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Oncology Intelligence

Kidney Cancer
There are three main types of kidney cancer: RCC, transitional cell cancer of renal pelvis, and Wilms tumor. Also included in this section is adrenal cancer.
There are approximately 62k new cases of RCC in the US each year. Most of these cases are RCCs that occur within the kidney, but also includes transitional cell cancers of the renal pelvis (5%), and Wilms tumor (1%). Kidney cancer incidence rates have remained stable for the last decade. There are approximately 14k deaths from kidney cancer each year in the US, and that rate is decreasing by about 1% per year. The 5- and 10-year relative survival rates for kidney cancer are 72% and 62%, respectively. Almost two-thirds of cases are diagnosed at a local stage, for which the 5-year relative survival rate is 92%. Five-year survival is lower for renal pelvis (49%) than for renal cell carcinoma (74%).
The global kidney cancer drug market is approximately 3.5 billion USD and is likely to reach USD 4.5 billion in 2020. Drugs currently approved for RCC include: aldesleukin, axitinib, bevacizumab, everolimus, pazopanib, sorafenib, sunitinib, and temsirolimus.
Historic & ongoing kidney clinical trials


News
Wednesday, September 21, 2016 6:00 PM|Laura S. Schmidt, W. Marston Linehan|Seminars in Oncology|Labels: kidney cancer
Kidney cancer is not a single disease but is made up of a number of different types of cancer classified by histology that are disparate in presentation, clinical course, and genetic basis. Studies of families with inherited renal cell carcinoma (RCC) have provided the basis for our understanding of the causative genes and altered metabolic pathways in renal cancer with different histologies. Von Hippel-Lindau disease was the first renal cancer disorder with a defined genetic basis. Over the next two decades, the genes responsible for a number of other inherited renal cancer syndromes including hereditary papillary renal carcinoma, Birt-Hogg-Dube´syndrome, hereditary leiomyomatosis and renal cell carcinoma, and succinate dehydrogenase-associated renal cancer were identified.
Thursday, September 15, 2016 6:45 AM|Wallace, E. M., Rizzi, J. P., Han, G., Wehn, P. M., Cao, Z., Du, X., Cheng, T., Czerwinski, R. M., Dixon, D. D., Goggin, B. S., Grina, J. A., Halfmann, M. M., Maddie, M. A., Olive, S. R., Schlachter, S. T., Tan, H., Wang, B., Wang, K., Xie, S., Xu, R., Yang, H., Josey, J. A.|Cancer Research recent issues|Labels: HIF, VEGF, kidney cancer
More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel–Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491–500. ©2016 AACR.
Thursday, September 15, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: mTOR, VEGF, kidney cancer
The European Commission approved Kisplyx lenvatinib from Eisai Co. Ltd. (Tokyo:4523) in combination with Afinitor everolimus to treat advanced renal cell carcinoma (RCC) in patients previously treated with a VEGF inhibitor.In May, FDA approved the inhibitor of multiple VEGF receptor tyrosine kinases for the same indication. The drug is marketed for thyroid cancer in the U.S. and EU, and is known as Lenvima in some countries.Novartis AG (NYSE:NVS; SIX:NOVN) markets Afinitor, an oral mammalian target of rapamycin (mTOR; FRAP; RAFT1) protein inhibitor.
Thursday, September 15, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: kidney cancer, clinical trial, financial
Peloton Therapeutics Inc. (Dallas, Texas) raised $52.4 million in a series D round. New investor Foresite Capital Management participated, as did all of Peloton's existing investors, including Remeditex, The Column Group (TCG), Tichenor Ventures, Topspin Fund and Nextech Invest.Peloton's lead program, PT2385, is in a dose-escalating Phase I study to treat advanced clear cell renal cell carcinoma (ccRCC). At the American Society of Clinical Oncology meeting in June, Peloton said a range of PT2385 doses led to one complete response and three partial responses, plus 16 cases of stable disease lasting at least 16 weeks, among 51 patients. PT2385 is a small molecule inhibitor of endothelial PAS domain protein 1 (HIF2A; HIF-2alpha; EPAS1) (see BioCentury Innovations, June 18, 2015). This month, Cancer Research published a paper characterizing PT2385's efficacy in cell line and patient-derived xenograft models of kidney cancer. Nature also published two papers with preclinical data for PT2399, an analogue of PT2385. One study described PT2399's specificity for HIF2A, while the second study showed that in patient-derived ccRCC xenografts, PT2399 showed more activity in tumors than RCC drug Sutent sunitinib from Pfizer Inc. (NYSE:PFE), with less toxicity.
Wednesday, September 14, 2016 10:11 PM|Maria V. Yusenko, Dmitry Zubakov, Gyula Kovacs|International Journal of Biological Sciences|Labels: ROS, kidney cancer, biomarker diagnostic

Due to overlapping morphology, malignant chromophobe renal cell carcinomas (RCC) and benign renal oncocytomas (RO) may pose a diagnostic problem. In the present study, we have applied different algorithms to evaluate the data sets obtained by hybridisation of pooled and also individual samples of renal cell tumours (RCT) onto two different gene expression platforms. The two approaches revealed high similarities in the gene expression profiles of chromophobe RCCs and ROs but also some differences. After identifying the differentially expressed genes by statistic analyses, the candidate genes were further selected by a real time and normal RT-PCR and their products were analysed by immunohistochemistry. We have identified CD82 and S100A1 as valuable markers for chromophobe RCC as well as AQP6 for ROs. However, these genes are expressed at the protein level in other types of RCTs as well albeit at a low frequency and low intensity. As none of the selected genes marks exclusively one type of RCTs, for the differential diagnosis of chromophobe RCCs and ROs, a set of markers such as CD82, S100A1 and AQP6 as well as some others would be an option in routine histological laboratories.

