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1
Gelbrich, Nadine, Hannes Ahrend, Anne Kaul, Lars-Ove Brandenburg, Uwe Zimmermann, Alexander Mustea, Martin Burchardt, Denis Gümbel, and Matthias B. Stope. "Different Cytokine and Chemokine Expression Patterns in Malignant Compared to Those in Nonmalignant Renal Cells." Analytical Cellular Pathology 2017 (2017): 1–8. http://dx.doi.org/10.1155/2017/7190546.
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Objective. Cytokines and chemokines are widely involved in cancer cell progression and thus represent promising candidate factors for new biomarkers. Methods. Four renal cell cancer (RCC) cell lines (Caki-1, 786-O, RCC4, and A498) and a nonmalignant renal cell line (RC-124) were examined with respect to their proliferation. The cytokine and chemokine expression pattern was examined by a DNA array (Human Cytokines & Chemokines RT2 Profiler PCR Array; Qiagen, Hilden, Germany), and expression profiles were compared. Results. Caki-1 and 786-O cells exhibited significantly increased proliferation rates, whereas RCC4 and A498 cells demonstrated attenuated proliferation, compared to nonmalignant RC-124 cells. Expression analysis revealed 52 cytokines and chemokines primarily involved in proliferation and inflammation and differentially expressed not only in malignant and nonmalignant renal cells but also in the four RCC cell lines. Conclusion. This is the first study examining the expression of 84 cytokines and chemokines in four RCC cell lines compared to that in a nonmalignant renal cell line. VEGFA, NODAL, and BMP6 correlated with RCC cell line proliferation and, thus, may represent putative clinical biomarkers for RCC progression as well as for RCC diagnosis and prognosis.
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Chang, Inyoub, Takbum Ohn, Daeun Moon, Young Hee Maeng, Bo Gun Jang, and Sang-Pil Yoon. "SNU-333 Cells as an Appropriate Cell Line for the Orthotopic Renal Cell Carcinoma Model." Technology in Cancer Research & Treatment 20 (January 2021): 153303382110384. http://dx.doi.org/10.1177/15330338211038487.
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Objective: To investigate a feasible candidate for an appropriate cell line for the orthotopic renal cell carcinoma (RCC) model. Methods: Normal human proximal tubule cells (HK-2) and RCC cells were used for MTT assay, Western blotting, sphere-forming assay, and orthotopic injection of BALB/c-nude mice. Immunohistochemistry was adopted in tissue arrays and orthotopic tumors. Results: Primary RCC cells showed resistance to a GPX4 inhibitor compared to HK-2 and to metastatic RCC cells, Caki-1. Caki-2 and SNU-333 cells showed resistance to ferroptosis via increased GPX4 and FTH1, respectively. RCC cells showed increased αSMA, in which Caki-2 and SNU-333 cells exhibited different epithelial–mesenchymal transition and cancer stem cell markers. Caki-1 and SNU-333 cells formed spheres in vitro and orthotopic tumor masses in vivo. The injected SNU-333 tumor only showed high intensities of CD10 and PAX8, markers of renal origin. Conclusion: SNU-333 cell line exhibited resistance via iron metabolism and stemness, and had tumor-initiating capacities in vitro and in vivo. These results suggest that among the cells tested, SNU-333 cells were the most promising for the establishment of an orthotopic RCC model for further researches.
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Toth, Alexander T., and Daniel C. Cho. "Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma." Journal of Kidney Cancer and VHL 7, no. 4 (December 14, 2020): 17–26. http://dx.doi.org/10.15586/jkcvhl.2020.156.
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Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.
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Toth, Alexander T., and Daniel Cho. "Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma." Journal of Kidney Cancer and VHL 7, no. 4 (December 14, 2020): 17–26. http://dx.doi.org/10.15586/jkcvhl.v7i4.156.
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Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.
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Kim, In-Ho, and Hyo Jin Lee. "The Frontline Immunotherapy-Based Treatment of Advanced Clear Cell Renal Cell Carcinoma: Current Evidence and Clinical Perspective." Biomedicines 10, no. 2 (January 24, 2022): 251. http://dx.doi.org/10.3390/biomedicines10020251.
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Approximately 400,000 patients are diagnosed with kidney cancer annually worldwide, leading to approximately 170,000 deaths. Renal cell carcinoma (RCC) accounts for more than 90% of kidney cancers. The most common histological subtype is clear cell RCC, which is found in approximately 85% of metastatic RCC cases. The VHL-HIF-VEGF axis is well known; therefore, targeting VEGF has been the mainstay for managing advanced clear cell RCC. Recently, the treatment landscape for advanced clear cell RCC has changed extensively. In particular, immune checkpoint inhibitor-based treatment showed promising results in front-line treatment and became the standard of care. Herein, we review the current evidence on front-line treatment options and discuss the clinical and future perspective.
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Akin, Ryan, David Hannibal, Margaret Loida, Emily M. Stevens, Elizabeth A. Grunz-Borgmann, and Alan R. Parrish. "Cadmium and Lead Decrease Cell–Cell Aggregation and Increase Migration and Invasion in Renca Mouse Renal Cell Carcinoma Cells." International Journal of Molecular Sciences 20, no. 24 (December 14, 2019): 6315. http://dx.doi.org/10.3390/ijms20246315.
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Metastatic renal cell carcinoma (RCC) remains an important clinical issue; the 5-year survival rate of patients with metastasis is approximately 12%, while it is 93% in those with localized disease. There is evidence that blood cadmium and lead levels are elevated in RCC. The current studies were designed to assess the impact of cadmium and lead on the progression of RCC. The disruption of homotypic cell–cell adhesion is an essential step in epithelial-to-mesenchymal transition and tumor metastasis. Therefore, we examined the impact of cadmium and lead on the cadherin/catenin complex in Renca cells—a mouse RCC cell line. Lead, but not cadmium, induced a concentration-dependent loss of E-cadherin, while cadmium, but not lead, increased p120-catenin expression, specifically isoform 1 expression. Lead also induced a substantial increase in matrix metalloproteinase-9 levels. Both cadmium and lead significantly decreased the number of Renca cell aggregates, consistent with the disruption of the cadherin/catenin complex. Both metals enhanced wound healing in a scratch assay, and increased cell migration and invasion. These data suggest that cadmium and lead promote RCC progression.
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Zhang, Peng, and Jae Y. Ro. "Renal cell carcinoma." annals of urologic oncology 1, no. 1 (November 15, 2018): 1–18. http://dx.doi.org/10.32948/auo.2018.11.1.
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The global incidence of cases of kidney cancer has increased rapidly, and a relatively high incidence of kidney cancer has been reported in developed countries such as Northern and Eastern Europe. Various factors can affect the incidence and mortality of kidney cancer, including demographic risk factors, lifestyle factors, iatrogenic risk factors, nutritional factors and diet, occupation, and genetic factors. Renal cell carcinoma (RCC) refers to a tumor group with heterogeneity derived from renal tubular cells, which form almost all kidney cancer types. Clear cell RCC (ccRCC) is the most frequent renal tumor subtype, accounting for 75% of renal cancer, followed by papillar RCC(pRCC) making up approximately 10% of RCC. Hematoxylin-eosin staining shows a clear, eosinophilic cytoplasm in ccRCC cells. Epithelial cells forming the papillae and tubules have pRCC histological characteristics. Traditionally, genetic mutations of VHL and MET are the genetic features in ccRCC and pRCC, respectively. Recently, a new concept supports the contribution of mutations in some chromatin-modifier genes, including polybromo 1 (PBRM1), SET domain containing 2 (SETD2), BRCA1-associated protein-1 (BAP1), and lysine (K)-specific demethylase 5C (KDM5C). The metabolic disease concept in renal cancer is noted by researchers worldwide. The PD-1 pathway has been valued by researchers of kidney cancer in recent years, and new agents, such as anti-PD-1 monoclonal antibodies (nivolumab and pembrolizumab) and CTLA4 inhibitors (Ipilimumab), have been approved to treat advanced RCC. Partial nephrectomy (PN) and radical nephrectomy (RN) remain the standard management option for local RCC with a stage of T1 and T2, respectively. PN can also be selected for T2 stage RCC in suitable cases. Even though targeted therapy consisting of mainly the anti-VEGF and anti-mTOR pathways is recommended as the first-line and second-line treatment for RCC, the effectiveness and side effect of these therapies should be improved in future research.
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Sato, Tomonori, Yoshihide Kawasaki, Masamitsu Maekawa, Shinya Takasaki, Kento Morozumi, Masahiko Sato, Shuichi Shimada, et al. "Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma." Metabolites 11, no. 1 (December 22, 2020): 1. http://dx.doi.org/10.3390/metabo11010001.
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Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells.
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Zhang, Xintao, Meng Zhang, Jianli Cheng, Zhaojie Lv, Feng Wang, and Zhiming Cai. "MiR-411 Functions as a Tumor Suppressor in Renal Cell Cancer." International Journal of Biological Markers 32, no. 4 (October 2017): 454–60. http://dx.doi.org/10.5301/ijbm.5000261.
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Background Recent studies have revealed that microRNAs (miRNAs) play important roles as oncogenes or tumor suppressors in tumorigenesis and tumor development, by negatively regulating protein expression. A previous study of microarrays identified that miR-411 was down-regulated in renal cell carcinoma (RCC), while few studies investigating the role of miR-411 in the pathogenesis of RCC have been performed. Methods We assessed the miR-411 expression in RCC and paired adjacent normal tissues, as well as in RCC cell lines and a normal renal cell line, by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Furthermore, the effects of miR-411 on RCC and normal renal cell proliferation, apoptosis and migration were determined using MTT assay, CCK-8 assay, flow cytometry and scratch wound assay following restoration of miR-411 with synthetic mimics. Results Results of qRT-PCR indicated that the expression of miR-411 was down-regulated in RCC tissues and cell lines when compared with adjacent normal tissues and a normal renal cell line. Further, results of CCK-8, MTT, cell scratch and transwell assay showed that over-expression of miR-411 suppressed RCC cell (786-0 and ACHN) proliferation and migration. Flow cytometry assay revealed that miR-411 could induce RCC cell apoptosis. However, overexpression of miR-411 had no obvious effect on normal renal cell line 293T Conclusions To sum up, miR-411 is significantly down-regulated and plays a role as a tumor suppressor in RCC. Further studies are warranted to determine the mechanisms of miR-411 in RCC pathogenesis and define the target genes of miR-411 in RCC.
