Agents In Renal Cell Carcinoma Research Articles

Bovine Meat and Milk Factor-like Sequences Are Frequently Detected in Renal Cell Carcinoma Tissues.

Previous studies have indicated a potential role of diet in the pathogenesis of renal cell carcinoma (RCC). Recently, circular bovine meat and milk factor (BMMF) DNAs have been identified in peritumoral tissues of human colon and breast cancers. Here, we investigated the prevalence of the DNA of these novel human pathogenic infectious agents in RCC and adjacent peritumoral renal tissues. DNA was extracted from formalin-fixed and paraffin-embedded (FFPE) RCC and peritumoral kidney tissues, including a test (n = 11) and a validation (n = 152) collection. BMMF1 and BMMF2 consensus primers were designed to screen for the presence of BMMF1- and BMMF2-like DNA. In addition, BMMF-specific PCR was performed on selected cases to test for the presence of additional regions of BMMF1 and BMMF2 genomes. A reference collection of hepatocellular carcinomas (HCCs; n = 60) and adjacent peritumoral liver tissues (n = 50) was also included. Our results demonstrated that BMMF1 and BMMF2 DNAs are frequently found in human RCC tissues and are particularly more prevalent in peritumoral kidney tissues. Of note, BMMF1 and BMMF2 genotype heterogeneity was higher in peritumoral kidney tissues compared to RCC tissues. This is the first study to directly test human FFPE tissues for BMMF1- and BMMF2-like DNA using consensus PCR and demonstrate BMMF DNA in neoplastic and peritumoral kidney tissues. The findings are in line with the recently proposed indirect etiopathogenetic role of BMMFs in, e.g., colorectal carcinogenesis. Follow-up studies are needed to explore the potential role of BMMFs in the etiopathogenesis of RCC.

Discovery of novel 1H-benzo[d]imidazole-4,7-dione based transglutaminase 2 inhibitors as p53 stabilizing anticancer agents in renal cell carcinoma

Overexpression of transglutaminase 2 (TGase 2; TG2) has been implicated in the progression of renal cell carcinoma (RCC) through the inactivation of p53 by forming a protein complex. Because most p53 in RCC has no mutations, apoptosis can be increased by inhibiting the binding between TG2 and p53 to increase the stability of p53. In the present study, a novel TG2 inhibitor was discovered by investigating the structure of 1H-benzo[d]imidazole-4,7-dione as a simpler chemotype based on the amino-1,4-benzoquinone moiety of streptonigrin, a previously reported inhibitor. Through structure–activity relationship (SAR) studies, compound 8j (MD102) was discovered as a potent TG2 inhibitor with an IC50 value of 0.35 µM, p53 stabilization effect and anticancer effects in the ACHN and Caki-1 RCC cell lines with sulforhodamine B (SRB) GI50 values of 2.15 µM and 1.98 µM, respectively. The binding property of compound 8j (MD102) with TG2 was confirmed to be reversible in a competitive enzyme assay, and the binding interaction was expected to be formed at the β-sandwich domain, a p53 binding site, in the SPR binding assay with mutant proteins. The mode of binding of compound 8j (MD102) to the β-sandwich domain of TG2 was analyzed by molecular docking using the crystal structure of the active conformation of human TG2. Compound 8j (MD102) induced a decrease in the downstream signaling of p-AKT and p-mTOR through the stabilization of p53 by TG2 inhibition, resulting in tumor cell apoptosis. In a xenograft animal model using ACHN cancer cells, oral administration and intraperitoneal injection of compound 8j (MD102) showed an inhibitory effect on tumor growth, confirming increased levels of p53 and decreased levels of Ki-67 in tumor tissues through immunohistochemical (IHC) tissue staining. These results indicated that the inhibition of TG2 by compound 8j (MD102) could enhance p53 stabilization, thereby ultimately showing anticancer effects in RCC. Compound 8j (MD102), a novel TG2 inhibitor, can be further applied for the development of an anticancer candidate drug targeting RCC.

Overexpression of SPHK1 associated with targeted therapy resistance in predicting poor prognosis in renal cell carcinoma.