Wednesday, September 14, 2016 5:53 PM|Zofia Wotschofsky, Julia Liep, Hellmuth-Alexander Meyer, Monika Jung, Ina Wagner, Alexander C. Disch, Klaus D. Schaser, Ingo Melcher, Ergin Kilic, Jonas Busch, Steffen Weikert, Kurt Miller, Andreas Erbersdobler, Hans-Joachim Mollenkopf, Klaus Jung|International Journal of Biological Sciences|Labels: kidney cancer

MicroRNAs (miRNAs) play a pivotal role in cancerogenesis and cancer progression, but their specific role in the metastasis of clear cell renal cell carcinomas (ccRCC) is still limited. Based on microRNA microarray analyses from normal and cancerous samples of ccRCC specimens and from bone metastases of ccRCC patients, we identified a set of 57 differentially expressed microRNAs between these three sample groups of ccRCC. A selected panel of 33 miRNAs was subsequently validated by RT-qPCR on total 57 samples. Then, 30 of the 33 examined miRNAs were confirmed to be deregulated. A stepwise down-regulation of miRNA expression from normal, over primary tumor to metastatic tissue samples, was found to be typical. A total of 23 miRNAs (miR-10b/-19a/-19b/-20a/-29a/-29b/-29c/-100/-101/-126/-127/-130/-141/-143/-145/-148a/-192/-194/-200c/-210/-215/-370/-514) were down-regulated in metastatic tissue samples compared with normal tissue. This down-regulated expression in metastatic tissue in comparison with primary tumor tissue was also present in 21 miRNAs. In cell culture experiments with 5-aza-2'-deoxycytidine and trichostatin A, epigenetic modifications were shown as one reason of this down-regulation. The altered miRNA profiles, comprising newly identified metastasis-associated miRNAs, termed metastamir and the predicted miRNA-target interactions together with the significant correlations of miRNAs that were either lost or newly appeared in the studied sample groups, afford a solid basis for further functional analyses of individual miRNAs in RCC metastatic progression.

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: kidney cancer, melanoma, clinical trial
To assess the safety and tolerability at increasing dose levels of PF-04518600 in patients with advanced or metastatic hepatocellular carcinoma (HCC), melanoma, clear cell renal cell carcinoma (RCC) or squamous cell head and neck cancer (SCCHN) in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: VEGF, kidney cancer, clinical trial
This protocol will generate safety data on nivolumab monotherapy for advanced Renal Cell Carcinoma (RCC) patients and will have as its primary objective, the assessment of high grade immune-mediated adverse events (IMAE) in this patient population treated with nivolumab. In addition to continuing the investigation of safety for RCC patients with clear cell histology and prior treatment with anti- vascular endothelial growth factor (VEGF) therapy, this study will explore the safety and efficacy data for RCC patients with non-clear cell histology and RCC patients with either histology and brain metastases.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: VEGF, kidney cancer, clinical trial
The purpose of this study is to evaluate the progression free survival (PFS), based on investigator radiologic review, of AGS-16C3F compared to axitinib in subjects with metastatic renal cell carcinoma.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: PD-1/PD-L1, kidney cancer, clinical trial
This is a phase 3 randomized trial evaluating the anti-tumor activity and safety of avelumab in combination with axitinib and of sunitinib monotherapy, administered as first-line treatment, in patients with advanced renal cell carcinoma
Wednesday, September 14, 2016 11:10 AM|Brian Shuch, Srinivas Vourganti, Julia C. Friend, Lee M. Zehngebot, W. Marston Linehan, Ramaprasad Srinivasan|Journal of Cancer|Labels: mTOR, kidney cancer

Chromophobe kidney cancer accounts for approximately 5% of cases of renal cell carcinoma (RCC). While the genetics of clear cell RCC has been a major focus of research, little is known about the biology of chromophobe tumors. There is ample preclinical rationale for the use of targeted therapy in clear cell tumors, and agents targeting the VHL/HIF pathway are now widely used in clinical practice. However, there is limited experience with targeted agents in non-clear cell tumors. Recently, a few case reports have emerged which report the use of mTOR inhibitors in chromophobe tumors. Here, we report our experience with targeted therapy in a patient with advanced chromophobe RCC who had a durable partial response to temsirolimus. We also include a literature review summarizing the published experience with targeted therapeutic approaches in chromophobe RCC. Additionally, the preclinical rationale for the use of mTOR inhibitors in this population based on our characterization of the hereditary form of chromophobe kidney cancer, Birt-Hogg-Dube syndrome, is discussed.

Wednesday, September 14, 2016 7:55 AM|TAKEZAWA, Y., IZUMI, K., SHIMURA, Y., AERKEN, M., NATSAGDORJI, A., IIJIMA, M., SHIGEHARA, K., NOHARA, T., NARIMOTO, K., KADONO, Y., KITAGAWA, Y., KONAKA, H., MIZOKAMI, A.|Anticancer Research recent issues|Labels: kidney cancer, IL

Renal cell carcinoma (RCC) is one of the most fatal urological malignancies. Approximately 30% of patients with RCC have metastasis at initial diagnosis and another 30% have metastasis after radical nephrectomy. Immunotherapy using interferon-α (IFN-α) and interleukin-2 (IL-2) has been the main treatment for metastatic RCC (mRCC) patients, with this therapy being still occasionally recommended. The aims of this study were to evaluate the efficacy of low-dose IL-2 and to investigate the prognosis of the patients. Study subjects included 37 patients who were clinically diagnosed with mRCC and received low-dose IL-2 therapy between December 1999 and October 2014. We investigated the relationship between prognosis and clinical features. The median overall survival (OS), that was calculated from the first use of cytokine therapy, was 19.8 months, while the median progression-free survival (PFS) was 3.82 months. PFS was prolonged in patients who received IL-2 as first-line therapy or second-line therapy following IFN-α therapy. IL-2 therapy should be used as a first- or second-line therapy following IFN-α therapy. IL-2 may have a lower response if it is used after molecular-targeted therapy or other treatments.

Wednesday, September 14, 2016 3:01 AM|PharmaTimes: News RSS|Labels: kidney cancer, regulatory
European regulators have approved a new second-line treatment option for patients with advanced kidney cancer.
Wednesday, September 14, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: MET, mTOR, VEGF, kidney cancer, regulatory
The European Commission approved Cabometyx cabozantinib from Exelixis Inc. (NASDAQ:EXEL) as monotherapy to treat advanced renal cell carcinoma (RCC) in patients previously treated with a VEGF inhibitor. The approval triggers a $60 million milestone payment to Exelixis from Ipsen Group (Euronext:IPN), which holds Cabometyx's rights outside the U.S., Canada and Japan (see BioCentury Extra, Feb. 29).Cabometyx is a tablet formulation of cabozantinib, a spectrum-selective kinase inhibitor of VEGF receptor 2 (VEGFR-2;KDR/Flk-1) and c-Met receptor tyrosine kinase (c-MET; MET; HGRF; c-Met proto-oncogene). It is approved in the U.S. for second-line treatment of RCC. Exelixis and Ipsen market a capsule form of cabozantinib as Cometriq for thyroid cancer.Exelixis gained $0.70 to $13.01 on Wednesday.
Tuesday, September 13, 2016 11:38 PM|Hongkai Wang, Junlong Wu, Weijie Gu, Beihe Wang, Fangning Wan, Bo Dai, Hailiang Zhang, Guohai Shi, Yijun Shen, Yiping Zhu, Yao Zhu, Dingwei Ye|Journal of Cancer|Labels: kidney cancer

Objectives: To examine whether serum adiponectin or leptin level has the ability to differentiate clear cell renal cell carcinoma (ccRCC) from other subtypes of renal cell carcinoma (RCC) in a Chinese population.

