the context of primary tumors and advanced metastatic disease, in both models. The RCC model was not converted to drug sensitivity using the intermittent protocol. Using these protocols did not enhance the efficacy when treating primary LM2-4 tumors. However, one of the high-dose intermittent pazopanib protocols increased median survival when treating advanced metastatic disease. In conclusion, these results overall suggest that primary tumors showing sensitivity to continuous pazopanib treatment may predict response to this drug when given at high doses intermittently in the context of advanced metastatic disease, that are otherwise resistant to the conventional protocol.

Prognostic role of N-Acetylgalactosaminyltransferase 10 in metastatic renal cell carcinoma.

BACKGROUND AND PURPOSE: A previous study demonstrated that GALNT10 affects the sensitivity of cancer cells to tyrosine kinase inhibitor (TKI) therapy. The aim of this study was to assess whether GALNT10 holds a prognostic role in metastatic renal cell carcinoma (mRCC) patients treated with TKI agents. RESULTS: GALNT10 had no statistical correlation with any other clinicopathological parameters except for route of gaining samples (P = 0.001) and Heng's risk stratification (P = 0.011). Patients with high level of GALNT10 had significantly shorter overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P = 0.002). Importantly, this relationship existed in OS and PFS analyses in sunitinib-treated patients and in OS analyses in sorafenib-treated patients (P = 0.024). In contrast to sorafenib group, percentage of partial response (PR) and stable disease (SD) were higher in sunitinib group, while percentage of progression disease (PD) was much lower. Univariate and multivariate analyses identified that GALNT10 was an independent prognostic factor for OS (HR = 1.938, P = 0.014), not for PFS (HR = 1.532, P = 0.065), in mRCC. Incorporating it into Heng's risk model could sharpen its efficacy in distinguishing patients with potential higher risk. MATERIALS AND METHODS: We retrospectively enrolled 138 mRCC patients treated with sunitinib or sorafenib at Zhongshan Hospital, Shanghai, China. A total of 111 valid cases were finally applied for analyses. CONCLUSIONS: These findings suggest that GALNT10 could be applied as a prognostic marker for OS in mRCC patients.

Cytoreductive Nephrectomy in the Tyrosine Kinase Inhibitor Era: A Question That May Never Be Answered.

Despite great interest, two randomised controlled trials (RCTs) of cytoreductive nephrectomy in the tyrosine kinase inhibitor setting in metastatic renal cell carcinoma have either closed early (SURTIME) or are recruiting very slowly (CARMENA) after 7 yr. Challenges in RCT delivery in uro-oncologic surgery are many. Multiple steps are needed to ensure strong recruitment to trials addressing important urologic cancer questions. Feasibility/pilot studies are key stepping stones towards successful delivery of surgical RCTs.

A Chinese medicine formula Gegen Qinlian decoction suppresses expansion of human renal carcinoma with inhibition of matrix metalloproteinase-2.

AIM OF STUDY: Gegen Qinlian decoction (GQLD) is an ancient Chinese medicine formula for treating diseases with inner heat. The aim of this study is to investigate the antitumor effect of GQLD in human renal carcinoma cell (RCC) and its possible mechanism. METHOD: High-performance liquid chromatography was used to identify and quantify active compounds in GQLD. Inhibition of tumor growth was determined by xenograft model. Cell viability on treatment with the decoction was determined by MTT assay; quantitative real-time polymerase chain reaction and immunoblotting were used to determine gene and protein expression; matrix metalloproteinase-2 (MMP-2) activity was detected by gelatin zymography and in vitro enzymatic reaction assay. RESULTS: Thirteen major peaks were detected in the decoction, 8 of which were identified as berberine, baicalin and baicalein, pueranin, daizidin, liquiritin, wogonoside, and wogonin. GQLD exhibited potent inhibition on xenografted expansion of RCC cells. Interestingly, GQLD treatment did not induce cell death to RCC cells, but blocked the neoangiogenesis in xenografted RCC tumor. Particularly, we found that GQLD significantly inhibited MMP-2 in RCC cells, which was involved as a critical factor in avascular growth of RCC. GQLD directly suppressed the enzyme activity of MMP-2. Radix Scutellariae was the major herbal component that contributed to the potent inhibition of MMP-2. CONCLUSION: The findings of this study provide experimental evidence of the inhibition of expansion and neoangiogenesis of renal carcinoma by Chinese medicine formula GQLD with involvement of MMP-2 suppression.

Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma.

PURPOSE: This international phase III trial (Investigating Torisel As Second-Line Therapy [INTORSECT]) compared the efficacy of temsirolimus (mammalian target of rapamycin inhibitor) and sorafenib (vascular endothelial growth factor receptor [VEGFR] tyrosine kinase inhibitor) as second-line therapy in patients with metastatic renal cell carcinoma (mRCC) after disease progression on sunitinib. PATIENTS AND METHODS: In total, 512 patients were randomly assigned 1:1 to receive intravenous temsirolimus 25 mg once weekly (n = 259) or oral sorafenib 400 mg twice per day (n = 253), with stratification according to duration of prior sunitinib therapy (≤ or > 180 days), prognostic risk, histology (clear cell or non-clear cell), and nephrectomy status. The primary end point was progression-free survival (PFS) by independent review committee assessment. Safety, objective response rate (ORR), and overall survival (OS) were secondary end points. RESULTS: Primary analysis revealed no significant difference between treatment arms for PFS (stratified hazard ratio [HR], 0.87; 95% CI, 0.71 to 1.07; two-sided P = .19) or ORR. Median PFS in the temsirolimus and sorafenib arms were 4.3 and 3.9 months, respectively. There was a significant OS difference in favor of sorafenib (stratified HR, 1.31; 95% CI, 1.05 to 1.63; two-sided P = .01). Median OS in the temsirolimus and sorafenib arms was 12.3 and 16.6 months, respectively. Safety profiles of both agents were consistent with previous studies. CONCLUSION: In patients with mRCC and progression on sunitinib, second-line temsirolimus did not demonstrate a PFS advantage compared with sorafenib. The longer OS observed with sorafenib suggests sequenced VEGFR inhibition may benefit patients with mRCC.

Bisebromoamide, an extract from Lyngbya species, induces apoptosis through ERK and mTOR inhibitions in renal cancer cells.

Advanced renal cell carcinoma (RCC) remains an incurable disease, and newer anticancer drugs are needed. Bisebromoamide, a novel cytotoxic peptide, was isolated from the marine cyanobacterium Lyngbya species at our laboratory in 2009. This compound specifically inhibited the phosphorylation of ERK in platelet-derived growth factor-activated normal rat kidney cells. The aim of this study was to evaluate the effect and elucidate the potential mechanism of Bisebromoamide actions on human RCC cells. Two renal cancer cell lines, 769-P and 786-O, were used. The effects of Bisebromoamide were analyzed employing assays for water-soluble Tetrazolium-1 salts. Apoptosis was determined by flow cytometric TUNEL analysis. Cell-cycle distributions were analyzed by flow cytometry using BrdU/propidium iodide (PI) staining. Kinases of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of Rapamycin (mTOR) pathway and Raf/MEK/ERK pathway were analyzed by Western blotting. After Bisebromoamide treatment for 48 and 72 h, cell viability was significantly decreased in both cell lines at 1 and 10 µmol/L. After treatment with 1 µmol/L Bisebromoamide for 72 h, apoptosis and the increased percentage of cells in the sub-G1 phase were observed in both cell lines. Bisebromoamide inhibited the phosphorylation of ERK and Akt in both cell lines tested. Similar effects were demonstrated for phosphorylation of mTOR and p70 S6. Bisebromoamide is a promising potential agent against RCC due to its ability to inhibit both the Raf/MEK/ERK and PI3K/Akt/mTOR pathways.

Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial.