Sphingosine kinase 1 (SPHK1) is a key enzyme that catalyzes the phosphorylation of sphingosine. Recent studies reported SPHK1 to be associated with renal cell carcinoma (RCC) progression by inducing targeted therapy resistance. However, the expression and the clinical significance of SPHK1 on RCC in those having received targeted therapy have not been elucidated. The present study explored the expression of SPHK1 in RCC tissues from targeted therapy recipients, the correlation of SPHK1 with clinicopathological parameters, and the effect of SPHK1 on RCC patient prognosis. Differential gene expression analysis of RCC treated with and without targeted therapy was performed. The correlations of SPHK1 expression with clinical parameters of RCC were examined. Gene set enrichment analysis (GSEA) was performed to clarify the potential role of SPHK1 associated with targeted therapy resistance. The value of SPHK1 as a diagnostic marker for RCC was also evaluated. The Kaplan-Meier method was applied to analyze the correlation between SPHK1 expression and patient survival rate by using the clinical data from patients with RCC. Significant overexpression of SPHK1 was detected in RCC treated with targeted therapy. SPHK1 expression was closely correlated with RCC progression-related clinicopathological parameters. Therefore, elevated SPHK1 could effectively diagnose RCC and distinguish RCC with an advanced clinical stage and a high pathological grade. SPHK1 was associated with the stemness of RCC cells via the activation of the Wnt, Hedgehog, or Notch signaling pathways in targeted drug-treated or untreated RCC. Survival analysis of a large cohort of RCC samples indicated overexpression of SPHK1 to be inversely correlated with the overall and disease-free survival of patients with RCC. Our study indicated that SPHK1 associated with targeted therapy resistance could serve as a potential prognostic marker and a valuable biomarker of response to angiogenic agents in RCC.

Imidazolylpyrrolone-Based Small Molecules as Anticancer Agents for Renal Cell Carcinoma.

An in silico study focused on known cancer-related target proteins, identified a selection of imidazo[4,5-b]pyrrolo[3,4-d]pyridines as potentially active. These compounds were prepared by a novel synthetic approach, designed and developed in-house, based on the reaction of 5-amino-4-cyanoformimidoyl imidazoles with N-substituted cyanoacetamides. The substituted imidazolylpyrrolones obtained, were cyclized intramolecularly to generate the intended imidazo[4,5-b]pyrrolo[3,4-d]pyridines in a process catalyzed by DBU. Treating the imidazolylpyrrolones with an excess of triethyl orthoformate and heating at 80 °C in the presence of acid catalysis led to imidazopyrrolodiazepines. These compounds were screened for their anticancer potential, using the renal cell carcinoma cell line model (A498 and 786-O cell lines). Two compounds exhibited IC50 values in the low micromolar range with a good selectivity index, when compared to non-neoplastic kidney cell line HK2 and the reference compounds rapamycin, cediranib and sunitinib.

An activated excretion-retarded tumor imaging strategy towards metabolic organs

Intraoperative fluorescence-based tumor imaging plays a crucial role in performing the oncological safe tumor resection with the advantage of differentiating tumor from normal tissues. However, the application of these fluorescence contrast agents in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) was dramatically hammered as a result of lacking active targeting and poor retention time in tumor, which limited the Signal to Noise Ratio (SNR) and narrowed the imaging window for complicated surgery. Herein, we reported an activated excretion-retarded tumor imaging (AERTI) strategy, which could be in situ activated with MMP-2 and self-assembled on the surface of tumor cells, thereby resulting in a promoted excretion-retarded effect with an extended tumor retention time and enhanced SNR. Briefly, the AERTI strategy could selectively recognize the Integrin αvβ3. Afterwards, the AERTI strategy would be activated and in situ assembled into nanofibrillar structure after specifically cleaved by MMP-2 upregulated in a variety of human tumors. We demonstrated that the AERTI strategy was successfully accumulated at the tumor sites in the 786-O and HepG2 xenograft models. More importantly, the modified modular design strategy obviously enhanced the SNR of AERTI strategy in the imaging of orthotopic RCC and HCC. Taken together, the results presented here undoubtedly confirmed the design and advantage of this AERTI strategy for the imaging of tumors in metabolic organs.