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Thakor, Parth, Wenzhe Song, Ramalingam B. Subramanian, Vasudev R. Thakkar, David A. Vesey, and Glenda C. Gobe. "Maslinic acid inhibits proliferation of renal cell carcinoma cell lines and suppresses angiogenesis of endothelial cells." Journal of Kidney Cancer and VHL 4, no. 1 (March 21, 2017): 16–24. http://dx.doi.org/10.15586/jkcvhl.2017.64.
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Despite the introduction of many novel therapeutics in clinical practice, metastatic renal cell carcinoma (RCC) remains a treatment-re-sistant cancer. As red and processed meat are considered risk factors for RCC, and a vegetable-rich diet is thought to reduce this risk, research into plant-based therapeutics may provide valuable complementary or alternative therapeutics for the management of RCC. Herein, we present the antiproliferative and antiangiogenic effects of maslinic acid, which occurs naturally in edible plants, particularly in olive fruits, and also in a variety of medicinal plants. Human RCC cell lines (ACHN, Caki-1, and SN12K1), endothelial cells (human umbilical vein endothelial cell line [HUVEC]), and primary cultures of kidney proximal tubular epithelial cells (PTEC) were treated with maslinic acid. Maslinic acid was relatively less toxic to PTEC when compared with RCC under similar experimental conditions. In RCC cell lines, maslinic acid induced a significant reduction in proliferation, proliferating cell nuclear antigen, and colony formation. In HUVEC, maslinic acid induced a significant reduction in capillary tube formation in vitro and vascular endothelial growth factor. This study provides a rationale for incorporating a maslinic acid–rich diet either to reduce the risk of developing kidney cancer or as an adjunct to existing antiangiogenic therapy to improve efficacy.
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Saylor, Philip J., and M. Dror Michaelson. "New Treatments for Renal Cell Carcinoma: Targeted Therapies." Journal of the National Comprehensive Cancer Network 7, no. 6 (June 2009): 645–56. http://dx.doi.org/10.6004/jnccn.2009.0045.
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Systemic treatment options for advanced renal cell carcinoma (RCC) have expanded considerably with the development of targeted therapies. Clear cell RCC commonly features mutation or inactivation of the von Hippel-Lindau gene and resultant overexpression of vascular endothelial growth factor (VEGF). The first drug to validate VEGF as a target in the treatment of clear cell RCC was the monoclonal antibody bevacizumab. Since then, anti-VEGF receptor therapy with multitargeted kinase inhibitors also has shown substantial efficacy. Sunitinib is now a standard first-line therapy for advanced disease and sorafenib is among the second-line treatment options. Other kinase inhibitors are in development. Mammalian target of rapamycin (mTOR) is a second validated therapeutic target as the mTOR inhibitor temsirolimus has been shown to prolong survival in first-line treatment of poor prognosis RCC of all histologies. Everolimus is an oral mTOR inhibitor and has been shown to prolong progression-free survival when used in second-line treatment. Non-clear cell and sarcomatoid RCC are both underrepresented in completed trials but are the subject of active research. Ongoing and planned studies will also evaluate the use of combinations of targeted agents, a strategy that is not advisable outside of clinical trials. Finally, postnephrectomy adjuvant treatment with targeted agents is not yet standard but is under investigation in phase III trials.
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George, Daniel J., Chung-Han Lee, and Daniel Heng. "New approaches to first-line treatment of advanced renal cell carcinoma." Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110347. http://dx.doi.org/10.1177/17588359211034708.
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The treatment of patients with renal cell carcinoma (RCC) is evolving rapidly, with promising new regimens being developed and approved for patients with advanced disease, particularly the combination of tyrosine kinase inhibitors with immune checkpoint inhibitors. Within the last 6 months, favorable first-line setting results for patients with clear cell RCC have been reported for the combination of cabozantinib plus nivolumab in the phase III CheckMate 9ER study, leading to its regulatory approval, and lenvatinib plus pembrolizumab in the phase III CLEAR study. Additional systemic first-line treatments for clear cell RCC include axitinib plus pembrolizumab, pazopanib, and sunitinib for favorable-risk patients and ipilimumab plus nivolumab, axitinib plus pembrolizumab, axitinib plus avelumab, and cabozantinib for intermediate- or poor-risk patients. In this review of novel approaches for first-line treatment of advanced RCC, we present an overview of current treatment strategies, the basis behind emerging treatment approaches, a summary of key results from the pivotal studies using tyrosine kinase inhibitor and immune checkpoint inhibitor combination therapy, novel treatments and strategies under development, and efforts for identifying biomarkers to guide treatment decisions.
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Cui, Ning, Qiang Han, Qizhen Cao, Kejun Wang, Xujia Zhou, Pingzhi Hou, Chao Liu, Lungang Chen, and Lin Xu. "Lefty A is involved in sunitinib resistance of renal cell carcinoma cells via regulation of IL-8." Biological Chemistry 402, no. 10 (August 9, 2021): 1247–56. http://dx.doi.org/10.1515/hsz-2021-0280.
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Abstract Renal cell carcinoma (RCC) is the third most frequent malignancy within urological oncology. Sunitinib has been used as the standard of treatment for first-line RCC therapy. Understanding mechanisms of sunitinib resistance in RCC cell is important for clinical therapy and drug development. We established sunitinib resistant RCC cells by treating cells with increasing concentrations of sunitinib and named resistant cells as RCC/SR. Lefty A, an important embryonic morphogen, was increased in RCC/SR cells. Targeted inhibition of Lefty via its siRNAs restored the sensitivity of renal resistant cells to sunitinib treatment. It was due to that si-Lefty can decrease the expression of interleukin-8 (IL-8) in RCC/SR cells. Knockdown of IL-8 abolished Lefty-regulated sunitinib sensitivity of RCC cells. Mechanistically, Lefty can regulate IL-8 transcription via activation of p65, one major transcription factor of IL-8. Collectively, our present revealed that Lefty A can regulate sunitinib sensitivity of RCC cells of via NF-κB/IL-8 signals. It indicated that targeted inhibition of Lefty might be a potent approach to overcome sunitinib resistance of RCC.
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Sarfaty, Michal, Moshe Leshno, Noa Gordon, Assaf Moore, Victoria Neiman, Eli Rosenbaum, and Daniel A. Goldstein. "Cost-effectiveness of nivolumab in advanced renal cell carcinoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e18338-e18338. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e18338.
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e18338 Background: In recent years, new drugs have been introduced to the second line setting of advanced renal cell carcinoma (RCC). Nivolumab increases overall survival and is associated with less toxicity compared to everolimus in this setting based on the Checkmate 025 study. However, due to nivolumab's high cost there is a need to define its value by considering both efficacy and cost. The objective of this study was to estimate the cost-effectiveness of nivolumab for the second-line treatment of advanced RCC from the US payer perspective. Methods: A Markov model was developed to compare the costs and effectiveness of nivolumab with those of everolimus or placebo in the second-line treatment of advanced RCC. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2016. Model robustness was addressed in univariable and probabilistic sensitivity analyses. We addressed the controversial issue of the extensive duration of immunotherapy treatment amongst long term survivors, which may or may not be approved by payers. Results: The total mean cost per-patient of nivolumab versus everolimus was $101,070 and $50,935, respectfully. Nivolumab generated a gain of 0.24 LYs (0.34 QALYs) over everolimus and 0.89 LYs (0.96 QALYs) over placebo. The incremental cost-effectiveness ratio (ICER) for nivolumab was $146,532/QALY versus everolimus and $105,232/QALY versus placebo. Limiting the maximal treatment duration of nivolumab to two years lowered the ICER to $121,788/QALY versus everolimus and $96,418/QALY versus placebo. Conclusions: Our analysis established an ICER of $146,532/QALY for nivolumab versus everolimus in second-line advanced RCC treatment.
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Albiges, Laurence, Damien Pouessel, Marie Beylot-Barry, Guido Bens, Diane Pannier, Céline Gavoille, Stephane Oudard, et al. "Nivolumab in metastatic nonclear cell renal cell carcinoma: First results of the AcSe prospective study." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 699. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.699.
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699 Background: AcSe Nivolumab (N), is a non-randomised, open-label, multicentric study to investigate the efficacy and safety of nivolumab monotherapy in patients (pts) with specific rare cancers (NCT03012581). We report on the non-clear cell renal cell carcinoma (RCC) cohort. Methods: Primary endpoint was objective response rate (ORR) at 12 weeks according to RECIST1.1. All pts receives N at 240mg IV every 2 weeks. Secondary endpoints included progression free survival (PFS), overall survival (OS), best response, and safety. Results: Between 07/2017 and 02/2019, 50 pts have been enrolled across 13 institutions. Median age was 61.4 years old, 70% were male. ECOG PS was 0, 1, 2, in 29%, 63% and 8% of pts respectively. Histological types were papillary (pRCC) type 2 (41%), chromophobe (18%), pRCC type I (10%), pRCC unclassified (8%), collecting duct carcinoma (CDC) (8%), and others (including predominant sarcomatoid, renal medullary carcinoma, MITF associated RCC, unclassified RCC). N was used in first line in 16%, second line in 54% and third line or beyond in 30%. IMDC risk group was 14%, 70% and 16% for good, intermediate and poor risk respectively. With a median follow up of 10.4 months (mo), 42 pts had discontinued N. The 12 weeks-ORR was 6% (3 PR), with stable disease in 49% and PD in 44% of pts. The best ORR was 10%. Median PFS was 3.9 mo (IC95% [2.9; 8.3]). At time of analysis, 25 pts (50%) had died and 12-months OS rate was 47.7% (IC95% [33.5; 67.8]). Overall, 31 pts (62%) have presented at least one grade ≥ 3 AE. No new safety signal with N was reported. 12 weeks-ORR and best ORR according to distinct histology are presented in table 1. Pts with PR were 1pRCC type 2, 1pRCC type 1, 1 CDC, 1 MITF RCC and 1 unclassified. Conclusions: We report the first prospective study of N single agent in non-clear cell RCC. N demonstrates limited activity in a pretreated and heterogeneous non- clear cell RCC population. Interestingly 1/4 CDC developed PR while no response was noted in chromophobe RCC. Clinical trial information: NCT03012581. [Table: see text]
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Cavalcanti, Elisabetta, Margherita Gigante, Vito Mancini, Michele Battaglia, Pasquale Ditonno, Carmela Capobianco, Raffaele I. Cincione, et al. "JAK3/STAT5/6 Pathway Alterations Are Associated with Immune Deviation inCD8+T Cells in Renal Cell Carcinoma Patients." Journal of Biomedicine and Biotechnology 2010 (2010): 1–13. http://dx.doi.org/10.1155/2010/935764.