Patients and methods: We recruited 198 consecutive patients who were treated with radical or partial nephrectomy in our department from September 2011 to June 2013. Their histological types were all malignant, including clear cell, papillary, chromophobe and unclassified RCC. We also enrolled 86 people with no cancer or cancer-related diseases as normal controls. We measured patients' preoperative blood samples for plasma adiponectin and leptin concentrations using an enzyme-linked immunosorbent assay method. Statistical methods were used to analyze ccRCC and other subtypes as they relate to serum adiponectin/leptin level and other factors such as body mass index or visceral fat area.

Results: In our database, normal controls had significantly higher circulating adiponectin (p < 0.001) and leptin levels (p < 0.001) than patients with RCC. Among the 198 RCC patients, 156 patients had ccRCC while 42 patients had other histological types. Serum adiponectin levels were lower in ccRCC patients than in non-clear-cell RCC patients (p = 0.004). However, the plasma leptin level was not differently distributed between ccRCC and non-ccRCC patients (p = 0.940). In multivariate analysis, we found that serum adiponectin level may be an independent predictor for discriminating ccRCC patients from others (p = 0.004). Furthermore, in the ccRCC subgroup, we observed that men with ccRCC had lower leptin (p < 0.001) and adiponectin (p = 0.002) levels, and diabetic patients had lower plasma adiponectin levels (p = 0.001).

Conclusions: Lower plasma adiponectin concentration was related to an increased incidence of ccRCC and may act as an independent predictor for ccRCC. Our study may help define the process from obesity to adipose tissue, to cytokines and finally to ccRCC.

Cabometyx™ (cabozantinib) is the first and only targeted therapy to improve Overall Survival (OS), Objective Response Rate (ORR), and Progression Free Survival (PFS) in RCC in METEOR randomized Ph...
Contributors : Rohit Mehra ; Pankaj Vats ; Marcin Cieslik ; Xuhong Cao ; Fengyun Su ; Sudhanshu Shukla ; Katayoon Kasaian ; Jesse K McKenney ; Saravana M Dhanasekaran ; Arul M Chinnaiyan
Series Type : Expression profiling by high throughput sequencing
Organism : Homo sapiens

Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma with distinctive morphologic and cytogenetic features. Here we carry out whole exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n=22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSGs) and/or evidence of alteration of Hippo pathway genes in 85% of samples.  PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes while other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion.  Mutations in the context of recurrent chromosomal losses amounted to bi-allelic alterations in these TSGs. As a read-out of Hippo pathway inactivation, a majority of cases (90%) exhibited increased nuclear YAP1 protein expression. To identify transcriptional targets of the Hippo pathway in kidney we performed PTPN14 knockdown followed by RNA-seq in 2 kidney cancer cell lines (CAKI-1 and A-704) and a normal kidney epithelial cell line (HK-2). PTPN14 siRNAs were first functionally validated in a MCF-7 TEAD reporter luciferase stable cell line. Both siRNAs showed comparable knockdown efficiency and significantly increased luciferase reporter activity. In 2 of the kidney cell lines PTPN14 knockdown increased cell proliferation compared to non-target controls. While we observed excellent correlation between genes dysregulated by either PTPN14 or LATS1 knockdown within each cell line (HK2, CAKI-1 and A704), the overlap across the 3 cell lines was only 23 genes. Further, these 23 genes did not show concordant differential expression in MTSCC tumors. Overall, these results illustrate the marked tissue specificity of Hippo pathway targets.Finally, taken together, nearly all cases of MTSCC exhibit some evidence of Hippo pathway dysregulation.

Tuesday, September 13, 2016 2:05 PM|L.B. Jilaveanu, B. Shuch, C. R. Zito, F. Parisi, M. Barr, Y. Kluger, L. Chen, H. M. Kluger|Journal of Cancer|Labels: PD-1/PD-L1, kidney cancer

Background: Expression of programmed death ligand (PD-L1/B7-H1/CD274) represents a mechanism of immune escape for renal cell carcinoma (RCC) cells. Drugs blocking PD-L1 or its receptor are in clinical development and early data suggests that tumor PD-L1 expression may predict response.

Patients and Methods: A tissue microarray (TMA) consisting of four biopsy cores from 34 matched pairs of nephrectomy and metastatic sites of clear cell RCC was used to assess PD-L1 expression by quantitative immunofluorescence. Assessment of intra- and inter-tumor heterogeneity and primary and metastatic tumor expression was performed using a method of Automated Quantitative Analysis (AQUA).

Results: The median AQUA scores were higher in metastatic than primary specimens (P < 0.0001). The correlation between PD-L1 expression in matched primary and metastatic specimens was weak (R= 0.24). Within a given tumor, variable PD-L1 staining heterogeneity was seen, however the degree of heterogeneity was similar in primary and metastatic sites (P = 0.482).

Conclusions: The weak correlation between PD-L1 expression in primary and metastatic sites for a given patient suggests that expression in nephrectomy specimens cannot be used to select metastatic RCC patients for PD-L1 and PD-1 inhibitors. The intra-tumor heterogeneity seen in both primary and metastatic specimens indicates that a single core biopsy might not be sufficient to determine PD-L1 expression.