The Emerging Role of Poly (ADP-Ribose) Polymerase Inhibitors as Effective Therapeutic Agents in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the sixth most common cancer in the US. However, no significant changes in management have occurred since the tyrosine kinase era until the recent breakthrough with checkpoint inhibitors. Therefore, the need for more therapeutic options is paramount. Our objective was to determine whether PARP inhibition represents a novel therapeutic option for RCC. We used publicly available COSMIC, GDC Data Portal, and cBioPortal databases to explore mutations in DNA repair genes in RCC tissues from the TCGA cohort. We treated a human normal renal epithelial cell line RPTEC/TERT1 and two human renal cancer cell lines ACHN and CAKI-2 with PARPi niraparib, olaparib, rucaparib, veliparib, and talazoparib. Cell survival, cell proliferation, clonogenic ability, and apoptosis were assessed. RCC xenografts in SCID mice were treated with PARPi to evaluate their efficacy in vivo. Data mining revealed that ~27-32% of RCC tissues contain mutations in homologous recombination genes. Niraparib and talazoparib were the most effective at reducing cell survival, proliferation, and clonogenic ability in vitro. Niraparib, talazoparib, and rucaparib were the most effective in reducing RCC xenograft growth in vivo. Agents such as PARPi that exploit mutations in DNA damage repair genes may be effective therapeutic options for RCC.

Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma.

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.

Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma

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.

Oxymatrine Inhibits Renal Cell Carcinoma Progression by Suppressing β-Catenin Expression

AimsOxymatrine (OMT) has been identified to possess immunomodulatory, antiinflammatory and anticancer properties. This study aimed to investigate its precise function and the underlying molecular mechanisms in renal cell carcinoma progression.MethodsThe antineoplastic effect of oxymatrine was investigated by CCK-8 assay, cell cycle analysis, apoptosis assay, wound healing experiment, transwell assay, and drug-sensitivity analysis in renal cancer cells following oxymatrine treatment. The modulation of oxymatrine on β-catenin was analyzed through western blot and immunofluorescence assay. β-catenin overexpression was employed to determine the key role of β-catenin in oxymatrine-inhibited renal cell carcinoma in vitro. In addition, animal model was established to investigate the effect of oxymatrine on tumor growth in vivo.ResultsOxymatrine inhibited renal cell carcinoma progression in vitro, including cell proliferation, apoptosis, migration, invasion and chemotherapy sensitivity. Further mechanistic studies demonstrated that oxymatrine exerted its antineoplastic effect through suppressing the expression of β-catenin. Moreover, in nude mice model, oxymatrine exhibited remarkable inhibition of tumor growth, which was consistent with our in vitro results.ConclusionsOur findings illuminate oxymatrine as an effective antitumor agent in renal cell carcinoma, and suggest it a promising therapeutic application in renal cell carcinoma treatment.

MP18-17 KNOCKDOWN OF PD-L1 IN MOUSE RENAL CELL CARCINOMA INHIBITS TUMOR GROWTH AND IMPROVE THE ANTI-TUMOR EFFECT OF SUNITINIB

INTRODUCTION AND OBJECTIVE:There are several unresolved issues regarding combined treatment with an immune checkpoint inhibitor and anti-angiogenic agent for renal cell carcinoma (RCC) patients. Th...

The Interplay between Inflammation, Anti-Angiogenic Agents, and Immune Checkpoint Inhibitors: Perspectives for Renal Cell Cancer Treatment.

Treatment options for metastatic renal cell carcinoma (RCC) have been expanding in the last years, from the consolidation of several anti-angiogenic agents to the approval of immune checkpoint inhibitors (ICIs). The rationale for the use of immunomodulating agents derived from the observation that RCC usually shows a diffuse immune-cell infiltrate. ICIs target Cytotoxic T Lymphocytes Antigen 4 (CTLA-4), programmed death 1 (PD-1), or its ligand (PD-L1), showing promising therapeutic efficacy in RCC. PD-L1 expression is associated with poor prognosis; however, its predictive role remains debated. In fact, ICIs may be a valid option even for PD-L1 negative patients. The establishment of valid predictors of treatment response to available therapeutic options is advocated to identify those patients who could benefit from these agents. Both local and systemic inflammation contribute to tumorigenesis and development of cancer. The interplay of tumor-immune status and of cancer-related systemic inflammation is pivotal for ICI-treatment outcome, but there is an unmet need for a more precise characterization. To date, little is known on the role of inflammation markers on PD-1 blockade in RCC. In this paper, we review the current knowledge on the interplay between inflammation markers, PD-1 axis, and anti-angiogenic agents in RCC, focusing on biological rationale, implications for treatment, and possible future perspectives.

Inhibition of Tumor Growth and Sensitization to Sunitinib by RNA Interference Targeting Programmed Death-ligand 1 in Mouse Renal Cell Carcinoma RenCa Model.