BACKGROUND: In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results. METHODS: Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov, number NCT00678392. FINDINGS: Median overall survival was 20.1 months (95% CI 16.7-23.4) with axitinib and 19.2 months (17.5-22.3) with sorafenib (hazard ratio [HR] 0.969, 95% CI 0.800-1.174; one-sided p=0.3744). Median investigator-assessed PFS was 8.3 months (95% CI 6.7-9.2) with axitinib and 5·7 months (4.7-6.5) with sorafenib (HR 0.656, 95% CI 0.552-0.779; one-sided p<0.0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 [17%]), diarrhoea (40 [11%]), and fatigue (37 [10%]) in 359 axitinib-treated patients and hand-foot syndrome (61 [17%]), hypertension (43 [12%]), and diarrhoea (27 [8%]) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20.7 months (95% CI 18.4-24.6) versus 12.9 months (10.1-20.4) in the axitinib group (p=0.0116), and 20.2 months (17.1-32.0) versus 14.8 months (12.0-17.7) in the sorafenib group (one-sided p=0.0020). INTERPRETATION: Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma. FUNDING: Pfizer Inc.

GSK-3 inhibition in vitro and in vivo enhances antitumor effect of sorafenib in renal cell carcinoma (RCC).

Sorafenib is a multikinase inhibitor approved for the systemic treatment of renal cell carcinoma (RCC). However, sorafenib treatment has a limited effect due to acquired chemoresistance of RCC. Previously, we identified glycogen synthase kinase-3 (GSK-3) as a new therapeutic target in RCC. Here, we observed that sorafenib inhibits proliferation and survival of RCC cells. Significantly, we revealed that sorafenib enhances GSK-3 activity in RCC cells, which could be a potential mechanism of acquired chemoresistance. We found that pharmacological inhibition of GSK-3 potentiates sorafenib antitumor effect in vitro and in vivo. Our results suggest that combining GSK-3 inhibitor and sorafenib might be a potential new therapeutic approach for RCC treatment.

Sorafenib for the treatment of renal cancer.

INTRODUCTION: Sorafenib was the first oral antiangiogenic multikinase inhibitor (Raf kinases, VEGF receptors 1 - 3, PDGF-beta, Flt-3, c-kit) for advanced renal cell carcinoma (RCC) to be approved. Since 2005, a total of six drugs have been approved for the treatment of RCC. AREAS COVERED: The preclinical and clinical development of sorafenib that led to its approval for advanced RCC is reviewed in this paper. Its safety, tolerability and efficacy are summarized and compared with other approved treatment options for RCC. Preliminary data on sequential treatment strategies and combination trials with other targeted drugs are also discussed. EXPERT OPINION: The efficacy and good tolerability of sorafenib in patients with RCC has already been confirmed by numerous studies. The drug proved to be suitable for patients of any age, with respect to efficacy and safety. Sequential use of sorafenib and other targeted drugs is characterized by only limited cross-resistance and many studies seem to indicate more clinical benefits and longer overall progression-free survival when sorafenib is administered as a first-line therapy. However, the optimal sequential therapy remains to be determined within prospective trials, such as the SWITCH study. In addition, we need predictive biomarkers to preselect the patients with the best chances of benefiting from sorafenib, in the context of personalized medicine.

Metastatic renal cell carcinoma treated sequentially with multiple VEGF receptor-targeted inhibitors--a case report.

Six targeted agents [sorafenib, sunitinib, temsirolimus, bevacizumab (plus interferon), everolimus and pazopanib] have been approved for the treatment of patients with metastatic renal cell carcinoma. As disease progression is inevitable, most patients will receive several lines of treatment. However, the choice regarding which sequence of drugs to use remains unclear, particularly concerning the drug class, i.e. those targeting the vascular endothelial growth factor (receptor) [VEGF(R)] pathway versus those acting on the mammalian target of rapamycin pathway. There appears to be no absolute crossresistance between tyrosine kinase inhibitors (TKIs) acting on the VEGF(R) pathway, and there have been numerous reports of two TKIs being successfully used in sequence. We report the case of a 63-year-old woman who responded for 24 months to three successive lines of treatment with different TKIs (sunitinib, axitinib and sorafenib). This suggests that TKIs targeting VEGFR should be considered as individual drugs and not as a single class.

Sequence therapy in patients with metastatic renal cell carcinoma: comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors.