Tuesday, September 13, 2016 11:40 AM|Top Health News -- ScienceDaily|Labels: HIF, kidney cancer
New insights into the potential for new classes of HIF inhibitors to restore control of the hypoxia response -- representing the potential foundation of a new cancer-fighting strategy -- are the focus of recently published research.
Sunday, September 11, 2016 11:00 PM|Fujita, Tetsuo; Nishi, Morihiro; Tabata, Ken-ichi; Matsumoto, Kazumasa; Yoshida, Kazunari; Iwamura, Masatsugu|Anti-Cancer Drugs - Published Ahead-of-Print|Labels: kidney cancer
C-reactive protein (CRP) is an independent prognostic factor for renal cell carcinoma (RCC). The aim of the present study was to investigate the overall prognostic impact of CRP in patients with metastatic RCC treated with sorafenib. Between April 2008 and December 2014, 40 consecutive patients with metastatic RCC were treated with sorafenib at our institution. The patients were divided into two cohorts according to the pretreatment CRP level: (i) a normal CRP cohort (<=0.30 mg/dl) and (ii) an elevated CRP cohort (>0.30 mg/dl). Kaplan-Meier overall survival analysis was carried out. The effects of selected variables on survival were assessed by multivariate regression using the Cox proportional hazards model. The normal CRP cohort included 16 patients (40.0%) and the elevated CRP cohort included 24 patients (60.0%). The normal CRP cohort showed significantly longer overall survival than the elevated CRP cohort (median, 52.0 vs. 17.0 months; P=0.0072). On multivariate analysis, normal CRP predicted longer overall survival (hazard ratio, 0.367; 95% confidence interval, 0.147-0.914; P=0.0313). Pretreatment normal CRP predicted better overall survival in patients with metastatic RCC treated with sorafenib and CRP level may be a useful biomarker for predicting overall survival of patients treated with sorafenib. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
Sunday, September 11, 2016 6:00 PM|Zhong-Qiang Guo, Tong Zheng, Baoen Chen, Cheng Luo, Sisheng Ouyang, Shouzhe Gong, Jiafei Li, Liu-Liang Mao, Fulin Lian, Yong Yang, Yue Huang, Li Li, Jing Lu, Bidong Zhang, Luming Zhou, Hong Ding, Zhiwei Gao, Liqun Zhou, Guoqiang Li, Ran Zhou, Ke Chen, Jingqiu Liu, Yi Wen, Likun Gong, Yuwen Ke, Shang-Dong Yang, Xiao-Bo Qiu, Naixia Zhang, Jin Ren, Dafang Zhong, Cai-Guang Yang, Jiang Liu, Hualiang Jiang|Cancer Cell|Labels: kidney cancer
Using a structure-based design followed by hit optimization, Guo et al. report small-molecule inhibitors that disrupt oncogenic SPOP-mediated pathways by blocking SPOP-substrate interactions and suppress human clear-cell renal cell carcinoma in vitro and in vivo, suggesting the potential of SPOP-targeted therapy.
Monday, September 5, 2016 10:32 PM|News-Medical.Net Kidney Cancer News Feed|Comments|Labels: kidney cancer
Obesity almost always increases cancer risk and worsens outcomes, but researchers led by scientists at Dana-Farber Cancer Institute report that overweight patients with advanced kidney cancer had significantly longer survival than those who were normal or underweight.
Monday, September 5, 2016 10:23 PM|News-Medical.Net VEGF News Feed|Comments|Labels: HIF, kidney cancer
A new class of drugs called HIF-2 inhibitors is more effective and better tolerated than the standard of care drug sunitinib in treating kidney cancer, researchers with the Kidney Cancer Program at Harold C. Simmons Comprehensive Cancer Center have found.
Friday, September 2, 2016 4:50 AM|Shin Kumagai, Kei Ishibashi, Masao Kataoka, Toshiki Oguro, Yuichirou Kiko, Tomohiko Yanagida, Ken Aikawa, Yoshiyuki Kojima|Cancer Science|Labels: VEGF, kidney cancer
Heparan sulfate-specific endosulfatase-2, SULF-2, can modulate the signaling of HSPG-binding proteins. The involvement of SULF-2 in cancer growth varies by cancer type. The roles of SULF-2 expression in the progression and prognosis of renal cell carcinomas (RCCs) have not yet been fully clarified. In the present study, the expression levels of SULF-2 mRNA and protein in 49 clinical RCC samples were determined by RT-PCR and immunostaining. The existence of RCCs with higher SULF-2 expression and lower SULF-2 expression compared to the adjacent normal kidney tissues was suggested. High SULF-2 expression was correlated with an early clinical stage and less invasive pathological factors. Low SULF-2 expression was correlated with an advanced stage and higher invasive factors. Three-year cancer-specific survival (CSS) for high SULF-2 RCCs and low SULF-2 RCCs were 100% and 71.4%, respectively (log-rank p = 0.0019), with a significantly shorter CSS observed in low SULF-2 RCC patients. The influence of SULF-2 expression level on Wnt/VEGF/FGF signaling, cell viability and invasive properties was examined in three RCC cell lines, Caki-2, ACHN and 786-O, using a SULF-2 suppression model involving siRNA or a SULF-2 overexpression model involving a plasmid vector. High SULF-2 expression enhanced Wnt signaling and Wnt-induced cell viability, but not cell invasion. In contrast, low levels of SULF-2 expression significantly enhanced both cell invasion and viability through the activation of VEGF/FGF pathways. RCCs with lower SULF-2 expression might have a higher potential for cell invasion and proliferation, leading to a poorer prognosis via the activation of VEGF and/or FGF signaling. This article is protected by copyright. All rights reserved.
Thursday, September 1, 2016 10:05 PM|Abu Aboud, O., Chen, C.-H., Senapedis, W., Baloglu, E., Argueta, C., Weiss, R. H.|Molecular Cancer Therapeutics current issue|Labels: WNT, kidney cancer, clinical trial

Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and one of the relatively few whose incidence is increasing. Because of the near universal resistance which occurs with the use of current treatment regimens, reprogrammed metabolic pathways are being investigated as potential targets for novel therapies of this disease. Borrowing from studies on other malignancies, we have identified the PAK4 and NAD biosynthetic pathways as being essential for RCC growth. We now show, using the dual PAK4/NAMPT inhibitor KPT-9274, that interference with these signaling pathways results in reduction of G2–M transit as well as induction of apoptosis and decrease in cell invasion and migration in several human RCC cell lines. Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. Furthermore, NAPRT1 downregulation, which we show occurs in all RCC cell lines tested, makes this tumor highly dependent on NAMPT for its NAD requirements, such that inhibition of NAMPT by KPT-9274 leads to decreased survival of these rapidly proliferating cells. When KPT-9274 was administered in vivo to a 786-O (VHL-mut) human RCC xenograft model, there was dose-dependent inhibition of tumor growth with no apparent toxicity; KPT-9274 demonstrated the expected on-target effects in this mouse model. KPT-9274 is being evaluated in a phase I human clinical trial in solid tumors and lymphomas, which will allow this data to be rapidly translated into the clinic for the treatment of RCC. Mol Cancer Ther; 15(9); 2119–29. ©2016 AACR.

