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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long noncoding RNAs (lncRNA) have recently emerged as important regulators in cancer cell proliferation and metastasis. However, the role of lncRNAs in metastatic clear cell renal cell carcinoma (ccRCC) remains unclear. Here, single-cell RNA sequencing data were analyzed from primary renal cell carcinoma and paired metastatic renal cell carcinoma specimens, and characterized the expression profiles of over 10,000 genes, including 1,874 lncRNAs. Further analysis revealed that lncRNAs exhibit cancer type- and tissue-specific expression across ccRCC cells. Interestingly, a number of lncRNAs (n = 173) associated with ccRCC metastasis, termed ccRCC metastasis-associated lncRNAs (CMAL). Moreover, functional analysis based on a CMAL-PCG coexpression network revealed that CMALs contribute to cell adhesion, immune response, and cell proliferation. In combination with survival analysis, 12 CMALs were identified that participate in TNF and hypoxia-inducible factor 1 signaling to promote ccRCC metastasis. Further investigation on intratumoral heterogeneity showed that some CMALs are selectively expressed in different subpopulations. IMPLICATIONS: To explore ccRCC metastasis, the current study performed a global dissection of lncRNAs and a complex genomic analysis of ccRCC tumor heterogeneity. The data shed light on the discovery of potential lncRNA biomarkers and lncRNA therapeutic targets.
Mol Cancer Res 2018 12
PMID:Dissecting LncRNA Roles in Renal Cell Carcinoma Metastasis and Characterizing Genomic Heterogeneity by Single-Cell RNA-seq. 3008 82

Metastatic renal cell carcinoma (mRCC) is a disease that portends poor prognosis despite an increasing number of novel systemic treatment options including new targeted therapies and immunotherapy. Ablative intervention directed at oligometastatic RCC has demonstrated survival benefit. Consequently, developing techniques for improved staging of mRCC on contemporary imaging modalities including X-ray computed tomography (CT), magnetic resonance imaging (MRI) and/or bone scan (BS) is a clinical priority. This is relevant for metastatic deposits too small to characterize or lymph nodes within physiological normality. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein highly expressed on prostate cancer epithelial cells. Recently, small molecules targeting the PSMA receptor, linked to radioactive isotopes have been developed for use with positron emission tomography (PET). Despite its nomenclature, PSMA has also been found to be expressed in the neovasculature of non-prostate cancers such as renal cell carcinoma (RCC) and hence PSMA PET/CT imaging has been proposed as an alternative staging modality. Preliminary small studies involving the use of PSMA PET/CT imaging in mRCC have been encouraging with evidence of improved staging sensitivity which has directly led to change in management in some cases. Given these early encouraging reports, we performed a comprehensive narrative review on the available evidence, including the scientific basis for PSMA expression in RCC, the role of PSMA PET/CT imaging with potential clinical implications in mRCC, its limitations and future opportunities.
Mol Imaging Biol 2019 10
PMID:A Review of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) in Renal Cell Carcinoma (RCC). 3061 28

The aim of the present study was to investigate the impact of metastatic sites and early tumor shrinkage (eTS) as prognostic predictive factors of metastatic renal cell carcinoma (mRCC) in molecular targeted therapy. A total of 209 advanced RCC cases treated with sorafenib, sunitinib, axitinib, pazopanib, temsirolimus and everolimus from our single institution were included in the present study. Several known prognostic predictive factors, including metastatic sites and the rate of eTS, were analyzed by Kaplan-Meier survival estimate analysis followed by Cox's proportional hazards model analysis. eTS was measured by three independent physicians. Four metastatic sites in the liver, bone, lymph nodes and brain as well as greater eTS were identified as potential independent predictors of overall survival (OS) in several cohorts: i) Metastatic RCC (n=194); ii) metastatic clear cell RCC (n=119); and iii) mRCC patients with eTS data (n=127). In sub-analyses of patients treated with each 1st line tyrosine kinase inhibitor, eTS was identified as a potentially potent predictor of OS in patients treated with axitinib. The liver, bone, lymph nodes, brain metastases and eTS were identified as independent predictive factors of OS by analyzing a limited Japanese cohort.
Mol Clin Oncol 2019 Jan
PMID:Early tumor shrinkage as a predictive factor of metastatic renal cell carcinoma in molecular targeted therapy: A single institutional study. 3065 87