BACKGROUND: The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined. OBJECTIVE: To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres. INTERVENTION: Sequence of systemic targeted treatment with sunitinib (n=85) or sorafenib (n=23) followed by EV (n=62) or another rTKI (n=46; sorafenib, n=35; sunitinib, n=11). MEASUREMENTS: We measured response rate (Response Evaluation Criteria in Solid Tumours 1.0) and toxicity. Survival analysis (Kaplan-Meier method and Cox regression) was conducted for progression-free survival (PFS) and overall survival (OS). RESULTS AND LIMITATIONS: Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8-5.4) for EV and 4.0 mo (3.2-4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9-52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6-39.5; p=0.03), but this difference lost statistical significance in multivariable-adjusted analyses. Intrinsic rTKI resistance was independently associated with inferior subsequent PFS (hazard ratio [HR]: 1.79; 95% CI, 1.15-3.62; p=0.015) and OS (HR: 6.54; 95% CI, 3.01-14.20; p<0.001). Limitations are the retrospective design, limited numbers of cases, and residual confounding factors. CONCLUSIONS: The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials.

Multikinase inhibitors in metastatic renal cell carcinoma: indirect comparison meta-analysis.

BACKGROUND: Randomized controlled trials (RCTs) of multikinase inhibitors sunitinib, sorafenib, and pazopanib have reported efficacy compared with results from placebo and interferon-α (INF-α). To date, these drugs have not been compared in head-to-head trials. OBJECTIVE: To review systematically the evidence of clinical effectiveness of multikinase inhibitors in the treatment of metastatic renal cell carcinoma (mRCC) and, via an indirect meta-analysis, to determine an optimal treatment among these agents. METHODS: A systematic literature search of MEDLINE, EMBASE, CANCERLIT, and Cochrane controlled trials register databases was performed. All RCTs of multikinase inhibitors (sorafenib, sunitinib, and pazopanib) used to treat mRCC were included. The study selection, data extraction, and quality assessment were performed independently by 2 reviewers, with all disagreements being resolved by consensus. The effects of multikinase inhibitors on progression-free survival (PFS) were compared using an indirect treatment comparison method with INF-α or placebo as a comparator. RESULTS: Four studies were included. Two studies examined sunitinib or sorafenib versus IFN-α, and the other 2 studies investigated sorafenib or pazopanib versus placebo. Compared with placebo, 2 interventions reported improvement for PFS (sorafenib: hazard ratio [HR] = 0.44, P = 0.01; pazopanib: HR = 0.46, P = 0.0001), whereas only sunitinib improved PFS over IFN-α (HR = 0.539, P = 0.001). An indirect comparison suggests that sunitinib is likely to demonstrate greater clinical benefit than sorafenib in terms of PFS (HR = 0.47; 95% CI, 0.316-0.713; P < 0.001), using IFN-α as the comparator. Sorafenib was not statistically different from pazopanib using placebo as the comparator in the indirect comparison (HR = 0.957; 95% CI, 0.657-1.39; P = 0.24). CONCLUSION: Some multikinase inhibitors have a favorably reported PFS for patients with mRCC compared with results using IFN-α or placebo. Our findings suggest that sunitinib might offer some clinical benefit over sorafenib in terms of PFS. No statistical difference was found between sorafenib and pazopanib treatments. However, these conclusions are based on 2 indirect comparisons of single RCTs. More RCTs are required to confirm these findings and investigate the clinical effectiveness of multikinase inhibitors in the treatment of mRCC.

Long-term response and postsurgical complete remissions after treatment with sunitinib malate, an oral multitargeted receptor tyrosine kinase inhibitor, in patients with metastatic renal cell carcinoma.

Receptor tyrosine kinase (RTK) inhibitors have revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and significantly extended survival in these patients. Sunitinib is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs-1, -2, and -3), platelet-derived growth factor receptors (PDGFRs-α and -ß), stem-cell factor receptor (KIT), FMS-like tyrosine kinase 3 (FLT3), colony-stimulating factor 1 receptor (CSF-1R), and glial cell line-derived neurotrophic factor receptor (REarranged during Transfection; RET). Sunitinib is approved multinationally for the treatment of advanced RCC, and is considered the reference standard of care for first-line treatment. In clinical trials, sunitinib has been associated with a consistent, distinct profile of adverse events. Here we describe three cases that show that it is possible to manage adverse events occurring during sunitinib therapy, and thus allow patients with mRCC to receive an effective dose of sunitinib in order to achieve long-term disease control. These cases also show that surgical resection, performed whenever possible, can help to improve control of metastatic disease and so avoid the unnecessary toxicity and high costs of prolonged antiangiogenic therapy.