Thursday, September 1, 2016 10:05 PM|Ascierto, M. L., McMiller, T. L., Berger, A. E., Danilova, L., Anders, R. A., Netto, G. J., Xu, H., Pritchard, T. S., Fan, J., Cheadle, C., Cope, L., Drake, C. G., Pardoll, D. M., Taube, J. M., Topalian, S. L.|Cancer Immunology Research recent issues|Labels: PD-1/PD-L1, kidney cancer

Pretreatment tumor PD-L1 expression has been shown to correlate with response to anti–PD-1/PD-L1 therapies. Yet, most patients with PD-L1+ tumors do not respond to treatment. The current study was undertaken to investigate mechanisms underlying the failure of PD-1–targeted therapies in patients with advanced renal cell carcinoma (RCC) whose tumors express PD-L1. Formalin-fixed, paraffin-embedded pretreatment tumor biopsies expressing PD-L1 were derived from 13 RCC patients. RNA was isolated from PD-L1+ regions and subjected to whole genome microarray and multiplex quantitative (q)RT-PCR gene expression analysis. A balance between gene expression profiles reflecting metabolic pathways and immune functions was associated with clinical outcomes following anti–PD-1 therapy. In particular, the expression of genes involved in metabolic and solute transport functions such as UGT1A family members, also found in kidney cancer cell lines, was associated with treatment failure in patients with PD-L1+ RCC. Conversely, tumors from responding patients overexpressed immune markers such as BACH2, a regulator of CD4+ T-cell differentiation, and CCL3 involved in leukocyte migration. These findings suggest that tumor cell–intrinsic metabolic factors may contribute to treatment resistance in RCC, thus serving as predictive markers for treatment outcomes and potential new targets for combination therapy regimens with anti–PD-1. Cancer Immunol Res; 4(9); 726–33. ©2016 AACR.

See related Spotlight by Ohashi, p. 719.

Wednesday, August 31, 2016 6:00 PM|Margolin K. |JAMA Oncology Current Issue|Labels: PD-1/PD-L1, kidney cancer, clinical trial
In this issue of JAMA Oncology, George and colleagues report a retrospective subset analysis of patients with advanced clear cell renal cancer (RCC) treated beyond first progression (PD) in the phase 2 randomized clinical trial evaluating 3 different nivolumab dose levels. In the original report, among 168 randomized/167 treated patients, the objective response rates were reported as 20%, 22%, and 20% for the 0.3-, 2.0-, and 10-mg/kg doses, respectively.
Sunday, August 21, 2016 6:00 PM|Yuanyuan Wang, Xingyi Guo, Michael J. Bray, Zhiyong Ding and Zhongming Zhao|Articles: MD Anderson Cancer Center|Labels: kidney cancer
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Recent large-scale next-generation sequencing analyses reveal that PBRM1 is the second most frequently mutated gene harboring many...
Sunday, August 14, 2016 10:05 PM|Pavia-Jimenez, A., Chen, W., Hill, H., Christie, A., Yousuf, Q., Williams, N., Xie, X.-J., Kapur, P., Brugarolas, J.|Clinical Cancer Research recent issues|Labels: kidney cancer

Renal cell carcinoma (RCC) is diagnosed in over 50,000 Americans annually and in the metastatic setting remains largely incurable. The development of new drugs is hampered by the lack of suitable preclinical animal models reproducing the characteristics of human tumors. To date, we have implanted tumors from over 700 kidney cancer patients orthotopically in mice. Our models include common tumor types, such as clear cell and papillary, but also rare tumor types such as translocation carcinomas and fumarate hydratase (FH)-deficient renal tumors from HLRCC patients. We have shown that tumor fragments implanted orthotopically into NOD/SCID mice result in tumors that reproduce: (i) histology, (ii) gene expression, (iii) DNA copy number alterations and (iv) mutations. Tumorgraft (TG)-bearing mice also reproduce paraneoplastic syndromes (paraneoplastic hypercalcemia). Furthermore, TGs recapitulate the treatment responsiveness of RCC in patients. We performed pharmacokinetic studies to determine appropriate administration regimens resulting in comparable exposures. TGs responded to drugs effective against RCC in patients (sunitinib and sirolimus, which accounts for 70% of the circulating drug after temsirolimus administration) and were resistant to ineffective drugs (erlotinib). TGs provide a superb platform to evaluate promising novel therapeutics. Data will be presented on the application of our TG platform to the evaluation of a first-in-class inhibitor of arguably the most important driver of RCC, the HIF-2 transcription factor. TGs were used to assess activity, validate a putative pharmacodynamic biomarker, identify biomarkers of sensitivity, and to assess the development of resistance. By leveraging a large and diverse TG platform, preclinical drug testing may be rigorously conducted, the most promising agents may be identified, and future clinical development may be effectively informed.

Citation Format: Andrea Pavia-Jimenez, Wenfang Chen, Haley Hill, Alana Christie, Qurratulain Yousuf, Noelle Williams, Xian-Jin Xie, Payal Kapur, James Brugarolas. Renal cancer tumorgrafts: A validated model to evaluate novel targeted therapies. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA10.

Sunday, August 14, 2016 10:05 PM|Lowerison, M., Leong, H. S., Fedyshyn, Y., Chambers, A. F., Lacefield, J., Power, N. E.|Clinical Cancer Research recent issues|Labels: kidney cancer

Our next generation PDX model of renal cell carcinoma (RCC) offers the ability to pre-determine de novo drug resistance in fresh patient tumor samples prior to targeted therapy. Implantation of tumor specimens into the chorioallantoic membrane (CAM) of the chicken embryo results in high engraftment efficiencies within two days permitting large-scale "tumor avatar" studies due to its angiogenic microenvironment. Functional tumor heterogeneity studies can be performed in context of drug resistance within two weeks, an approach that could guide the selection of drugs and anticipate outcomes for RCC patients. This ultrafast PDX model is mirrored by high-frequency ultrasound imaging that permits quantitation of tumor volume and tumor vascularity in a high-throughput manner. Using this "tumor avatar" model paired with a prospective RCC patient cohort, we observe intratumoral functional heterogeneity in the context of Sunitinib treatment as determined by high-frequency ultrasound imaging, highlighting its interventional potential in the clinic.

Citation Format: Matt Lowerison, Hon S. Leong, Yaroslav Fedyshyn, Ann F. Chambers, James Lacefield, Nicholas E. Power. PDXovo: Ultra-fast in vivo drug sensitivity matrices for renal cell carcinoma patients prior to administration of targeted therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A09.