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To investigate the molecular mechanisms underlying altered T cell response in renal cell carcinoma (RCC) patients, we compared autologous and allogeneicCD8+T cell responses against RCC line from RCC patients and their HLA-matched donors, using mixed lymphocyte/tumor cell cultures (MLTCs). In addition, we analyzed the expression of molecules associated with cell cycle regulation. Autologous MLTC responderCD8+T cells showed cytotoxic activity against RCC cell lines; however the analysis of the distribution ofCD8+T-cell subsets revealed that allogenic counterparts mediate superior antitumor efficacy. In RCC patients, a decreased proliferative response to tumor, associated with defects in JAK3/STAT5/6 expression that led to increased p27KIP1 expression and alterations in the cell cycle, was observed. These data define a molecular pathway involved in cell cycle regulation that is associated with the dysfunction of tumor-specificCD8+effector cells. If validated, this may define a therapeutic target in the setting of patients with RCC.
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Takahashi, Masayuki, Kei Daizumoto, Megumi Tsuda, Yoshito Kusuhara, Hidehisa Mori, Terumichi Shintani, Tomoya Fukawa, et al. "Correlation of insulin-receptor expression with efficacy of axitinib in patients with advanced renal cell carcinoma." Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017): 442. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.442.
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442 Background: Axitinib has demonstrated high efficacy with well-controlled adverse events (AEs) for advanced renal cell carcinoma (RCC). Recently, nivolumab has been approved for advanced RCC. However, it is very expensive in Japan and may cause severe immune-related AEs. There is no clue to choose axitinib or nivolumab as the second-line for advanced RCC. Previously we identified the gene set which may predict poor prognosis of RCC patients (Takahashi m et.al., Proc Natl Acad Sci U S A., 98: 9754, 2001) and have sought to elucidate whether insulin receptor (INSR) expression in the gene set may predict the resistance for axitinib as a biomarker. Methods: Axitinib was administered in 36 patients in our department between January 2008 and April 2015. Median age was 70 (36-84) years old with 22 males and 14 females. Histological subtype included clear cell RCC (n=27, 75.0%), clear cell + sarcomatoid component (n=3), collecting duct carcinoma (n=2), papillary, sarcomatoid, mucinous tubular and spindle cell carcinoma (MTSCC), and unknown in each one. Axitinib was administered in two patients as the first line, 21 patients as the second line, and 13 patients as ≥ the third line. Tissue of primary tumor was available in 20/36 patients, including 16 clear cell RCC and 4 other subtypes. Immunohistochemical INSR expression was examined and correlated with survival of the patients with axitinib. Results: Objective response rate was 27.6%, progression-free survival (PFS) was 16.3 months, and overall survival (OS) was 41.9 months in clear cell RCC patients. Patients with low INSR expression (n=7) had significantly shorter PFS (68 vs. 586 days, p<0.001) and OS (169 vs. 1027 days, p=0.004) compared with those with high INSR expression (n=13). If only clear cell RCC was evaluated, patients with low INSR expression (n=3) had significantly shorter PFS (77 vs. 586 days, p=0.008) and OS (294 vs. 1027 days, p=0.016) compared with those with high INSR expression (n=13). Conclusions: Axitinib was highly effective for advanced clear cell RCC. However, immunohistochemically low expression of INSR in the primary tumor may predict the resistance for axitinib and those patients may be more suitable for immune checkpoint inhibitors.
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Zhou, Xianzheng, Do Youn Jun, Amy Morck Thomas, Xin Huang, Lan-Qing Huang, Josef Mautner, Wa Mo, Paul F. Robbins, Drew M. Pardoll, and Elizabeth M. Jaffee. "Diverse CD8+ T-Cell Responses to Renal Cell Carcinoma Antigens in Patients Treated with an Autologous Granulocyte-Macrophage Colony-Stimulating Factor Gene-Transduced Renal Tumor Cell Vaccine." Cancer Research 65, no. 3 (February 1, 2005): 1079–88. http://dx.doi.org/10.1158/0008-5472.1079.65.3.
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Abstract A phase I clinical trial with granulocyte-macrophage colony-stimulating factor tumor cell vaccines in patients with metastatic renal cell carcinoma (RCC) showed immune cell infiltration at vaccine sites and delayed-type hypersensitivity (DTH) responses to autologous tumor cells indicative of T-cell immunity. To further characterize RCC T-cell responses and identify relevant RCC-associated antigens, we did a detailed analysis of CD8+ T-cell responses in two vaccinated RCC patients who generated the greatest magnitude of DTH response and also displayed a strong clinical response to vaccination (>90% reduction in metastatic tumor volume). Three separate CD8+ T-cell lines (and subsequent derived clones) derived from patient 24 recognized distinct RCC-associated antigens. One recognized a shared HLA-A*0201-restricted antigen expressed by both renal cancer cells and normal kidney cells. This recognition pattern correlated with a positive DTH test to normal kidney cells despite no evidence of impairment of renal function by the patient's remaining kidney after vaccination. A second line recognized a shared HLA-C7-restricted antigen that was IFN-γ inducible. A third line recognized a unique HLA-A*0101-restricted RCC antigen derived from a mutated KIAA1440 gene specific to the tumor. In addition, two independent CTL lines and three clones were also generated from patient 26 and they recognized autologous tumor cells restricted through HLA-A*0205, HLA-A/B/C, and HLA-B/C. These results show that paracrine granulocyte-macrophage colony-stimulating factor tumor vaccines may generate a diverse repertoire of tumor-reactive CD8+ T-cell responses and emphasize the importance of polyvalency in the design of cancer immunotherapies.
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Yan, Xieqiao, Zhihong Chi, Lu Si, Chuanliang Cui, Yan Kong, Bixia Tang, Lili Mao, et al. "Clinicopathologic features of Xp11.2 translocation renal cell carcinoma and its response to target therapy." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e16559-e16559. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e16559.
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e16559 Background: Xp11.2 translocation renal cell carcinoma (RCC) is a unique RCC subtype with high malignant potential and poor prognosis, its natural course and response to systemic therapy are not fully understood. We analyzed the clinic features of this distinct entity and the benefit of systemic therapy in these patients. Methods: Between May 2006 and December 2019, 1113 consecutive patients diagnosed with RCC from Peking university cancer hospital (Beijing, China) were reviewed, data of the clinical characteristics and outcome of patients with metastatic Xp11.2 RCC were retrospectively collected. Tumor response to systemic therapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions. Results: Metastatic Xp11.2 translocation RCC was found in 41 cases. The median PFS and Median OS was 6.3 months (4.4 - 8.8) and 17.3 months (12.4 - 21.8) for the whole cohort, respectively. First-line treatment mainly included sunitinib (n = 12), sorafenib (n = 13), axitinib (n = 6), and pazopanib (n = 4), and the median PFS of these regimens was 5.4 months, 5.1 months, 9.4 months, 8.3 months, respectively. Twenty-three patients received subsequent therapies, the median PFS and the median OS was 4.3 months and 12 months for the second-line therapy(n = 21), 4.3 months and 14.1 months for the third-line therapy(n = 11), 2.4 months and 9.6 months for the fourth-line therapy(n = 6). Conclusions: Metastatic Xp11.2 translocation RCC is an aggressive disease. Vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) agents appeared to demonstrate some efficacy, the combination of VEGFR-TKI and immune checkpoint inhibitor (ICI) might be a useful tool for the treatment of metastatic Xp11.2 translocation RCC.
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Sun, Xiang, Longhua Lou, Kezhao Zhong, and Lijuan Wan. "MicroRNA-451 regulates chemoresistance in renal cell carcinoma by targeting ATF-2 gene." Experimental Biology and Medicine 242, no. 12 (April 21, 2017): 1299–305. http://dx.doi.org/10.1177/1535370217701625.