Third-line sorafenib after sequential therapy with sunitinib and mTOR inhibitors in metastatic renal cell carcinoma.

BACKGROUND: Sunitinib and everolimus have been approved for first- and second-line treatment, respectively, in metastatic renal cell carcinoma (mRCC). The role of sorafenib, which is approved for second-line treatment after cytokines failure, is presently to be defined. OBJECTIVE: To determine whether third-line sorafenib after sequential use of sunitinib and mammalian target of rapamycin inhibitors (everolimus or temsirolimus) is feasible and effective. DESIGN, SETTING, AND PARTICIPANTS: One hundred fifty medical records of patients with mRCC treated with first-line sunitinib between January 2006 and January 2010 were reviewed at four participating centers. Data regarding patients treated with the sequence sunitinib-everolimus or temsirolimus-sorafenib were extracted. Central analysis of radiographic images was performed using RECIST criteria to determine progression-free survival (PFS) and overall response rate (oRR) to sorafenib treatment. MEASUREMENTS: PFS and oRR to sorafenib were the primary end points. Secondary outcomes were safety and overall survival (OS). RESULTS AND LIMITATIONS: Thirty-four patients were eligible for the study. A median PFS of 4 mo (range: 3-6 mo) and a median OS of 7 mo since sorafenib treatment (range: 6-10 mo) were reported. Of the patients, 23.5% showed response to sorafenib, with an overall disease control rate (complete responses plus partial responses plus stable disease) of 44%. Selection bias, data incompleteness, and absence of study design are inevitable limitations of the study, although central review can strengthen the quality of presented data. CONCLUSIONS: Third-line sorafenib appears to be active and well tolerated in mRCC after first-line sunitinib and second-line everolimus or temsirolimus, with no patients interrupting sorafenib because of toxicity or lack of compliance. Prospective, placebo-controlled trials are completely lacking and are required in this setting.

Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear-cell renal cell carcinoma receiving vascular endothelial growth factor-targeted therapy.

OBJECTIVE: To investigate the utility of tumour carbonic anhydrase IX (CAIX) expression and histological features for predicting the outcome in patients with metastatic clear-cell renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy. PATIENTS AND METHODS: We identified 118 patients with mRCC initiating first-line VEGF-targeted therapy, including 94 with clinical and histological data, and available tissue. The primary endpoint was to detect an interaction between sorafenib vs sunitinib treatment and CAIX status on tumour shrinkage. Other treatment outcomes were also assessed. RESULTS: There was heterogeneity in tumour responsiveness to sunitinib or sorafenib according to CAIX status; the mean shrinkage was -17% vs -25% for sunitinib-treated patients with high vs low tumour CAIX expression, compared to -13% vs +9% for sorafenib-treated patients (P interaction, 0.05). A higher tumour clear-cell component was independently associated with greater tumour shrinkage (P= 0.02), response (P= 0.02) and treatment duration (P= 0.02). CONCLUSIONS: Although CAIX expression had no prognostic value in patients with clear-cell mRCC treated with VEGF-targeted therapy, it might be a predictive biomarker for response to sorafenib treatment. Patients with a higher clear-cell component in their tumours are likely to have a superior clinical benefit from VEGF-targeted therapy.

UOK 262 cell line, fumarate hydratase deficient (FH-/FH-) hereditary leiomyomatosis renal cell carcinoma: in vitro and in vivo model of an aberrant energy metabolic pathway in human cancer.