Sunday, July 17, 2016 10:05 PM|Haake, S. M., Weyandt, J. D., Rathmell, W. K.|Molecular Cancer Research recent issues|Labels: kidney cancer

The renal cell carcinomas (RCC), clear cell, papillary, and chromophobe, have recently undergone an unmatched genomic characterization by The Cancer Genome Atlas. This analysis has revealed new insights into each of these malignancies and underscores the unique biology of clear cell, papillary, and chromophobe RCC. Themes that have emerged include distinct mechanisms of metabolic dysregulation and common mutations in chromatin modifier genes. Importantly, the papillary RCC classification encompasses a heterogeneous group of diseases, each with highly distinct genetic and molecular features. In conclusion, this review summarizes RCCs that represent a diverse set of malignancies, each with novel biologic programs that define new paradigms for cancer biology. Mol Cancer Res; 14(7); 589–98. ©2016 AACR.

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S-TRAC is the First RCC Trial of a Tyrosine Kinase Inhibitor to Prolong Disease-Free Survival in the Adjuvant Setting

NEW YORK--(BUSINESS WIRE)--Pfizer Inc. (NYSE:PFE) today announced that the S-TRAC clinical trial (Sunitinib Trial in Adjuvant Renal Cancer), a Phase 3 study of SUTENT versus placebo in the adjuvant setting, met its primary endpoint of improving disease-free survival (DFS) as determined by blinded independent central review in patients with renal cell carcinoma (RCC) who are at high risk for recurrence after surgery. The S-TRAC trial is the first RCC trial of a tyrosine kinase inhibitor (TKI) to prolong DFS in the adjuvant setting.

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Thursday, June 30, 2016 10:05 PM|Hawkins, R. E., Gore, M., Shparyk, Y., Bondar, V., Gladkov, O., Ganev, T., Harza, M., Polenkov, S., Bondarenko, I., Karlov, P., Karyakin, O., Khasanov, R., Hedlund, G., Forsberg, G., Nordle, O., Eisen, T.|Clinical Cancer Research recent issues|Labels: kidney cancer, biomarker diagnostic, clinical trial

Purpose: To prospectively determine the efficacy of naptumomab estafenatox (Nap) + IFNα versus IFN in metastatic renal cell carcinoma (RCC).

Experimental Design: In a randomized, open-label, multicenter, phase II/III study, 513 patients with RCC received Nap (15 μg/kg i. v. in three cycles of four once-daily injections) + IFN (9 MU s.c. three times weekly), or the same regimen of IFN monotherapy. The primary endpoint was overall survival (OS).

Results: This phase II/III study did not meet its primary endpoint. Median OS/PFS for Nap + IFN patients was 17.1/5.8 months versus 17.5/5.8 months for the patients receiving IFN alone (P = 0.56; HR, 1.08/P = 0.41; HR, 0.92). Post hoc exploratory subgroup and trend analysis revealed that the baseline plasma concentrations of anti-SEA/E-120 (anti-Nap antibodies) for drug exposure and IL6 for immune status could be used as predictive biomarkers. A subgroup of patients (SG; n = 130) having concentrations below median of anti-SEA/E-120 and IL6 benefitted greatly from the addition of Nap. In SG, median OS/PFS for the patients treated with Nap + IFN was 63.3/13.7 months versus 31.1/5.8 months for the patients receiving IFN alone (P = 0.02; HR, 0.59/P = 0.02; HR, 0.62). Addition of Nap to IFN showed predicted and transient immune related AEs and the treatment had an acceptable safety profile.

Conclusions: The study did not meet its primary endpoint. Nap + IFN has an acceptable safety profile, and results from post hoc subgroup analyses showed that the treatment might improve OS/PFS in a baseline biomarker-defined RCC patient subgroup. The results warrant further studies with Nap in this subgroup. Clin Cancer Res; 22(13); 3172–81. ©2016 AACR.

Saturday, June 18, 2016 12:05 PM|Elsevier|JournalTOCs API - The Lancet Oncology (50 articles)|Labels: MET, mTOR, VEGF, kidney cancer, clinical trial

Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial

The Lancet Oncology, Vol. , No. (2016) pp. -
Publication date: Available online 5 June 2016 Source:The Lancet Oncology Author(s): Toni K Choueiri, Bernard Escudier, Thomas Powles, Nizar M Tannir, Paul N Mainwaring, Brian I Rini, Hans J Hammers, Frede Donskov, Bruce J Roth, Katriina Peltola, Jae Lyun Lee, Daniel Y C Heng, Manuela Schmidinger, Neeraj Agarwal, Cora N Sternberg, David F McDermott, Dana T Aftab, Colin Hessel, Christian Scheffold, Gisela Schwab, Thomas E Hutson, Sumanta Pal, Robert J Motzer Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53–0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41–0·62]; p&lt;0·0001) and objective response (17% [13–22] with cabozantinib vs 3% [2–6] with everolimus; p&lt;0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Funding Exelixis Inc.

Thursday, June 16, 2016 6:00 PM|Seppo Vainio|Cancers|Labels: WNT, kidney cancer
Renal cell carcinoma (RCC) accounts for 90% of all kidney cancers. Due to poor diagnosis, high resistance to the systemic therapies and the fact that most RCC cases occur sporadically, current research switched its focus on studying the molecular mechanisms underlying RCC. The aim is the discovery of new effective and less toxic anti-cancer drugs and novel diagnostic markers. Besides the PI3K/Akt/mTOR, HGF/Met and VHL/hypoxia cellular signaling pathways, the involvement of the Wnt/β-catenin pathway in RCC is commonly studied. Wnt signaling and its targeted genes are known to actively participate in different biological processes during embryonic development and renal cancer. Recently, studies have shown that targeting this pathway by alternating/inhibiting its intracellular signal transduction can reduce cancer cells viability and inhibit their growth. The targets and drugs identified show promising potential to serve as novel RCC therapeutics and prognostic markers. This review aims to summarize the current status quo regarding recent research on RCC focusing on the involvement of the Wnt/β-catenin pathway and how its understanding could facilitate the identification of potential therapeutic targets, new drugs and diagnostic biomarkers.
Tuesday, June 7, 2016 9:22 AM|News-Medical.Net Kidney Cancer News Feed|Comments|Labels: kidney cancer
In a large randomized study, the immunotherapy drug nivolumab, a checkpoint inhibitor, was shown to be a safe and effective therapy for kidney cancer even in patients who continued treatment after their disease progressed.
Tuesday, June 7, 2016 6:23 AM|News-Medical.Net Kidney Cancer News Feed|Comments|Labels: MET, mTOR, VEGF, kidney cancer
Data presented today at the American Society of Clinical Oncology congress showed that cabozantinib, a next generation tyrosine kinase inhibitor (TKI) can extend the lives of patients by nearly two years following failure of one or more anti-angiogenic therapies almost five months longer than everolimus, a current standard of care therapy.
Thursday, June 2, 2016 7:31 AM|Malouf, G. G., Su, X., Zhang, J., Creighton, C. J., Ho, T. H., Lu, Y., Raynal, N. J.-M., Karam, J. A., Tamboli, P., Allanick, F., Mouawad, R., Spano, J.-P., Khayat, D., Wood, C. G., Jelinek, J., Tannir, N. M.|Clinical Cancer Research Online First Articles|Labels: kidney cancer

