Fibroblast Growth Factor Receptor 1 as a Target for the Therapy of Renal Cell Carcinoma

Tsimafeyeu, Ilya; Bratslavsky, Gennady

doi:10.1159/000370118

Cited by 13 publications

(7 citation statements)

References 69 publications

(48 reference statements)

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“…The distinctive kinase inhibition profile of lenvatinib, specifically its inhibitory activity against FGFRs, may enable it to overcome FGF‐mediated escape mechanisms from VEGF signaling inhibition, and likely, at least partially, underlies the clinical efficacy of the combination of lenvatinib plus everolimus seen in patients with mRCC. Both FGFR1 and FGFR2 are overexpressed in mRCC, and FGF signaling in RCC tumor cells is also associated with malignancy and intrinsic resistance to VEGFR inhibition . The combined targeting of the FGFR and mTOR pathways in RCC tumor cells may also be another mechanism underlying the observed clinical activity of the lenvatinib plus everolimus combination (Fig.…”

Section: Discussionmentioning

confidence: 99%

Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus

et al. 2017

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The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, plus everolimus, a mammalian target of rapamycin (mTOR) inhibitor, significantly improved clinical outcomes versus everolimus monotherapy in a phase II clinical study of metastatic renal cell carcinoma (RCC). We investigated potential mechanisms underlying the antitumor activity of the combination treatment in preclinical RCC models. Lenvatinib plus everolimus showed greater antitumor activity than either monotherapy in three human RCC xenograft mouse models (A‐498, Caki‐1, and Caki‐2). In particular, the combination led to tumor regression in the A‐498 and Caki‐1 models. In the A‐498 model, everolimus showed antiproliferative activity, whereas lenvatinib showed anti‐angiogenic effects. The anti‐angiogenic activity was potentiated by the lenvatinib plus everolimus combination in Caki‐1 xenografts, in which fibroblast growth factor (FGF)‐driven angiogenesis may contribute to tumor growth. The combination showed mostly additive activity in vascular endothelial growth factor (VEGF)‐activated, and synergistic activity against FGF‐activated endothelial cells, in cell proliferation and tube formation assays, as well as strongly suppressed mTOR‐S6K‐S6 signaling. Enhanced antitumor activities of the combination versus each monotherapy were also observed in mice bearing human pancreatic KP‐1 xenografts overexpressing VEGF or FGF. Our results indicated that simultaneous targeting of tumor cell growth and angiogenesis by lenvatinib plus everolimus resulted in enhanced antitumor activity. The enhanced inhibition of both VEGF and FGF signaling pathways by the combination underlies its superior anti‐angiogenic activity in human RCC xenograft models.

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Section: Discussionmentioning

confidence: 99%

Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus

et al. 2017

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“…Results included well-established mechanisms of tumorigenesis in ccRCC such as cellular response to hypoxia as well as epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor signaling pathways. [18][19][20][21][22][23][24] Additionally, besides involvement of several growth factor receptor pathways, extracellular matrix organization was found in 72.7% of all malignant specimens and was often accompanied by collagen catabolism and positive regulation of cellular motility, all of which are involved in promoting metastasis. For HLA class I, platelet degranulation was also considered as a tumorigenic process leading to pro-angiogenic signaling, as shown for ovarian cancer.…”

Section: Lc-ms/ms Identifies a High Amount Of Naturally Presented Hlamentioning

confidence: 99%

“…They include the cellular response to hypoxia, epidermal growth factor receptor, platelet-derived growth factor, and fibroblast growth factor receptor signaling pathways. [18][19][20][21][22][23][24] Therefore, we provided first-time evidence that key proteins representing the carcinogenesis of RCC give rise to MHC-binding peptides and are therefore targetable by the adaptive specific T cell response.…”

Section: Introductionmentioning

confidence: 99%

Carcinogenesis of renal cell carcinoma reflected in HLA ligands: A novel approach for synergistic peptide vaccination design

et al. 2016

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Despite recent advances in immunotherapy of renal cell carcinoma (RCC), peptide vaccination strategies still lack an approach for personalized peptide vaccination that takes intra-and inter-tumoral heterogeneity and biological characteristics into account. In this study, we use an immunoprecipitation and mass spectrometry-based approach supplemented by network analysis of HLA ligands to target this goal. By analyzing HLA-presented peptides for HLA class I and II of 11 malignant and 6 non-malignant kidney tissue samples, more than 2,700 peptides and 1,600 corresponding source proteins were identified.

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“…These proteins are key players in cell proliferation, differentiation, and signaling pathways and have critical involvement in developmental processes. In addition, these proteins are also considered as potential targets for designing therapies against RCC1213.…”

Section: Resultsmentioning

confidence: 99%

Gene expression-based biomarkers for discriminating early and late stage of clear cell renal cancer

Bhalla

Chaudhary

Kumar

et al. 2017

Sci Rep

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In this study, an attempt has been made to identify expression-based gene biomarkers that can discriminate early and late stage of clear cell renal cell carcinoma (ccRCC) patients. We have analyzed the gene expression of 523 samples to identify genes that are differentially expressed in the early and late stage of ccRCC. First, a threshold-based method has been developed, which attained a maximum accuracy of 71.12% with ROC 0.67 using single gene NR3C2. To improve the performance of threshold-based method, we combined two or more genes and achieved maximum accuracy of 70.19% with ROC of 0.74 using eight genes on the validation dataset. These eight genes include four underexpressed (NR3C2, ENAM, DNASE1L3, FRMPD2) and four overexpressed (PLEKHA9, MAP6D1, SMPD4, C11orf73) genes in the late stage of ccRCC. Second, models were developed using state-of-art techniques and achieved maximum accuracy of 72.64% and 0.81 ROC using 64 genes on validation dataset. Similar accuracy was obtained on 38 genes selected from subset of genes, involved in cancer hallmark biological processes. Our analysis further implied a need to develop gender-specific models for stage classification. A web server, CancerCSP, has been developed to predict stage of ccRCC using gene expression data derived from RNAseq experiments.

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Fibroblast Growth Factor Receptor 1 as a Target for the Therapy of Renal Cell Carcinoma

Cited by 13 publications

References 69 publications

Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus

Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus

Carcinogenesis of renal cell carcinoma reflected in HLA ligands: A novel approach for synergistic peptide vaccination design

Gene expression-based biomarkers for discriminating early and late stage of clear cell renal cancer

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