Energy deregulation and abnormalities of tumor cell metabolism are critical issues in understanding cancer. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is an aggressive form of RCC characterized by germline mutation of the Krebs cycle enzyme fumarate hydratase (FH), and one known to be highly metastatic and unusually lethal. There is considerable utility in establishing preclinical cell and xenograft models for study of disorders of energy metabolism, as well as in development of new therapeutic approaches targeting of tricarboxylic acid (TCA) cycle enzyme-deficient human cancers. Here we describe a new immortalized cell line, UOK 262, derived from a patient having aggressive HLRCC-associated recurring kidney cancer. We investigated gene expression, chromosome profiles, efflux bioenergetic analysis, mitochondrial ultrastructure, FH catabolic activity, invasiveness, and optimal glucose requirements for in vitro growth. UOK 262 cells have an isochromosome 1q recurring chromosome abnormality, i(1)(q10), and exhibit compromised oxidative phosphorylation and in vitro dependence on anaerobic glycolysis consistent with the clinical manifestation of HLRCC. The cells also display glucose-dependent growth, an elevated rate of lactate efflux, and overexpression of the glucose transporter GLUT1 and of lactate dehydrogenase A (LDHA). Mutant FH protein was present primarily in edematous mitochondria, but with catalytic activity nearly undetectable. UOK 262 xenografts retain the characteristics of HLRCC histopathology. Our findings indicate that the severe compromise of oxidative phosphorylation and rapid glycolytic flux in UOK 262 are an essential feature of this TCA cycle enzyme-deficient form of kidney cancer. This tumor model is the embodiment of the Warburg effect. UOK 262 provides a unique in vitro and in vivo preclinical model for studying the bioenergetics of the Warburg effect in human cancer.

Cytoreductive nephrectomy in metastatic clear-cell renal cell carcinoma: perspectives in the tyrosine kinase inhibitor era.

Cytoreductive nephrectomy in combination with adjuvant immunotherapy is an established treatment option for selected patients with metastatic clear-cell renal cell carcinoma (mCC-RCC). Multitargeted antiangiogenic and mammalian target of rapamycin tyrosine kinase inhibitors (TKIs) are now established treatment paradigms in patients with mCC-RCC. Given that all the recent seminal TKI trials in mCC-RCC provide no evidence base for the use of cytoreductive nephrectomy in the TKI era, it is not presently clear where such a surgical approach fits into the treatment paradigm. This review summarizes the evidence for the management of mCC-RCC and outlines novel approaches to be tested within future trials if the initial proposed phase III trials in this setting, using sunitinib, are successful. Overall, two principal questions need addressing. First, is cytoreductive nephrectomy necessary in the TKI era? Second, if so, what is the most appropriate scheduling of TKI therapy with cytoreductive nephrectomy?

Metastasis is promoted by a bioenergetic switch: new targets for progressive renal cell cancer.

Targeted therapies have demonstrated clinical benefit with limited impact on long-term disease specific survival in the treatment of renal cell cancer (RCC). New opportunities for the treatment of tumors that are resistant or have relapsed, are needed. Increased anaerobic glucose fermentation to lactate (aerobic glycolysis), leading to oxygen- and mitochondria-independent ATP generation is a hallmark of aggressive cancer growth. This metabolic shift results in increased lactate production via cycling through the pentose phosphate pathway (PPP), and plays an important role in tumor immune escape, progression and resistance to immune-, radiation- and chemo-therapy. This study explored the activity and impact of the oxidative and nonoxidative branches of the PPP on RCC to evaluate new therapeutic options. Activity was determined in the oxidative branch by glucose-6-phosphate-dehydrogenase (G6PD) activity, and in the nonoxidative branch by the total transketolase activity and the specific expression of the transketolase-like-1 (TKTL1) protein. Transketolase and G6PD activity were intensely elevated in tumor tissues. Transketolase, but not G6PD activity, was more elevated in metastasizing tumors and TKTL1 protein was significantly overexpressed in progressing tumors (p = 0.03). Lethal tumors, where surrogate parameters such as grading and staging had failed to predict progression, showed intensive TKTL1 protein expression. RCC was found to have activated oxidative and nonoxidative glucose metabolism through the PPP, displaying a bioenergetic shift toward nonoxidative glucose fermentation in progressing tumors. The coexistence of cancer cells with differentially regulated energy supplies provides new insights in carcinogenesis and novel anticancer targets.