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Renal cell carcinoma (RCC) is a malignant tumor, which severely threatens human’s life, moreover, the multi-drug resistance (MDR) under RCC undoubtedly strengthen the difficulties in the treatment. MiR-451 has been considered to play an important role in regulation of MDR in several cancers, but the role of it in MDR of RCC has not been explored. This study aims to explore the mechanism of miR-451 as a target to regulate chemotherapy resistance, which is crucial for further exploring novel therapy for RCC. Two human cell lines (ACHN and GRC-1) were performed in this study and adriamycin (ADM) was used to construct MDR cell lines. qRT-PCR was used to determine the mRNA expression of miR-451 and ATF-2. Weston blot was used to determine protein expression. MTT assay and flow cytometry were used for assessing cell viability and apoptosis, individually. Luciferase reporter assay was used to detect the targeting of miR-451 and ATF-2. Results presented that the expression of miR-451 was higher in low MDR cell line (ACHN) comparing with the high MDR cell line (GRC-1), while the expression of ATF-2 revealed an opposite results. MiR-451 targeted ATF-2 and regulated its expression. Overexpression of miR-451 strengthened drug resistance, decreased cell viability, and increased cell apoptosis of GRC-1 pretreated by ADM, while overexpressed ATF-2 reversed the effect induced by miR-451 overexpression. Then miR-451 knockdown improved drug susceptibility, decreased cell apoptosis, and increased cell viability of ACHN induced by ADM, however, ATF-2 suppression reversed the low rate of cell apoptosis and high rate of cell viability induced by miR-451 knockdown. Our results revealed that miR-451 regulates the drug resistance of RCC by targeting ATF-2 gene, which might be critical for overcoming MDR in RCC patients. Impact statement This is the first study to emphasize the expression of miR-451 on regulating multi-drug resistance (MDR) in renal cell carcinoma (RCC). Our study found that miR-451 regulates the drug resistance of RCC by targeting ATF-2, which might be critical for overcoming MDR in RCC patients. This study not only provides solid theory foundation for the clinical therapy, but also offers unique insights for the further RCC research. Furthermore, the study helps us to understand the mechanism of MDR, which was crucial for identifying the chemoresistance on several related tumors.
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Martin Aguilar, Ana Elena, Haidé Nayeli Núñez-López, and Juan C. Carlos Ramirez-Sandoval. "Sorafenib as second-line treatment in metastatic renal cell carcinoma: A prospective cohort." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e17077-e17077. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e17077.
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e17077 Background: Sequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with advanced or metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a 2nd-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI). Methods: Prospective observational cohort in Mexico City (July 2012 to July 2019). We included 148 subjects with metastatic RCC, treated by nephrectomy and who had RCC progression despite treatment with sunitinib (n = 144) or pazopanib (n = 4). All patients received sorafenib 400 mg orally twice a day on a continuous dosing schedule until disease progression or intolerable toxicity. The primary endpoint was time to progression evaluated every 12-16 weeks. Risk factors were classified according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC-RF) prognostic model. Results: Mean age of cohort was 58±10 years, 104 (70%) were male, 51 (35%) had none of IMDC-risk factors, and the most common sites of metastasis before sorafenib treatment were lung (n = 79, 53%) and bone (n = 30, 20%). The median progression-free survival and survival after the introduction of sorafenib treatment was 8.5 months (95% IC 6.8-10.2) and 40.1 months (95% IC 35.2-45.0) respectively. Median overall survival from RCC diagnosis to death was 71 months (95% CI 63.9-79.4). Median progression-free survival was longer in advanced RCC with none IMDC-RF compared with subjects with ≥2 IMDC-RF (10.3 [95%CI 6.1-14.6] vs 7.9 [95%CI 5.8-9.9] mo. respectively, p = 0.035). Age > 65 decreased risk of progression after sorafenib therapy (OR 0.33, 95% CI 0.14-0.77, p = 0.010). Median progression-free survival in subjects > 65 yrs old was longer (14 months, 95% CI 9.2-17.9) compared to subjects ≤65 yrs (7.2 months, 95% CI 5.5-8.9, p = 0.018). Adverse events associated to sorafenib occurred in 118 (80%) subjects: hand-foot syndrome (n = 118, 80%), diarrhea (n = 113, 76%), hypothyroidism (41, 28%), and mucositis (84, 57%). Any adverse events corresponding to a grade > 2 occurred in 48 (32%) patients. Conclusions: Sequential inhibition of VEGF with sorafenib as a 2nd-line treatment may benefit patients with metastatic RCC, especially in subjects > 65 yrs old. Further clinical trials are needed.
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Ratta, Raffaele, and Aristotelis Bamias. "Sequential medical therapy in renal carcinoma." Cancer Breaking News 4, no. 3 (December 15, 2016): 6–11. http://dx.doi.org/10.19156/cbn.2016.0022.
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Renal cell carcinoma (RCC) is the ninth most common cancer in humans. In the last decade, a better understanding of the molecular mechanisms underlying tumorigenesis, angiogenesis, cell growth and proliferation, and the discovery of molecular alterations involved in RCC pathogenesis, have led to the identification of molecular targets of great clinical interest that have revolutionized the treatment of metastatic RCC (mRCC). Sunitinib, pazopanib and bevacizumab plus interferon-alpha remain the standard first-line treatments: these agents have significantly improved prognosis in mRCC. Everolimus, axitinib and sorafenib have demonstrated significant efficacy as second-line therapies. Nivolumab and cabozantinib are the most promising new-generation agents in the treatment of RCC. All of these agents, given in sequence, have extended life expectancy of RCC patients from 13 months in the cytokine era to over 20 months. Despite this improvement, it is not easy to establish the right sequence in which to administered different agents because there aren’t yet ways to identify or select patients likely to benefit or those who could be resistant to specific drugs. In this review we present clinical data on the sequential treatment in RCC and discuss key factors that need to be considered when physicians make treatment decisions for individual patients.
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Lee, Jae-Lyun, Marek Ziobro, Rustem Gafanov, Vsevolod Borisovich Matveev, Cristina Suarez, Frede Donskov, Frederic Pouliot, et al. "KEYNOTE-427 cohort B: First-line pembrolizumab (pembro) monotherapy for advanced non‒clear cell renal cell carcinoma (NCC-RCC)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 4569. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.4569.
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4569 Background: Efficacy of PD-1 inhibitors (or any therapy) in NCC-RCC has not been established. KEYNOTE-427 (NCT02853344) is a single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced clear cell RCC (cohort A) and NCC-RCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed NCC-RCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Additional end points: duration of response (DOR), population description by sarcomatoid differentiation, histology and PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n = 118), chromophobe 13% (n = 21), unclassified 16% (n = 26); 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At median follow-up of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CR, 33 [20.0%] PR). Median DOR was not reached. For responding pts, 81.5% had a response ≥6 mo. 12-mo PFS and OS rates were 22.8% and 72.0%, respectively. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified NCC-RCC; for responding pts, 82.1%, 50.0%, and 87.5% had a response ≥6 mo, respectively. Median DOR was not reached in any group. ORR (95% CI) was 44.7% (28.6-61.7) for pts with sarcomatoid differentiation (n = 38). ORR (95% CI) was 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS < 1, respectively. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 11% of pts. 6 pts died of AEs, 2 of TRAEs (pneumonia and cardiac arrest). Conclusions: Single-agent pembro showed encouraging antitumor activity in NCC-RCC, especially with papillary or unclassified histology. Safety profile of pembro was as expected. Updated data with additional follow-up will be presented. Clinical trial information: NCT02853344.
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Messai, Yosra, Zaeem Noman, Meriem Hasmim, Bassam Janji, Laurence Albiges, Bernard Escudier, and Salem Chouaib. "Role of ITPR1/HIF-2α axis in protecting renal cancer cells against natural killer cells." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 417. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.417.
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417 Background: Clear cell renal cell carcinomas frequently display inactivation of VHL gene leading to increased level of hypoxia inducible factors (HIFs). The specific role of VHL mutations and selective activation of HIF-2 alpha in modulating RCC susceptibility to cytotoxic immune response remains largely unknown. Methods: In this study, we used 786-0 RCC VHL-mutated cell line selectively induces HIF-2 alpha stabilization.Chromium release cytotoxicity assay was regularly used to evaluate tumor target cells sensitivity to NK-mediated lysis. Confocal microscopy was aso used to analyse immunologic synapse formation and for autophagy studies. Immunochemistry staining using RCC tissue microarrays was performed to evaluate HIF-2 alpha and ITPR1 expression in RCC patients. Results: We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK-mediated lysis as compared to the VHL-corrected cell line (WT7). This resistance was found to require HIF-2α stabilization. Based on global gene expression profiling and ChIP assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF-2α and targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Interestingly, using a large group (235) of RCC patients,we demonstrated the existence of a significant correlation between HIF-2α and ITPR1 expression Mechanistically, HIF-2α in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NK mediated killing through the activation of autophagy in target cells by NK derived signal. Both ITPR1 and Beclin-1 silencing in 786-0 cells inhibited NK-induced autophagy and subsequently increased Granzyme B activity in target cells. Finally, in vivo ITPR1 targeting significantly enhanced the NK-mediated tumor regression. Conclusions: Our data provide insights into the link between HIF-2α, the ITPR1-related pathway and natural immunity and strongly suggest a role for the HIF-2α /ITPR1 axis in regulating RCC cell survival. Futur NK cell-based immunotherapy should integrate HIF-2/ITPR1 axis as intrinsic feature of resistance tumor cells to improve NK cell response in RCC patients.
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Haupt, Sonja, Michele Tisdale, Michelle Vincendeau, Mary Anne Clements, David T. Gauthier, Raymond Lance, O. John Semmes, et al. "Human endogenous retrovirus transcription profiles of the kidney and kidney-derived cell lines." Journal of General Virology 92, no. 10 (October 1, 2011): 2356–66. http://dx.doi.org/10.1099/vir.0.031518-0.
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The human genome comprises approximately 8–9 % of human endogenous retroviruses (HERVs) that are transcribed with tissue specificity. However, relatively few organs have been examined in detail for individual differences in HERV transcription pattern, nor have tissue-to-cell culture comparisons been frequently performed. Using an HERV-specific DNA microarray, a core HERV transcription profile was established for the human kidney comparing 10 tissue samples. This core represents HERV groups expressed uniformly or nearly so in non-tumour kidney tissue. The profiles obtained from non-tumour tissues were compared to 10 renal tumour tissues (renal cell carcinoma, RCC) derived from the same individuals and additionally, to 22 RCC cell lines. No RCC cell line or tumour-specific differences were observed, suggesting that HERV transcription is not altered in RCC. However, when comparing tissue transcription to cell line transcription, there were consistent differences. The differences were irrespective of cancer state and included cell lines derived from non-tumour kidney tissue, suggesting that a specific alteration of HERV transcription occurs when establishing cell lines. In contrast to previous publications, all known HERV-derived tumour antigens, including those identified in RCC, were expressed both in multiple RCC cell lines and several non-tumour tissue-derived cell lines, a result that contrasts with findings from patient samples. The results establish the core kidney transcription pattern of HERVs and reveal differences between cell culture lines and tissue samples.