There are several unresolved issues regarding the combined treatment with an immune checkpoint inhibitor and anti-angiogenic agent for renal cell carcinoma (RCC) patients. The purpose of this study was to address the inhibitory effects of programmed death-ligand 1 (PD-L1) expression on growth and sensitivity to sunitinib in the mouse RCC RenCa model. We established RenCa/sh-PD-L1 by transfecting RenCa cells with a plasmid carrying a short hairpin RNA targeted against PD-L1. The growth pattern of RenCa/sh-PD-L1 with or without sunitinib was compared to that of RenCa cells transfected with control plasmid alone (RenCa/Co). No significant difference in growth or sensitivity to sinitinib was noted between RenCa/sh-PD-L1 and RenCa/Co cells in vitro. The tumor volume in mice subcutaneously injected with RenCa/sh-PD-L1 was significantly smaller than that with RenCa/Co. Treatment of mice bearing each tumor with sunitinib resulted in a significant reduction of the RenCa/sh-PD-L1 tumor compared to the RenCa/Co tumor. Moreover, infiltration by CD8+ T cells of RenCa/sh-PD-L1 tumors was significantly higher than that of RenCa/Co tumors, irrespective of treatment with sunitinib. Suppressed expression of PD-L1 could increase tumor-infiltrating CD8+ T cells and result in growth inhibition as well as enhanced sensitivity to sunitinib in the RenCa model.

PET imaging in renal cancer.

Worldwide, over 400 000 new cases of kidney cancer were diagnosed and over 175 000 deaths anticipated in 2018. It is ranked as the 14th most common cancer in women and 9th most common in men. Imaging is important for initial detection, staging, and monitoring to assist treatment planning, but conventional anatomic imaging is limited. Although functional PET/CT has proven helpful in the diagnosis and management of many cancers, its value in renal cell carcinoma (RCC) is still in evolution. FDG is probably the most useful radiotracer in RCC, although CAIX imaging can be helpful in clear cell RCC. Current research on PET imaging agents in RCC including 89Zr bevacizumab, 89Zr geruntuximab, 18F fluoro-L-thymidine (FLT), prostate-specific membrane antigen (PSMA), 11C choline, 18F sodium fluoride (NaF), and18F fluorodeoxyglucose (FDG) have shown some interesting results for detection and prognosis of the disease. Many innovative radiotracers have been tested in RCC, but robust differentiation of primary disease from normal parenchyma remains elusive for almost all of them. The metastatic setting and response to therapy for this cancer are more favorable PET applications. Continued research in promising molecular tracers will hopefully advance both diagnostic and therapeutic strategies to ultimately eradicate RCC.

Immunomodulatory Therapies for Renal Cell Carcinoma.

Renal Cell Carcinoma (RCC) is the most common tumor originating from the kidneys. In comparison to other solid tumors, RCC is poorly sensitive to conventional therapeutic modalities. As such, metastatic RCC (mRCC) continues to be associated with high rates of morbidity and mortality. Targeted agents have shown remarkable progress in RCC management with improved patients' outcomes, but rarely induce complete response and patients develop resistance to therapy eventually. However, it is well known that RCC represents one of the most immunogenic cancers and is able to evoke immune response naturally, thus prompted the emergence of several immunotherapeutic strategies in the management of RCC with variable degrees of success. Modulating the immune system with cytokines, vaccines, and T-cell modulating agents offer hope for the patients with RCC. This review critically summarizes the state of the art in RCC therapeutic regimen with immunomodulation agents. We will focus on the clinical data and ongoing clinical trials exploring the use of immunotherapy with different agents for RCC. In addition, different novel immunotherapeutic agents are being investigated for their combination therapy with other immune therapies or other modalities. Prospects (e.g., potential future immunological targets, combination regimens, appropriate sequencing) for immune therapies of RCC are also set forth in this work.

Check point inhibitors a new era in renal cell carcinoma treatment.