Renal cell carcinoma encompass distinct diseases with different pathologic features and distinct molecular pathways. Immune checkpoint inhibitors targeting the programmed death receptor ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) pathway alone or in combination have greatly changed clinical management of metastatic renal cell carcinoma, now competing with antiangiogenic drugs in monotherapy for first-line treatment. However, long-term response rates are low, and biomarkers are needed to predict treatment response. Quantification of PD-L1 expression by immunohistochemistry was developed as a promising biomarker in clinical trials, but with many limitations (different antibodies, tumour heterogeneity, specimens, and different thresholds of positivity). Other biomarkers, including tumour mutational burden and molecular signatures, are also developed and discussed in this review.
Int J Mol Sci 2019 Apr 04
PMID:Targeting the PD-1/PD-L1 Pathway in Renal Cell Carcinoma. 3098 68

Immunotherapy has changed the therapeutic scenario of metastatic renal cell carcinoma (mRCC), however the evaluation of disease response to immune-checkpoint inhibitors is still an open challenge. Response evaluation criteria in solid tumors (RECIST) 1.1 criteria are the cornerstone of response assessment to anti-neoplastic treatments, but the use of anti-programmed death receptor 1 (PD1) and other immunotherapeutic agents has shown atypical patterns of response such as pseudoprogression. Therefore, immune-modified criteria have been developed in order to more accurately categorize the disease response, even though their use in the everyday clinical practice is still limited. In this review we summarize the available evidence on this topic, with particular focus on the application of immune-modified criteria in the setting of mRCC.
Int J Mol Sci 2019 Aug 30
PMID:The Evaluation of Response to Immunotherapy in Metastatic Renal Cell Carcinoma: Open Challenges in the Clinical Practice. 3148 Mar 48

Introduction: In recent years, the treatment landscape of metastatic renal cell carcinoma (mRCC) has been improved using immune-checkpoint inhibitors (ICI). Nevertheless, the number of patients experiencing clinical benefit from immunotherapy is still limited, while others obtain more benefit from tyrosine kinase inhibitors (TKI). The identification of prognostic and predictive factors would be crucial to better select patients most likely to benefit from immunotherapy among the other potentially available therapeutic options.Areas covered: This systematic review summarizes the current knowledge (2010-2019) on molecular prognostic and predictive biomarkers, assessed in peripheral blood and/or from tumor tissue, in mRCC patients treated with ICI.Expert opinion: Among all the biomarkers analyzed, PD-L1 expression on tumor tissue is the most studied. It has an unfavorable prognostic role for patients treated with TKI, which seems to be overcome by ICI-based combinations. Nevertheless, no clear predictive role of immunotherapy efficacy has been observed for PD-L1 in mRCC. Emerging evidence regarding pro-angiogenic or pro-immunogenic genomic and transcriptomic signatures suggests a potential predictive role in patients treated with ICI-based combinations. The rationale for TKI-ICI combinations is based on tumor microenvironment and genomic background, which represent the target of these two main therapeutic options for mRCC.
Expert Rev Mol Diagn 2020 02
PMID:Prognostic and predictive molecular biomarkers in metastatic renal cell carcinoma patients treated with immune checkpoint inhibitors: a systematic review. 3160 27