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Sarkissian, Gaiane, Patricia Fergelot, Pierre-Jean Lamy, Jean-Jacques Patard, Stephane Culine, Patrick Jouin, Nathalie Rioux-Leclercq, and Bruno Darbouret. "Identification of Pro-MMP-7 as a Serum Marker for Renal Cell Carcinoma by Use of Proteomic Analysis." Clinical Chemistry 54, no. 3 (March 1, 2008): 574–81. http://dx.doi.org/10.1373/clinchem.2007.090837.
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Abstract Background: No validated renal cell carcinoma (RCC) marker is known for detection of asymptomatic disease in selected populations or for prognostic purposes or treatment monitoring. We identified immunogenic proteins as tumor markers for RCC by combining conventional proteome analysis with serological screening, and we investigated the diagnostic clinical value of such markers in serum. Methods: We studied the immunogenic protein expression profile of CAL 54, a human RCC cell line, by 2-dimensional electrophoresis combined with immunoblotting using sera from healthy donors compared with RCC patients. We developed a homogeneous, fluorescent, dual-monoclonal immunoassay for metalloproteinase 7 (MMP-7) and used it to measure MMP-7 in sera from 30 healthy donors, 30 RCC patients, and 40 control patients. Results: Pro-MMP-7 (29 kDa; pI 7.7) in the CAL 54 cell line secretome was an immunogenic protein reactive with RCC patient sera but not with control sera. The concentrations of pro-MMP-7 were increased (P <0.0001) in sera of RCC patients (median 7.56 μg/L; range 3.12–30.5 μg/L) compared with healthy controls (median 2.13 μg/L; range 0.17–3.5 μg/L). Serum pro-MMP-7 had a sensitivity of 93% (95% CI 78%–99%) at a specificity of 75% (59%–87%) for RCC in the samples tested. Conclusion: Proteomics technology combined with serology led to the identification of serum pro-MMP-7 as a marker of RCC and represents a powerful tool in searching for candidate proteins as biomarkers.
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Malouf, Gabriel, Federico A. Monzon, Jerome Couturier, Vincent Molinie, Bernard J. Escudier, Philippe Camparo, Pheroze Tamboli, Christopher G. Wood, and Nizar M. Tannir. "Genomic analysis of translocation renal cell carcinoma: Association of frequent 3p loss and poor outcome." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 360. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.360.
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360 Background: Translocation renal cell carcinoma (RCC) is a rare subtype of kidney cancer that is characterized by translocations involving TFEB or TFE3 genes. We recently reported that adults with translocation RCC have worse prognosis than pediatric and adolescent patients (Malouf et al, J Urol, 2011), however little is known about the genetic and epigenetic differences between these groups. Methods: Cytogenomic analysis was performed with 250K SNP microarrays (Affymetrix) on 19 tumor specimens of translocation RCC (Age <18 (n=6); Age >=18 (n=13) and 2 established cell lines (UOK109, UOK146). Changes in global DNA methylation levels were measured by using pyrosequencing of highly repetitive LINE-1 sequences on 27 tumor samples. Results were correlated with the patients’ clinical data. Results: 3p loss was observed in 8 patients (42%) and was associated with other chromosomal alterations frequently seen in clear-cell RCC such as 9p loss. Patients with 3p loss showed poor overall survival (OS) as compared to patients without 3p loss (Median OS 12.7 month vs. not reached) [p=0.03]. There was no association found between 3p loss and clinico-pathological variables such as AJCC stage, age and gender. The UOK146 cell line also showed 3p and 9p loss. Young patients (<18 years) displayed fewer number of genetic abnormalities as compared to older patients (p=0.02). Moreover, Line-1 methylation was found to be lower in adult as compared to young patients (76.7% vs. 71.1%, p=0.02). Conclusions: Our results show that a subset of translocation RCC is characterized by a genetic profile similar to that of clear-cell RCC and these tumors seem to behave aggressively. Studies to determine the presence of VHL mutation in these tumors are underway. Adult patients display higher genetic abnormalities and lower Line-1 methylation as compared to young patients. These results might explain the different behavior of pediatric and adult translocation RCC.
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Larroquette, Mathieu, Félix Lefort, Luc Heraudet, Jean-Christophe Bernhard, Alain Ravaud, Charlotte Domblides, and Marine Gross-Goupil. "Therapeutic Management of Metastatic Clear Cell Renal Cell Carcinoma: A Revolution in Every Decade." Cancers 14, no. 24 (December 17, 2022): 6230. http://dx.doi.org/10.3390/cancers14246230.
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Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010–2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival.
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Gudapati, Prathyusha, and Mouna Abouamara. "Clear cell renal cell carcinoma with stage IV cavoatrial tumour thrombus extension and rapid metastatic reoccurrence postsurgical treatment with review of current treatment strategies." BMJ Case Reports 15, no. 3 (March 2022): e248156. http://dx.doi.org/10.1136/bcr-2021-248156.
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Renal cell carcinoma (RCC) is the most aggressive urological malignancy, with a high recurrence rate. Despite the rapid evolution of the treatment of RCC from non-specific cytotoxic therapies to specific novel combination therapies, the general prognosis for advanced RCC remains poor because patients’ responses to these therapies vary. Herein, we present the case of a male in early forties who was diagnosed with a right lower pole renal mass with a level IV tumour thrombus, which was later confirmed as stage IIIc clear cell RCC. About 19 months after radical nephrectomy (curative surgery), the patient was diagnosed with a biopsy-proven metastatic disease, which was not responsive to first-line treatment owing to insufficient data on the best treatment regimen. Herein, we also present a literature review on the pathological impact of genomic alterations in tumour suppressors and highlight emerging paradigm shifts in the treatment of RCC.
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Ho, Jar-Yi, Ren-Jun Hsu, Chieh-Lin Wu, Wen-Liang Chang, Tai-Lung Cha, Dah-Shyong Yu, and Cheng-Ping Yu. "Ovatodiolide Targetsβ-Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–16. http://dx.doi.org/10.1155/2013/161628.
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Dysregulatedβ-catenin signaling is intricately involved in renal cell carcinoma (RCC) carcinogenesis and progression. Determining potentialβ-catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening forβ-catenin signaling inhibitors involvedin silicoinquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell linesin vitroand 2 RCC cell lines in a mouse xenograft model. The synergistic effects of ovatodiolide and sorafenib or sunitinib were examined in 2 TKI-resistant RCC cell lines. Ovatodiolide, a pure compound ofAnisomeles indica, inhibitedβ-catenin signaling and reduced RCC cell viability, survival, migration/invasion, andin vitrocell orin vivomouse tumorigenicity. Cytotoxicity was significantly reduced in a normal kidney epithelial cell line with the treatment. Ovatodiolide reduced phosphorylatedβ-catenin (S552) that inhibitedβ-catenin nuclear translocation. Moreover, ovatodiolide decreasedβ-catenin stability and impaired the association ofβ-catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potentβ-catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy.
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Soleimani, Maryam, Lucia Nappi, and Christian Kollmannsberger. "Avelumab and axitinib combination therapy for the treatment of advanced renal cell carcinoma." Future Oncology 16, no. 36 (December 2020): 3021–34. http://dx.doi.org/10.2217/fon-2020-0586.
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Owing to an improved understanding of the immunobiological profile of renal cell carcinoma (RCC), the past few years have ushered in significant changes in systemic therapies for advanced stage RCC. First-line treatment with single-agent tyrosine kinase inhibitors (TKI) has been virtually replaced for most patients by immunotherapy combinations. The first of such treatments was the dual immune checkpoint inhibitor combination of ipilimumab and nivolumab. More recently, the combination of an immune checkpoint inhibitor and a TKI has also moved into the first-line setting. This review summarizes the pharmacologic properties, evidence for use and safety of avelumab, a PD-L1 inhibitor and axitinib a small-molecule TKI, each as monotherapy, and in combination for the management of metastatic RCC.
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Rouvinov, Keren, Endre Z. Neulander, Elena Kan, Murad Asali, Samuel Ariad, and Wilmosh Mermershtain. "Testicular Metastasis from Renal Cell Carcinoma: A Case Report and Review of the Literature." Case Reports in Oncology 10, no. 1 (April 27, 2017): 388–91. http://dx.doi.org/10.1159/000473698.
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Testicular metastases from renal cell carcinoma (RCC) are extremely rare. To the best of our knowledge, only 33 cases have been described in the literature. Most of the reported cases are of unilateral testicular metastasis from RCC. We report a case of metachronous ipsilateral testicular metastasis from RCC in a 78-year-old man 6 years after nephrectomy. Scrotal ultrasonography showed a 4 × 5 cm mass in the right testis. Right inguinal orchiectomy was performed for diagnosis. Computed tomography revealed liver and lung metastases. First-line therapy with sunitinib was started in November 2016 for metastatic RCC.
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Meskawi, Malek, Roger Valdivieso, Paolo Dell’Oglio, Vincent Trudeau, Alessandro Larcher, and Pierre I. Karakiewicz. "The Role of Everolimus in Renal Cell Carcinoma." Journal of Kidney Cancer and VHL 2, no. 4 (December 30, 2015): 187–94. http://dx.doi.org/10.15586/jkcvhl.2015.43.