Background: DNA methylation is a heritable covalent modification that is developmentally regulated and is critical in tissue-type definition. Although genotype-phenotype correlations have been described for different subtypes of renal cell carcinoma (RCC), it is unknown if DNA methylation profiles correlate with morphological or ontology based phenotypes. Here we test the hypothesis that DNA methylation signatures can discriminate between putative precursor cells in the nephron. Experimental designs: We performed deep profiling of DNA methylation and transcriptome in diverse histopathological RCC subtypes and validated DNA methylation in an independent dataset as well as in The Cancer Genome Atlas Clear Cell and Chromophobe Renal Cell Carcinoma Datasets. Results: Our data provide the first mapping of methylome epi-signature and indicates that RCC subtypes can be grouped into two major epi-clusters: C1 which encompasses clear-cell RCC, papillary RCC, mucinous and spindle cell carcinomas and translocation RCC; C2 which comprises oncocytoma and chromophobe RCC. Interestingly, C1 epi-cluster displayed three fold more hypermethylation as compared to C2 epi-cluster. Of note, differentially methylated regions between C1 and C2 epi-clusters occur in gene bodies and intergenic regions, instead of gene promoters. Transcriptome analysis of C1 epi-cluster suggests a functional convergence on Polycomb targets, whereas C2 epi-cluster displays DNA methylation defects. Furthermore, we find that our epigenetic ontogeny signature is associated with worse outcomes of patients with clear-cell RCC. Conclusion: Our data defines the epi-clusters that can discriminate between distinct RCC subtypes and for the first time define the epigenetic basis for proximal versus distal tubule derived kidney tumors.

Wednesday, June 1, 2016 1:00 AM|Feldman, R. D., Ding, Q., Hussain, Y., Limbird, L. E., Pickering, J. G., Gros, R.|The FASEB Journal recent issues|Labels: kidney cancer

Although aldosterone is a known regulator of renal and cardiovascular function, its role as a regulator of cancer growth and spread has not been widely considered. This study tested the hypothesis that aldosterone regulates cancer cell growth/spread via G protein–coupled estrogen receptor (GPER) activation. In vitro in murine renal cortical adenocarcinoma (RENCA) cells, a widely used murine in vitro model for the study of renal cell adenocarcinoma, aldosterone increased RENCA cell proliferation to a maximum of 125 ± 3% of control at a concentration of 10 nM, an effect blocked by the GPER antagonist G15 or by GPER knockdown using short interfering (sh) RNA techniques. Further, aldosterone increased RENCA cell migration to a maximum of 170 ± 20% of control at a concentration of 100 nM, an effect also blocked by G15 or by GPER down-regulation. In vivo, after orthotopic RENCA cell renal transplantation, pulmonary tumor spread was inhibited by pharmacologic blockade of aldosterone effects with spironolactone (percentage of lung occupied by metastasis: control = 68 ± 13, spironolactone = 26 ± 8, P < 0.05) or inhibition of aldosterone synthesis with a high dietary salt diet (percentage of lung: control = 44 ± 6, high salt = 12 ± 3, P < 0.05), without reducing primary tumor size. Additionally, adrenalectomy significantly reduced the extent of pulmonary tumor spread, whereas aldosterone infusion recovered pulmonary metastatic spread toward baseline levels. Finally, inhibition of GPER either with the GPER antagonist G15 or by GPER knockdown comparably inhibited RENCA cell pulmonary metastatic cancer spread. Taken together, these findings provide strong evidence for aldosterone serving a causal role in renal cell cancer regulation via its GPER receptor; thus, antagonism of GPER represents a potential new target for treatment to reduce metastatic spread.—Feldman, R. D., Ding, Q., Hussain, Y., Limbird, L. E., Pickering, J. G., Gros, R. Aldosterone mediates metastatic spread of renal cancer via the G protein–coupled estrogen receptor (GPER).

Tuesday, May 24, 2016 10:02 AM|Lawson, K. A., Mostafa, A. A., Shi, Z. Q., Spurrell, J., Chen, W., Kawakami, J., Gratton, K., Thakur, S., Morris, D. G.|Clinical Cancer Research Online First Articles|Labels: kidney cancer

Purpose:In addition to their direct cytopathic effects, oncolytic viruses are capable of priming anti-tumor immune responses. However, strategies to enhance the immunotherapeutic potential of these agents are lacking. Here, we investigated the ability of the multi-tyrosine kinase inhibitor and first-line metastatic renal cell carcinoma (RCC) agent, sunitinib, to augment the anti-tumor immune response generated by oncolytic reovirus. Experimental Design:In vitro, oncolysis and chemokine production were assessed in a panel of human and murine RCC cell lines following exposure to reovirus, sunitinib or their combination. In vivo, the RENCA syngeneic murine model of RCC was employed to determine therapeutic and tumor-specific immune responses following treatment with reovirus (intra-tumoral), sunitinib or their combination. Parallel investigations employing the KLN205 syngeneic murine model of lung squamous cell carcinoma (NSCLC) were conducted for further validation Results:Reovirus mediated oncolysis and chemokine production was observed following RCC infection. Reovirus monotherapy reduced tumor burden and was capable of generating a systemic adaptive anti-tumor immune response evidenced by increased numbers of tumor-specific CD8+ IFN- producing cells. Co-administration of sunitinib with reovirus further reduced tumor burden resulting in improved survival, decreased accumulation of immune suppressor cells and the establishment of protective immunity upon tumor re-challenge. Similar results were observed for KLN205 tumor bearing mice, highlighting the potential broad applicability of this approach. ConclusionsThe ability to repurpose sunitinib for augmentation of reovirus' immunotherapeutic efficacy positions this novel combination therapy as an attractive strategy ready for clinical testing against a range of histologies, including RCC and NSCLC.