Third-line sunitinib is occasionally used for selected patients with metastatic renal cell carcinoma (mRCC). The aim of the present study was to evaluate the clinical significance of third-line sunitinib after failure of first-line cytokine therapy and second-line sorafenib in patients with clear-cell mRCC. A total of 14 consecutive patients with clear-cell mRCC treated with third-line sunitinib between December 2008 and February 2012 were enrolled in the present study. Disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and relative dose intensity (RDI) were compared with those of first-line (n=20) and second-line (n=14) sunitinib treatment. The DCR was 42.9%, the median PFS was 12.0 months, and the median OS was 20.0 months for third-line sunitinib; there were no statistically significant differences compared with first-line and second-line sunitinib. The mean RDI was significantly lower for third-line sunitinib compared with first- and second-line sunitinib (P=0.0003 and 0.0109, respectively). Therefore, third-line sunitinib is an effective treatment option for selected patients with mRCC, as optimized therapeutic efficacy was obtained with a relatively low dose of sunitinib.
Mol Clin Oncol 2019 Nov
PMID:Outcome of third-line sunitinib after sequential therapy with cytokines and sorafenib in metastatic renal cell carcinoma. 3161 62

We previously showed that alterations in mTOR pathway genes were correlated with response to rapalog therapy in metastatic renal cell carcinoma (mRCC), when the analysis focused on extremes of response. Herein, we expand on the prior cohort and examine genetic correlations with rapalog response in a dataset not selected for extremes of response. Tumors from 58 patients from the phase III trial of temsirolimus and 51 local patients with mRCC treated with rapalogs were studied. Somatic mutations were investigated using a targeted sequencing platform covering 27 genes. Clinical benefit (CB) was defined as patients with complete remission, partial response, or stable disease lasting at least 22 weeks. Mutational analyses focused on 5 mTOR pathway genes (TSC1, TSC2, MTOR, PTEN, PIK3CA) and 6 genes commonly mutated in RCC (BAP1, KDM5C, PBRM1 SETD2, TP53, and VHL). Among the 109 patients, 93 (85%) patients had clear cell histology, and 31 (28%) showed CB. Nine of 30 (30%) patients harboring mTOR pathway mutations in their tumor achieved CB versus 22 of 79 (28%) in the wild-type group. There was no distinct association between any individual or combination of mTOR pathway gene mutations and CB. Three of 7 patients with TSC1 mutations showed CB. In addition, none of the 6 genes commonly mutated in RCC showed a mutation pattern that correlated with CB. Overall, in this large and diverse population of patients with mRCC, there is no suggestion of a correlation between response to rapalog therapy and mutation status for mTOR pathway genes.
Mol Cancer Ther 2020 02
PMID:Mutations and Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma. 3165 62

The treatment landscape for metastatic renal cell carcinoma (mRCC) and urothelial carcinoma (mUC) has evolved rapidly in recent years with the approval of several checkpoint inhibitors. Despite these advances, survival rates for metastatic disease remain poor, and additional strategies will be needed to improve the efficacy of checkpoint inhibitors. Combining anti-VEGF/VEGFR agents with checkpoint inhibitors has emerged as a potential strategy to advance the immunotherapy paradigm, because VEGF inhibitors have immunomodulatory potential. Cabozantinib is a tyrosine kinase inhibitor (TKI) whose targets include MET, AXL, and VEGFR2. Cabozantinib has a unique immunomodulatory profile and has demonstrated clinical efficacy as a monotherapy in mRCC and mUC, making it a potentially suitable partner for checkpoint inhibitor therapy. In this review, we summarize the current status of immunotherapy for mRCC and mUC and discuss the development of immunotherapy-TKI combinations, with a focus on cabozantinib. We discuss the rationale for such combinations based on our growing understanding of the tumor microenvironment, and we review in detail the preclinical and clinical studies supporting their use.
Mol Cancer Ther 2019 12
PMID:Cabozantinib in Combination with Immunotherapy for Advanced Renal Cell Carcinoma and Urothelial Carcinoma: Rationale and Clinical Evidence. 3179 25

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.
Int J Mol Sci 2019 Dec 14
PMID:Cadmium and Lead Decrease Cell-Cell Aggregation and Increase Migration and Invasion in Renca Mouse Renal Cell Carcinoma Cells. 3184 10


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