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Everolimus (RAD001) is an orally administered agent that inhibits the mammalian target of rapamycin serine-threonine kinase. A phase III pivotal trial on everolimus, published in 2008, provided the first evidence for the efficacy of sequential therapy for patients with metastatic clear cell renal cell carcinoma (RCC). In this study, everolimus was used after failure of one or several previous lines of therapy, and it demonstrated a 3-month survival benefit relative to placebo. Currently, based on the level 1 evidence, everolimus represents the molecule of choice for third-line therapy after failure of previous two tyrosine kinase inhibitors (TKIs). However, second-line use after failure of one TKI is challenged by two new molecules (nivolumab and cabozantinib), which proved to have better efficacy with similar toxicity profile. In non-clear cell metastatic RCC, the current evidence recommends everolimus as a second-line therapy after failure of previous first-line sunitinib.
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Rajasekaran, Narendiran, Trenton House, Carina Crystal Magdaleno, and Archana Varadaraj. "Assembly and localization of extracellular matrix protein fibronectin modulates Natural killer cell infiltration in tumor spheroids." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 62.08. http://dx.doi.org/10.4049/jimmunol.208.supp.62.08.
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Abstract Natural Killer cells (NK), the major innate effector cells, with their broad cytotoxicity against tumors are ideal candidates for immunotherapy. Once having entered the malignant site, NK cells encounter a complex environment composed of tumor cells, non-tumor cells along with the extra cellular matrix (ECM). As one of the integral components of the tumor microenvironment (TME), the normal regulation of the extra cellular matrix (ECM) is necessary to prevent tumor progression and metastasis. Nevertheless, the impact of the matrix architecture found in solid tumors on immune cells and especially NK cells is not well characterized. Here we investigated the role of Fibronectin, a fibrous ECM protein, and its assembly and localization on NK cell infiltration into clear cell renal cell carcinoma (ccRCC) spheroids. 3D tumor spheroids established from the ccRCC cell line 786-O (RCC-) that lacks the Von Hippel-Lindau (VHL) gene are incapable of fibronectin assembly in their ECM. However, addition of the VHL gene into the 786-O cells (RCC+) reversed this phenotype facilitating fibronectin assembly. Fibronectin in RCC-spheroids exhibited prominent peripheral localization in contrast to RCC+ spheroids where fibronectin was detected towards the center of the spheroid. Coincident with fibronectin localization, PKH26 labeled Natural killer cell line, NKL, showed significantly increased infiltration into RCC+ spheroids compared to RCC-spheroids that lacked the tumor suppressor VHL. Thus, assembly and localization of fibronectin modulates NK cell infiltration in RCC tumors. Supported by grants from NIH U54MD012388 (NR and AV) and NIH U54CA143925 (NACP-NAU) to NR.
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Hainsworth, John D., David R. Spigel, and F. Anthony Greco. "Renal cell carcinoma (RCC) presenting as cancer of unknown primary (CUP): Diagnosis by molecular tumor profiling (MTP)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e15501-e15501. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e15501.
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e15501 Background: CUP is a heterogeneous clinicopathologic syndrome representing many types of occult clinically undetectable primary neoplasms. With the advent of MTP, the tissue of origin in CUP is frequently identified when used in concert with immunohistochemistry (IHC) and clinical features. Histopathology alone is usually not specific, and diagnostic IHC is often limited. Diagnosis of the RCC subset of CUP has important therapeutic potential given the availability of multiple approved biologic therapies, and the use of MTP may facilitate the correct diagnosis. Methods: 488 CUP patients (pts) seen between 2008 – 2012 had MTP (RT-PCR 92-gene assay, CancerTYPE ID, bioTheranostics, Inc.) of their archived tumor specimens. The clinicopathologic features were reviewed and, where feasible, subsequent additional IHC stains were obtained to support the MTP diagnosis. The response and survival to first-line RCC site-specific therapy were evaluated. Results: RCC was the MTP diagnosis in 22 pts (4.5%), including papillary in 8, clear cell in 7, and unknown subtype in 7. Histology included poorly differentiated carcinoma in 15 and adenocarcinoma in 7 (4 with papillary features, 1 with clear cell features). None had evidence of a primary renal lesion detectable by abdominal computed tomography, and the sites of metastasis most often included retroperitoneal nodes (63%), mediastinal nodes (31%), lung (22%), and bone (18%). Diagnostic RCC IHC stains were performed initially in only 3 tumors (14%), but RCC IHC stains (RCC, PAX 8, others) performed later supported the MTP diagnosis in 7 of 9 tumors where remaining tissue was available. 16 pts received first-line RCC targeted therapies (objective response rate was 18%, median survival of 13.4). Conclusions: RCC is a subset of CUP which can be diagnosed by MTP. RCC is usually not suspected in the absence of clear cell features, and occult RCC appears to commonly be the papillary subtype. RCC IHC may be diagnostic in some CUP tumors, but may be omitted in the initial pathologic evaluation. CUP-RCC pts are important to identify as they may benefit from standard RCC targeted therapies, and respond poorly to empiric chemotherapy.
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Cai, Yangke, Meng Zhang, Xiaofu Qiu, Bingwei Wang, Yu Fu, Jun Zeng, Jian Bai, and Guosheng Yang. "Upregulation of FBXW7 Suppresses Renal Cancer Metastasis and Epithelial Mesenchymal Transition." Disease Markers 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/8276939.
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Background and Objective. FBXW7, known as a general tumor suppressor, is commonly lowly expressed in metastatic malignancies. We aim to investigate the potential influence of FBXW7 overexpression on renal cell carcinoma (RCC) metastasis. Methods. We employed quantitative real-time PCR (qRT-PCR) and Western blotting (WB) to quantify the FBXW7 expression in RCC cell lines. Upregulation of FBXW7 was performed in vitro on RCC cells using the lentivirus covering coding region FBXW7 cDNA sequence, and functional tests were performed to verify FBXW7 overexpression on migration and invasion of RCC cells. Moreover, WB was employed to determine the expressions of MMP-2, MMP-9, and MMP-13, as well as EMT markers in the transfected RCC cells. Results. FBXW7 was significantly downregulated in RCC cell lines, dominated by 786-O and ACHN, when compared to normal renal cell line HK-2. Moreover, upregulation of FBXW7 in 786-O and ACHN cell lines significantly inhibited cell migration and invasion, as well as EMT. Present study also showed that FBXW7 was involved in the migration and invasion of RCC cells via regulating the expressions of MMP-2, MMP-9, and MMP-13. Conclusion. Our findings demonstrate that upregulation of FBXW7 inhibits RCC metastasis and EMT. FBXW7 is a potential therapeutic target for RCC patients.
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Plimack, Elizabeth R., and Gary R. Hudes. "Selecting Targeted Therapies for Patients With Renal Cell Carcinoma." Journal of the National Comprehensive Cancer Network 9, no. 9 (September 2011): 997–1006. http://dx.doi.org/10.6004/jnccn.2011.0084.
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Advanced renal cell carcinoma (RCC) is a heterogeneous disease with variable histology, biology, and response to treatment. In the past 5 years, 6 new agents have been approved for the treatment of RCC, and many more are in clinical development. With an ever-increasing number of treatment options, selecting among them for a particular patient can be a daunting task for clinicians. This article describes how treatment choice can be guided by the disease setting and histology, as well as patient characteristics, comorbidities, and preference within the context of available data. Results from clinical trials are combined with practical considerations to make recommendations for first-line and subsequent treatment of patients with clear cell and non-clear cell RCC. These recommendations should supplement the current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of advanced RCC.
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Valsecchi, Matias Emanuel, Aakanksha Asija, Takami Sato, Carol L. Shields, Jerry A. Shields, Jennifer Richards-Yutz, Arupa Ganguly, Michael J. Mastrangelo, and Jianqing Lin. "Development of renal cell carcinoma in patients with primary uveal melanoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e15563-e15563. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e15563.
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e15563 Background: Somatic mutations of BRCA1 associated protein1 (BAP1), a tumor suppressor gene, located on chromosome 3p21.1 is found in 50% of primary uveal melanoma (UM) and has been linked to an aggressive phenotype. It is recently reported that somatic BAP1 mutation is also found in 15% of renal cell carcinomas (RCC). We hypothesize that germ line or somatic mutation of BAP1 may contribute the carcinogenesis of patients (pts) who have both UM and RCC. Methods: Retrospective chart review on patients with primary UM treated at Wills Eye Institute and Thomas Jefferson University between 1997 and 2012 revealed 15 patients with both UM and histologically proven RCC. Clinical information on these patients was analyzed. Tumor tissue and blood specimens were also collected for BAP1 gene mutation analysis. Results: Of the 15 patients, 12 (80%) were males. Median age at diagnosis of UM was 57 years old. Six of these patients developed liver metastasis on follow-up (40%). From 8 patients whose pathology data on RCC were available, 6 of them were clear cell type (75%), one was papillary type-1 and one was multilocular cystic subtype. The diagnosis of RCC proceeded the UM diagnosis in 5 of 15 patients, while the diagnoses were made concurrently in 4 patients. Six patients were diagnosed with UM first. For pts who had genetic testing on UM, chromosome 3 abnormalities are the most common abnormalities found. Peripheral blood specimens were tested for 2 patients and germ-line BAP1 mutation was not discovered. Detailed tumor tissue BAP1 mutation analysis is ongoing. Conclusions: The development of RCC is relative common for UM and the molecular mechanism is being determined. It is male dominant in sex and mostly clear cell type in histology of RCC. Further gene mutation analysis and its association with clinical data will be reported.
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Markowitsch, Sascha D., Olesya Vakhrusheva, Patricia Schupp, Yasminn Akele, Jovana Kitanovic, Kimberly S. Slade, Thomas Efferth, et al. "Shikonin Inhibits Cell Growth of Sunitinib-Resistant Renal Cell Carcinoma by Activating the Necrosome Complex and Inhibiting the AKT/mTOR Signaling Pathway." Cancers 14, no. 5 (February 22, 2022): 1114. http://dx.doi.org/10.3390/cancers14051114.