In the United States, the estimated number of new cases of renal cell carcinoma (RCC) is approximately 65,000 case with about 15,000 deaths in the year of 2018 (Siegel et al. in CA Cancer J Clin 68(1):7, 2018). RCC as an immunogenic malignancy is supported by many theories and facts which include tumor richness of lymphocytes infiltrate, the occurrence of spontaneous tumor regression, and the proved effect of traditional immunotherapy (Finke et al. in J Immunother 11(1):1-11, 1992), all these factors support the potential therapeutic effect of the novel immunotherapeutic agents in RCC. Historically, complete tumor regression in metastatic RCC is achievable in a minority of patients through traditional immunotherapies such as high-dose interleukin-2 (IL-2) (Fyfe et al. in J Clin Oncol 13(3):688, 1995) and interferon-alfa (IFNa) (Negrier et al. in N Engl J Med 338(18):1272, 1998); however due to the significant rate of toxicities and low efficacy; accordingly the targeted therapy with tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor-antibodies (VEGF) became the standard and prevalent treatment approach for advanced RCC both in front and subsequent lines of therapy (Escudier et al. in Ann Oncol. 25(Suppl 3):iii49-iii56, 2014). A new avenue of immunotherapy utilizing novel strategy to block immune checkpoints has emerged in a new era for RCC treatment (Ascierto et al. in J Transl Med 12:291, 2014). Results from clinical trials are encouraging in both front-line and second-line settings, in a phase III trial (CheckMate 025) nivolumab compared to everolimus improved overall survival in previously treated metastatic RCC who had progressed on prior treatment with targeting agents (Motzer et al. in N Engl J Med 373:1803, 2015). CheckMate 214, a phase III trial, demonstrated superior overall survival and objective response with combined checkpoint inhibitors compared to sunitinib in Treatment-Naïve Advanced RCC among intermediate- and poor-risk group (Motzer et al. in N Engl J Med. 378(14):1277-1290, 2018). In this review, we discuss the systemic Immunotherapy with checkpoint inhibitors that have been approved or are currently being investigated in RCC, clinical experience with these agents, and its future development.

MP72-12 CO-TREATMENT WITH L-METHADONE INCREASES THE EFFICACY OF ANTITUMOR AGENTS IN RENAL CELL CARCINOMA CELLS IN VITRO

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II1 Apr 2018MP72-12 CO-TREATMENT WITH L-METHADONE INCREASES THE EFFICACY OF ANTITUMOR AGENTS IN RENAL CELL CARCINOMA CELLS IN VITRO Birgit Stadlbauer, Heike Pohla, Christian Stief, and Alexander Buchner Birgit StadlbauerBirgit Stadlbauer More articles by this author , Heike PohlaHeike Pohla More articles by this author , Christian StiefChristian Stief More articles by this author , and Alexander BuchnerAlexander Buchner More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2296AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In leukemia and glioblastoma cells, a significant increase of apoptosis rates was observed in vitro under cytostatic therapy by activation of the μ-opioid receptor with methadone. This study investigated the effect of methadone co-treatment in renal cell carcinoma (RCC) cells in the presence of different antitumor agents. METHODS The clear-cell RCC cell line RCC-26 was incubated with different antitumor drugs (doxorubicin, mitoxantrone, axitinib and others). The ratio of cells in apoptosis after 5 days was analyzed using flow cytometry with annexin V-APC and 7AAD double staining. In each setting, the cells were co-incubated with various concentrations of L-methadone and D,L-methadone (0-30μg/ml). The opioid antagonist naloxone served as negative control. Additionally, cell proliferation assays (Cell Titer 96 AQueous One Solution, Promega) and cell migration assays (Automated Cellular Analysis System, MetaVi Labs) were conducted. Furthermore, gene expression analysis including pathway analysis was performed using microarrays (Affymetrix GeneChip Prime View with ca. 49,000 transcripts) to reveal changes in cell biology caused by methadone co-treatment. RESULTS Incubation of RCC-26 cells with 1μM doxorubicin resulted in 32% apoptosis after 5 days. Co-incubation with L-methadone showed a dose-dependent increase of apoptosis rate up to 78% (2.4-fold increase). The effect of D,L-methadone was similar but less pronounced. Control experiments with naloxone instead of methadone showed no influence on the apoptosis rate. Comparable results were achieved with other tumor cell lines, e.g. A172 glioblastoma cells. RCC-26 proliferation was significantly decreased by co-incubation with L-methadone and doxorubicin vs. one of these drugs alone. Cell migration assays showed a complete inhibition of RCC-26 migration by co-incubation with 10ng/ml L-methadone and 1μM doxorubicin. Microarray analysis identified 333 upregulated and 69 downregulated genes (≥2-fold change of expression level, p<0.05) caused by L-methadone in RCC-26 cells. CONCLUSIONS Co-incubation with L-methadone enhances the therapeutic effect of antitumor drugs in renal cell carcinoma cells and in various other tumor cell lines. The increase of the cytostatic effect depends on the combination of cell line and antitumor agent. The combination of L-methadone with certain antitumor drugs might be a promising new approach to increase the therapeutic efficacy in renal cell carcinoma. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e956 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Birgit Stadlbauer More articles by this author Heike Pohla More articles by this author Christian Stief More articles by this author Alexander Buchner More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Adjuvant antiangiogenic agents in post-nephrectomy renal cell carcinoma (RCC): A systematic review and meta-analysis.