Thursday, April 28, 2016 9:59 AM|BILLFELDT, N. K., BANYAI, D., KOVACS, G.|Anticancer Research recent issues|Labels: WNT, kidney cancer

Background/Aim: The canonical β-catenin pathway is involved in the development of Wilms' tumor, but its role in adult renal cell tumors (RCT) of embryonal origin is not yet known. Materials and Methods: We sequenced the catenin beta 1 (CTNNB1) gene in papillary RCTs, applied the TOPflash/FOPflash reporter plasmid system on cell lines, and examined the β-catenin protein expression by immunohistochemistry. Results: The absence of mutations in CTNNB1 and low TOPflash/FOPflash ratio in tumor cell lines indicated the absence of active Wingless-type MMTV integration site family (WNT) signaling in RCTs. The weakly cytoplasmic tending towards membranous expression of β-catenin in RCT is analogous to cellular differentiation in the embryonal kidney rather than tumorigenic activation of WNT signaling. Conclusion: The localization of β-catenin in papillary RCT, metanephric adenoma and mucinous tubular and spindle-cell carcinoma corresponds to that of emerging tubules of kidney at distinct stage of maturation, indicating their embryonal origin.

Thursday, April 28, 2016 9:59 AM|CUMPĂNAS, A. A., CIMPEAN, A. M., FERICIAN, O., CEAUSU, R. A., SARB, S., BARBOS, V., DEMA, A., RAICA, M.|Anticancer Research recent issues|Labels: PDGF, VEGF, kidney cancer

Background/Aim: Studies developed in the field of platelet-derived growth factors/platelet-derived growth factor receptors (PDGFs/PDGFRs) inhibition have focused on the therapeutic effects on tumor cells, neglecting their potential effects on tumor blood vessels. We herein propose a differential and critic assessment of platelet-derived growth factor B (PDGF-B) and platelet-derived growth factor receptor β (PDGFRβ) in renal cell carcinoma, correlated with the four main vascular patterns previously reported by our team. Materials and Methods: PDGF-B and PDGFRβ were evaluated on 50 archival paraffin embedded specimens related to vascular endothelial growth factor (VEGF), its inhibitory isoform VEGF165b and vascular patterns. Results and Conclusion: Our results support the involvement of VEGF165b in the phosphorylation of PDGFRβ with an inhibitory effect on endothelial proliferation and migration. The simultaneous action of PDGF-B/PDGFRβ and VEGF165b on the same type of receptor may explain the resistance to antiangiogenic therapy, which depends on the degree of modulation of PDGFRβ phosphorylation.

Thursday, April 28, 2016 9:59 AM|CHANG, W.-S., LIAO, C.-H., TSAI, C.-W., HU, P.-S., WU, H.-C., HSU, S.-W., JI, H.-X., HSIAO, C.-L., BAU, D.-T.|Anticancer Research recent issues|Labels: kidney cancer, IL

Background/Aim: Renal cell carcinoma (RCC) accounts for approximately 3% of all cancer-related mortalities worldwide and the risk factors for the development of RCC have not yet been fully elucidated. Mounting proteomic evidence suggests that inflammatory process plays a role in RCC etiology and interleukin-10 (IL-10) is an important immunosuppressive cytokine. However, little is known on the contribution of IL-10 genotypes to RCC. This study aimed at evaluating the contribution of IL-10 promoter A-1082G (rs1800896), T-819C (rs3021097), A-592C (rs1800872) genetic polymorphisms to the risk of RCC in Taiwan. Materials and Methods: Associations of the three IL-10 polymorphic genotypes with the risk of RCC were examined among 92 RCC patients and 580 age- and gender-matched cancer-free controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Results: The pilot results showed that the percentages of TT and TC for IL-10 T-819C genotypes were significantly higher in the RCC patient group than those in the healthy control group. The CC genotype carriers were of lower risk for RCC (odds ratio (OR)=0.33, 95% confidence interval (CI)=0.12-0.93, p=0.0369). There is no difference in the distribution of A-1082G or A-592C genotype between the RCC and control groups. Conclusion: The CC genotype of IL-10 T-819C genotype may have a protective effect on RCC risk in Taiwan. Further investigation with larger sample size in addition to genotype-phenotype correlation and intracellular mechanisms are our future work.

Monday, April 25, 2016 1:00 PM|Bristol-Myers Squibb Canada - News Releases|Labels: PD-1/PD-L1, kidney cancer, regulatory
OPDIVO™ is the first and only anti PD-1 immuno-oncology agent in Canada approved for the treatment of advanced or metastatic renal cell carcinoma to deliver significant overall survival Announcement marks third approval for OPDIVO™ in just over six months, in a third distinct tumour type
Friday, March 18, 2016 5:00 PM|World Journal of Urology|MedWorm: Cancer Therapy|Comments|Labels: kidney cancer
Conclusions MUC1 is differentially expressed in benign renal tissue, primary RCC and RCC metastasis. Membranous MUC1 expression was significantly elevated in pulmonary metastases compared to non-pulmonary lesions, which may reflect individual biology and putative response to MUC1-based anti-cancer therapy. (Source: World Journal of Urology)
Wednesday, March 2, 2016 4:00 PM|Molecular Diagnosis and Therapy|MedWorm: Cancer Therapy|Comments|Labels: kidney cancer
In this study, we illustrated the pathogenic and prognostic role of EMT in RCC. In addition, we reconstructed, by literature analysis, the different pathways implicated in the EMT process, thus supporting the rational for future EMT-directed therapeutic approaches for RCC patients. (Source: Molecular Diagnosis and Therapy)

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Sunday, February 14, 2016 4:00 PM|Oncology (Williston Park, N.Y.)|MedWorm: Transitional Cell Carcinoma|Comments|Labels: kidney cancer, ovarian cancer
Authors: Ramalingam P Abstract Epithelial ovarian cancer comprises a heterogeneous group of tumors. The four most common subtypes are serous, endometrioid, clear cell, and mucinous carcinoma. Less common are transitional cell tumors, including transitional cell carcinoma and malignant Brenner tumor. While in the past these subtypes were grouped together and designated as epithelial ovarian tumors, these tumor types are now known to be separate entities with distinct clinical and biologic behaviors. From a therapeutic standpoint, current regimens employ standard chemotherapy based on stage and grade rather than histotype. However, this landscape may change in the era of personalized therapy, given that most subtypes (with the exception of high-grade serous carcinoma) are relatively ...
Monday, February 1, 2016 4:00 PM|British Journal of Cancer|MedWorm: Transitional Cell Carcinoma|Comments|Labels: mTOR, kidney cancer
Regulator of cullins-1 expression knockdown suppresses the malignant progression of muscle-invasive transitional cell carcinoma by regulating mTOR/DEPTOR pathway British Journal of Cancer 114, 305 (02 February 2016). doi:10.1038/bjc.2015.444 Authors: W Wang, H Chen, Z Liu, P Qu, J Lan, H Chen, L Zou & J Qiu (Source: British Journal of Cancer)