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Therapy resistance remains a major challenge in treating advanced renal cell carcinoma (RCC), making more effective treatment strategies crucial. Shikonin (SHI) from traditional Chinese medicine has exhibited antitumor properties in several tumor entities. We, therefore, currently investigated SHI’s impact on progressive growth and metastatic behavior in therapy-sensitive (parental) and therapy-resistant Caki-1, 786-O, KTCTL-26, and A498 RCC cells. Tumor cell growth, proliferation, clonogenic capacity, cell cycle phase distribution, induction of cell death (apoptosis and necroptosis), and the expression and activity of regulating and signaling proteins were evaluated. Moreover, the adhesion and chemotactic activity of the RCC cells after exposure to SHI were investigated. SHI significantly inhibited the growth, proliferation, and clone formation in parental and sunitinib-resistant RCC cells by G2/M phase arrest through down-regulation of cell cycle activating proteins. Furthermore, SHI induced apoptosis and necroptosis by activating necrosome complex proteins. Concomitantly, SHI impaired the AKT/mTOR pathway. Adhesion and motility were cell line specifically affected by SHI. Thus, SHI may hold promise as an additive option in treating patients with advanced and therapy-resistant RCC.
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Mitsogiannis, Iraklis C., Maria Mitsogianni, Maria Papathanassiou, Maria Anagnostou, Ioannis Tamposis, Lampros Mitrakas, Maria Samara, Vassilios Tzortzis, and Panagiotis J. Vlachostergios. "Current Options for Second-Line Systemic Therapy in Metastatic Renal Cell Carcinoma." Journal of Kidney Cancer and VHL 9, no. 3 (September 29, 2022): 29–40. http://dx.doi.org/10.15586/jkcvhl.v9i3.243.
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Standard systemic therapy of advanced renal cell carcinoma (RCC) involves targeting angiogenesis, mainly through tyrosine kinase inhibitors (TKI) against the vascular endothelial growth factor receptor (VEGFR) pathway and targeting the immune checkpoints, namely, programmed death-1 (PD-1) or its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). With current strategies of combining these two approaches in the front-line setting, less is known about optimal selection of therapy upon development of resistance in the second and later lines of treatment for progressive disease. This review discusses currently available therapeutic options in patients who have progressive RCC after prior treatment with double immune check-point inhibitors (ICIs) or ICI-TKI combinations.
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Alekseev, B. Ya, I. M. Shevchuk, and A. D. Kaprin. "Individual approach in choosing second-line targeted therapy for metastatic renal cell carcinoma." Cancer Urology 14, no. 2 (July 7, 2018): 68–78. http://dx.doi.org/10.17650/1726-9776-2018-14-2-68-78.
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Renal cell carcinoma (RCC) is one of the most common genitourinary malignancies worldwide. Approximately 25–30 % of newly diagnosed patients have metastatic RCC (mRCC), whereas in 20–30 % of cases, dissemination occurs after radical surgical treatment. The development of targeted and immunooncological agents in recent years significantly increased survival in patients with mRCC. However, clinicians faced a problem of choosing an optimal therapeutic regimen to achieve maximum effectiveness of the treatment. This article discusses the choice of second-line drugs for mRCC, advantages of axitinib and its optimal dosage, and efficacy of sunitinib depending on the disease prognosis.
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Vats, Pankaj, Saravana Dhanasekaran, Rohit Malik, Yupin Zhang, Xuhong Cao, Fengyun Su, Rui Wang, et al. "Integrative genomic profiling of RCC treated with second-line nivolumab." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 720. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.720.
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720 Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer comprising up to 80% of RCC. Anti-vascular endothelial growth factor receptor (VEGFR) is a common therapy. Immune checkpoint inhibitor therapy with anti-PD1 antibody Nivolumab is a standard second line option in mccRCC. Overall response rate with Nivolumab however is only 25%. Since there is a critical need to develop and refine predictive biomarkers for anti-PD1 checkpoint inhibitor immunotherapy, we undertook a genomics based approach to gain further insights. Methods: Archival pre-treatment tissues from 37 metastatic mccRCC patients who had received anti-VEGFR first and then Nivolumab were collected and profiled by integrated next generation sequencing (NGS) including whole exome sequencing and RNA sequencing. Integrative NGS analysis was used to discover somatic mutations, indels, copy-number alterations and gene expression changes among the samples in this cohort. In-addition, we characterized the T-Cell clone type by adaptive immunoSEQ TCR sequencing on the matched tumor/benign adjacent tissue samples. Clinical outcome data was correlated with high throughput sequencing results to delineate the characteristics of responders and non-responders. Results: Integrative NGS profiling and analysis of ccRCC tumors revealed 1) the characteristic copy number alteration including frequent loss at 3p, 8p21.3 and 9p21.3 as well as gain at 5q, and 12p12.1. 2) a low mutational burden 3) tumors with PBRM1 mutation were relatively enriched in the “No Clinical Benefit Category”. 4) CD8 immunohistochemistry showed significant enrichment of CD8+ cells ( pval-0.05) in the clinical benefit group compared to patients with no-clinical benefit. The clinical benefit group tended to have higher number of TCR clones. Conclusions: Integrative genomic sequencing analysis of ccRCC tumors in Nivolumab treated patients revealed CD8 expression as a putative biomarker. Greater T-cell clonotypes & clonal expansion correlated with clinical benefit. PBRM1 mutant status did not select for clinical benefit. A model combining CD8 expression with T-cell characteristics was developed.
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Ahn, Chae Ryeong, Jinbong Park, Jai-Eun Kim, Kwang Seok Ahn, Young Woo Kim, Minjeong Jeong, Hong Jun Kim, Sun Hyang Park, and Seung Ho Baek. "Cinnamaldehyde and Hyperthermia Co-Treatment Synergistically Induces ROS-Mediated Apoptosis in ACHN Renal Cell Carcinoma Cells." Biomedicines 8, no. 9 (September 17, 2020): 357. http://dx.doi.org/10.3390/biomedicines8090357.
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Renal cell carcinoma (RCC) represents the most common form of kidney cancer, which accounts for 3–5% newly diagnosed cancer cases. Since limited therapies are available for RCC, a search for new options is required. Therefore, in this study, we evaluated the combination effect of cinnamaldehyde (CNM) and hyperthermia treatment. CNM treatment combined with 43 °C hyperthermia synergistically increased cytotoxicity in RCC cell line ACHN cells. Through Western blot assays, we observed increased apoptosis signaling and decreased proliferation/metastasis signaling, along with a repressed heat shock protein 70 level. In flow cytometry analyses, CNM and hyperthermia combination clearly induced apoptosis and mitochondrial potential of ACHN cells, while arresting the cell cycle. Investigation of reactive oxygen species (ROS) suggested a significant increase of ROS generation by CNM and 43 °C hyperthermia co-treatment. We could verify that ROS is crucial in the apoptotic action of combination treatment with CNM and hyperthermia through further experiments regarding an ROS scavenger. Overall, we suggest CNM and hyperthermia combination treatment as an alternative option of anticancer strategies for RCC.
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Thouvenin, Jonathan, Claire Masson, Philippe Boudier, Denis Maillet, Sabine Kuchler-Bopp, Philippe Barthélémy, and Thierry Massfelder. "Complete Response in Metastatic Clear Cell Renal Cell Carcinoma Patients Treated with Immune-Checkpoint Inhibitors: Remission or Healing? How to Improve Patients’ Outcomes?" Cancers 15, no. 3 (January 27, 2023): 793. http://dx.doi.org/10.3390/cancers15030793.
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Renal-cell carcinoma (RCC) accounts for 2% of cancer diagnoses and deaths worldwide. Clear-cell RCCs represent the vast majority (85%) of kidney cancers and are considered morphologically and genetically as immunogenic tumors. Indeed, the RCC tumoral microenvironment comprises T cells and myeloid cells in an immunosuppressive state, providing an opportunity to restore their activity through immunotherapy. Standard first-line systemic treatment for metastatic patients includes immune-checkpoint inhibitors (ICIs) targeting PD1, in combination with either another ICI or with antiangiogenic targeted therapy. During the past few years, several combinations have been approved with an overall survival benefit and overall response rate that depend on the combination. Interestingly, some patients achieve prolonged complete responses, raising the question of whether these metastatic RCC patients can be cured. This review will focus on recent therapeutic advances in RCC and the clinical and biological aspects underpinning the potential for healing.
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Phatak, Hemant, Ruth Kim, Ting Yu, Jill Dreyfus, Julie A. Gayle, Christina L. Wassel, Stan Krulewicz, and Ying Zheng. "Real-world outcome study among patients with renal cell carcinoma (RCC) receiving checkpoint inhibitors (CPIs)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e16073-e16073. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e16073.
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e16073 Background: North America has one of the highest rates of RCC, and in 2018, 65,340 new cases were diagnosed in the US alone. Tyrosine kinase inhibitors have been a mainstay treatment for RCC. However, the first CPI, nivolumab, was approved by the FDA as a second-line treatment for RCC in late 2015 and as a first-line therapy in combination with ipilimumab in 2018. In this study, real-world outcomes in patients with RCC receiving CPIs were examined. Methods: An observational study was conducted from March 1, 2015, to December 31, 2017, using the Premier Healthcare Database, a hospital discharge database. Patients with RCC aged ≥18 years were identified by ICD-9/10 codes and were included if they received a CPI during the study period, irrespective of treatment line. Comorbidities were assessed in a 6-month look-back period commencing at the time of first CPI treatment and RCC diagnosis. 34 distinct immune-related adverse events (irAEs) were identified in a 90-day look-back period from time of the irAE to determine if patients had received a CPI during that time. Patients were followed for 90 days after the irAE to determine if CPI treatment was reinitiated. Results: During the study period, 1228 patients with RCC received a CPI, of whom 719 (59%) had ≥1 irAE. Approximately 95% of patients received nivolumab and the remaining 5% received an off-label CPI. At the time of initial CPI treatment, patients who experienced any irAE during the study period had a higher Charlson Comorbidity Index (5.1±3.2 vs 4.2±3.0; p < 0.001) and were more likely to be hospitalized on an emergent basis than those without an irAE (9.0% vs 5.1%; p = 0.005). Patients with an irAE also had a higher average number of previous immune-related or immunocompromised comorbid conditions (0.33±0.57 vs 0.12±0.36; p < 0.001). After experiencing an irAE, 65% of patients reinitiated a CPI within 90 days. Conclusions: The majority of RCC patients receiving a CPI, mostly anti-PD-1 agents, experienced an irAE, and patients with irAEs had a higher comorbidity burden than those without irAEs. Most patients with irAEs reinitiated CPI treatment within 90 days.