689 Background: The role of antiangiogenic agents in advanced RCC is well established. However, it is still not clear whether this benefit can be extrapolated to the adjuvant setting. In this meta-analysis of 3 randomized control trials (RCTs), we sought to determine the efficacy of these agents in RCC patients who underwent nephrectomy with high risk of relapse. Methods: We searched three databases, including Pubmed, Embase, and Cochrane Central Register of Controlled Trials to identify RCTs comparing antiangiogenic agents to placebo in post-nephrectomy RCC patients. We evaluated: 1) the effect of antiangiogenics in highest risk groups as defined by individual studies; 2) the role of each agent separately; and 3) the effect in clear-cell RCC population. Outcomes of interest included overall survival (OS) and disease-free survival (DFS). The overall effect was pooled using the DerSimonian and Laird random effects models Results: Three RCTs (N = 3693 patients) were identified. All studies were comparing placebo to antiangiogenics: sunitinib, sorafenib, and pazopanib. Overall, antiangiogenics did not improve DFS (HR 0.92, 95% CI 0.78 to 1.07) or OS (HR 0.99, 95% CI 0.79 to 1.25). These results persisted when restricting the analysis to patients with clear cell carcinoma and patients with highest risk of relapse. Similarly, sunitinib did not show any improvement in the entire studied group for either DFS (HR 0.89, 95% CI 0.67 to 1.19) or OS (HR 1.11, 95% CI 0.90 to 1.37). In addition, when restricting the analysis to the high risk group, sunitinib did not show any advantage in terms of DFS (HR 0.85, 95% CI 0.67 to 1.07) and OS (HR 1.04, 95% CI 0.83 to 1.31). Conclusions: Based on the available evidence, antiangiogenics do not seem to add an advantage over placebo in terms of OS and DFS in high risk RCC patients after nephrectomy. Further studies are needed to identify the patient population which might derive a benefit from antiangiogenics in the adjuvant setting.

The Role of Compounds Derived from Natural Supplement as Anticancer Agents in Renal Cell Carcinoma: A Review.

Renal Cell Carcinoma (RCC) is the most prominent kidney cancer derived from renal tubules and accounts for roughly 85% of all malignant kidney cancer. Every year, over 60,000 new cases are registered, and about 14,000 people die from RCC. The incidence of this has been increasing significantly in the U.S. and other countries. An increased understanding of molecular biology and the genomics of RCC has uncovered several signaling pathways involved in the progression of this cancer. Significant advances in the treatment of RCC have been reported from agents approved by the Food and Drug Administration (FDA) that target these pathways. These agents have become drugs of choice because they demonstrate clinical benefit and increased survival in patients with metastatic disease. However, the patients eventually relapse and develop resistance to these drugs. To improve outcomes and seek approaches for producing long-term durable remission, the search for more effective therapies and preventative strategies are warranted. Treatment of RCC using natural products is one of these strategies to reduce the incidence. However, recent studies have focused on these chemoprevention agents as anti-cancer therapies given they can inhibit tumor cell grow and lack the severe side effects common to synthetic compounds. This review elaborates on the current understanding of natural products and their mechanisms of action as anti-cancer agents. The present review will provide information for possible use of these products alone or in combination with chemotherapy for the prevention and treatment of RCC.

The Evaluation and Comparing of Cytotoxic Effects of Ferula gummosa Gum, Scutellaria lindbergii, Kelussia odoratissima and Artemisia kopetdaghensis Extracts on ACHN Cell Line.