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He, Linfu, Wenjing Shi, Xiaocui Liu, Xiaohuan Zhao, and Zhicai Zhang. "Anticancer Action and Mechanism of Ergosterol Peroxide from Paecilomyces cicadae Fermentation Broth." International Journal of Molecular Sciences 19, no. 12 (December 7, 2018): 3935. http://dx.doi.org/10.3390/ijms19123935.
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Isaria cicadae, a medicinal food fungus, is a fruit from Paecilomyces cicadae. In this study, we purified ergosterol peroxide (EP) from the fermentation broth of P. cicadae and investigated its effects on renal cell carcinoma (RCC) cells, in vitro. EP was purified from P. cicadae fermentation broth. The human RCC cell line 786-0 was used to analyze the anticancer mechanism of EP and inhibit its effect on cancer cell proliferation, in vitro. EP with a validated structure showed a yield rate of 20.1 mg/L and a purity of 96%. EP significantly inhibited RCC cell growth and clone formation in vitro. In addition, EP suppressed the migration and invasion, triggered the apoptosis, and modulated the cell cycle of RCC cells, in a dose-dependent manner. It also downregulated β-catenin expression. EP could be routinely produced through P. cicadae. It fights RCC cells in vitro through multiple mechanisms, including suppressing cell growth, colonization, migration, and invasion, arresting the cell cycle, attenuating β-catenin pathways, and triggering apoptosis.
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Motzer, Robert J., Toni K. Choueiri, David F. McDermott, Thomas Powles, Yann-Alexandre Vano, Saurabh Gupta, Jin Yao, et al. "Biomarker analysis from CheckMate 214: nivolumab plus ipilimumab versus sunitinib in renal cell carcinoma." Journal for ImmunoTherapy of Cancer 10, no. 3 (March 2022): e004316. http://dx.doi.org/10.1136/jitc-2021-004316.
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BackgroundThe phase 3 CheckMate 214 trial demonstrated higher response rates and improved overall survival with nivolumab plus ipilimumab versus sunitinib in first-line therapy for advanced clear-cell renal cell carcinoma (RCC). An unmet need exists to identify patients with RCC who are most likely to benefit from treatment with nivolumab plus ipilimumab.MethodsIn exploratory analyses, pretreatment levels of programmed death ligand 1 were assessed by immunohistochemistry. Genomic and transcriptomic biomarkers (including tumor mutational burden and gene expression signatures) were also investigated.ResultsBiomarkers previously associated with benefit from immune checkpoint inhibitor-containing regimens in RCC were not predictive for survival in patients with RCC treated with nivolumab plus ipilimumab. Analysis of gene expression identified an association between an inflammatory response and progression-free survival with nivolumab plus ipilimumab.ConclusionsThe exploratory analyses reveal relationships between molecular biomarkers and provide supportive data on how the inflammation status of the tumor microenvironment may be important for identifying predictive biomarkers of response and survival with combination immunotherapy in patients with RCC. Further validation may help to provide biomarker-driven precision treatment for patients with RCC.
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Fay, André P., Marcella Callea, Kathryn P. Gray, Thai Huu Ho, Jiaxi Song, Ingrid Carvo, Megan E. Lampron, et al. "PD-L1 expression in non-clear cell renal cell carcinoma." Journal of Clinical Oncology 32, no. 4_suppl (February 1, 2014): 424. http://dx.doi.org/10.1200/jco.2014.32.4_suppl.424.
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424 Background: Programmed death-1 (PD-1) receptor negatively regulates T cell-mediated responses.PD-1 ligand (PD-L1) is aberrantly expressed in clear cell renal cell carcinoma (ccRCC) and is associated with worse prognosis. Levels of PD-L1 expressions in non-ccRCC and its association with clinicopathological features and survival are unknown. Methods: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 97 patients with chromophobe (CHR), papillary (PAP), translocation Xp11.2 (TrL) RCC and oncoytoma (ONC) and were included in the analysis. PD-L1 expression was evaluated by immunohistochemistry using a mouse monoclonal anti-PD-L1 antibody (405.9A11). The assay was validated using FFPE cell line controls known to be positive or negative for PD-L1 expression by flow cytometry. PD-L1 tumor positivity (PD-L1+) was defined as ≥5% tumor cell membrane staining. For PD-L1 expression in immune cells, a combined score based on the intensity of infiltrate and percentage of positive cells was used. Baseline characteristics including stage/grade, and survival data were collected. Comparisons between PD-L1 expression and clinicopathological features were evaluated using chisq or wilcoxon rank sum tests. Cox model tests for association of PD-L1 expression with OS in univariate and multivariable analysis. Results: Among 97 patients, 12 (12.4%) were considered PD-L1+ in tumor cells: 2/36 (5%) of CHR RCC, 5/50 (10%) of PAP RCC, 3/7 (43%) of TrL RCC, and 2/4 (50%) of ONC. PD-L1 positivity in tumor cells was significantly associated with higher stage (p=0.026) and grade (p=0.046), as well as lower OS on univariate (p=0.02) but not multivariate analysis (p=0.29). On the other hand, PD-L1 positivity by immune cells was observed in 50 (51.5%) patients: 13/36 (36%) of CHR RCC, 30/50 (60%) of PAP RCC, 6/7 (86%) of TrL RCC, and 1/4 (25%) of ONC. PD-L1 positivity in immune cells did not correlate with stage (p=0.7), grade (p=0.1) or OS (p=0.8). Conclusions: PD-L1 expression is variable in non-ccRCC and depends on histology and tumor vs. immune cells scoring. Only PD-L1 positivity in tumors cells was associated with aggressive features. Patients with non-ccRCC should not be automatically excluded from trials of agents that target the PD-1/PD-L1 pathway.
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Takayama, Tatsuya, Mitsuhiro Kitagawa, Naohisa Takaoka, Naoyuki Sugiyama, Kaori Igarashi, Miki Miyazaki, Takayuki Sugiyama, Fumitake Kai, Tomoyoshi Soga, and Seiichiro Ozono. "Renal cell carcinoma with a novel germ-line mutation in isocitrate dehydrogenase 1 (IDH1) and its functional study." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e15568-e15568. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e15568.
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e15568 Background: Recently, omics study such as metabolome analysis and whole genome sequencing has been applied to various disorders. We predicted the dysfunction of isocitrate dehydrogenase 1 (IDH1) in renal cell carcinoma (RCC) using metabolome analysis and identified a novel mutation of IDH1. In addition, we examined its function. Methods: We determined the global-scale metabolome profiling of human RCC by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS), and compared the metabolite levels of tumors and paired normal tissues in 10 patients with RCC. We performed the genotyping of IDH1 and von Hippel-Lindau (VHL) gene. We also performed transfection experiments by using Lipofectamine and measured the enzymatic activity of IDH1 in RCC cell lines. All protocols were performed by the Institutional Review Board (IRB) of Hamamatsu University School of Medicine and Keio University. Informed consent was obtained from the patient in accordance with the IRB of Hamamatsu University School of Medicine. Results: The acceleration of glycolysis with low level of NADPH and citrate in one patient led to IDH1 dysfunction followed by identifying a novel missense mutation, V178I. In transfection experiment, the reductive activity of IDH1 variant (V178I) increased 2.5 times than that of IDH1 wild type while the oxidative activity of IDH1 variant oxidative activity was as well as that of IDH1 wild type. Furthermore, in the metabolome analysis using labeling glutamine, RCC cell lines deficient in the von Hippel-Lindau (VHL) protein preferentially use reductive glutamine metabolism. On the other hand, this patient with V178I mutation of IDH1 had no VHL mutation. Conclusions: Metabolome analysis led to the identification a novel IDH1 missense mutation in RCC. This mutation might be involved with acceleration of reductive reaction in tricarboxylic acid cycle. Metabolome analysis using CE-TOFMS could be a powerful tool for the global-scale exploration of disease-specific metabolism.
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Roberto, Michela, Maria Bassanelli, Elsa Iannicelli, Silvana Giacinti, Chiara D’Antonio, Anna Maria Aschelter, and Paolo Marchetti. "Clinical Outcome of Third-Line Pazopanib in a Patient with Metastatic Renal Cell Carcinoma." Case Reports in Oncological Medicine 2015 (2015): 1–4. http://dx.doi.org/10.1155/2015/629046.
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Background.Renal cell carcinoma accounts for about 2-3% of all malignant tumors. The prevalence of brain metastases from RCC is less than 20% of cases. Traditionally, whole brain radiotherapy as well as the latest stereotactic radiosurgery improves both survival and local tumor control. These treatments also allow stabilization of clinical symptomatology. However, validated treatment guidelines for RCC patients with brain metastases are not yet available on account of the frequent exclusion of such patients from clinical trials. Moreover, limited data about the sequential use of three therapies, changing the class of agent, have been published up to now.Case Report.We report the case of a patient with metastatic RCC who developed disease progression after sunitinib and everolimus as first-line and second-line therapy, respectively. Thus, he underwent a multimodality treatment with pazopanib, as third-line therapy, to control systemic disease and radiosurgery directed on the new brain metastasis. To date, the patient is still receiving pazopanib, with progression-free survival and overall survival of 43 and 103 months, respectively.Conclusion.In a context characterized by different emerging options, with no general consensus on the optimal treatment strategy, the use of pazopanib in pretreated patients could be a suitable choice.