Renal cell carcinoma (RCC) is one of most fatal cancers. In most patients it is resistant to chemotherapy. Ferula gummosa gum, Scutellaria lindbergii, Kelussia odoratissima, and Artemisia kopetdaghensis are herbs about which there are some cytotoxic activity reports. In this study, cytotoxic and apoptotic activity of these four extracts on RCC cell line (ACHN) were evaluated and compared (ACHN) cells were treated with different concentrations of herbal extracts (15-500 μg/mL). Cell proliferation was determined after 24, 48, and 72 h. by MTT assay. Apoptotic cells were determined using PI staining of DNA fragmentation by flow cytometry. Cell viability decreased with all herbal extracts in ACHN cells by 24, 48, and 72 h. as compared with control. Extracts induced a sub-G1 peak in flow cytometry histogram of treated cells indicating apoptotic cell death is involved in extracts induced-toxicity. Results imply that four herbal extracts inhibit the growth of ACHN cells as a concentration- and time-dependent manner. Also, results show that apoptosis is proposed as the possible mechanism of action. So, four herbal extracts could be considered as good anticancer agents in RCC after further studies.

Abstract 167: Ibrutinib regulates tumor microenvironment and enhances response to everolimus in renal cell carcinoma mouse models

Abstract Introduction: Ibrutinib (ibr), a first-in-class, once-daily, oral inhibitor of Bruton’s tyrosine kinase (BTK), is indicated for the treatment of patients with CLL/SLL, MCL and WM. Ibr also inhibits EGFR/HER2 and has demonstrated efficacy against EGFR+ NSCLC and HER2+ breast cancer in vitro and in xenograft models (Gao 2014; Chen 2016). Further, ibr modulated host immunity and enhanced anti-PD-L1 activity in solid tumor models otherwise insensitive to BTK or HER kinase inhibition (Sagiv-Barfi 2015), suggesting that ibr may be active in renal cell carcinoma (RCC) via multiple mechanisms. Here we determined the impact of ibr alone and in combination with everolimus (eve) on tumor growth and the tumor microenvironment in syngeneic and xenograft RCC mouse models. Methods: Cell proliferation was determined with CellTiter-Glo using a 3-day treatment regimen. Subcutaneous implantation of 786-0 and Renca cells established xenograft and syngeneic models in nude and immune-competent mice. Treatment started when tumor volume reached 150 mm3 (786-0) or 55 mm3 (Renca) and was measured twice weekly. Immunophenotying of tumor infiltrates was determined by flow cytometry. For Treg differentiation, magnetically-sorted CD4+CD25- mouse splenic T cells were stimulated with anti-CD3/CD28 antibodies and TGF-β1 for 5 days. Results: Ibr significantly inhibited the growth of syngeneic Renca tumors (TGI%=32.4 at Day 19, p≤0.05) in Balb/c mice and enhanced the efficacy of eve, although Renca cells were not sensitive to ibr in vitro. The combination significantly reduced the numbers of splenic and tumor Tregs in addition to reducing PD-1 expression on tumor CD8+ T cells. Consistently, in vitro Treg differentiation assays revealed that, while the combination of ibr and eve significantly reduced Treg differentiation, either drug alone showed little effect. In 786-0 xenograft model, ibr alone slowed tumor growth in a subgroup of mice and significantly enhanced the effect of eve (p≤0.05 or 0.01). To identify whether BTK or EGFR/HER2 is the target, CGI-1746, a BTK inhibitor, and lapatinib, an EGFR/HER2 inhibitor, were tested. Surprisingly, both CGI-1746 and lapatinib were active in inhibiting tumor growth (TGI%=26.7 or 37.6 respectively, p≤0.05 or 0.01), and slightly potentiated the efficacy of eve. However, consistent with ibr results, neither CGI-1746 nor lapatinib showed any effect on the cell growth of 786-0 cells. Conclusion: This study suggests that ibr has antitumor activity against RCC alone and when combined with eve in animal models. This effect may be mediated by modulation of the tumor microenvironment, such as inhibiting Treg differentiation and suppressing PD-1 expression on CD8+ T cells, and both BTK and EGFR/HER2 are involved. Further investigation is needed to clarify the mechanism of action, but the results here provide a rationale for ibr as a novel agent for RCC in combination with mTOR inhibitors. Citation Format: Jun Chen, Chun-Te Chen, Jing Liu, Jeff Hsu, Taisei Kinoshita, Betty Y. Chang. Ibrutinib regulates tumor microenvironment and enhances response to everolimus in renal cell carcinoma mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 167. doi:10.1158/1538-7445.AM2017-167