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GLI2 expression levels in radical nephrectomy specimens as a predictor of disease progression in patients with metastatic clear cell renal cell carcinoma following treatment with sunitinib

View Article: PubMed Central - PubMed

ABSTRACT

The aim of the present study was to investigate the role of the Hedgehog signaling pathway in the progression of metastatic clear cell renal cell carcinoma (m-ccRCC) as well as the molecular targets of sunitinib, an inhibitor of multiple tyrosine kinases. A total of 39 patients subjected to radical nephrectomy who were diagnosed with m-ccRCC and were subsequently treated with sunitinib were enrolled in the present study. The expression levels of the Hedgehog signaling proteins (GLI1, GLI2, cyclin D1, cyclin E and transforming growth factor-β) and major molecular targets of sunitinib [vascular endothelial growth factor receptor (VEGFR)-1 and −2, and platelet-derived growth factor receptor-α and -β] in primary RCC specimens were assessed by immunohistochemical staining. The expression levels of GLI2, VEGFR-1, VEGFR-2 and pre-treatment C-reactive protein as well as the Memorial Sloan-Kettering Cancer Center risk were identified as significant predictors of progression-free survival (PFS). Of these, only GLI2 expression was independently correlated to PFS according to multivariate analysis. Furthermore, treatment with sunitinib resulted in a marked inhibition of GLI2 expression in the parental human RCC ACHN cell line, but not in ACHN cells with acquired resistance to sunitinib. These findings suggested that GLI2 may be involved in the acquisition of resistance to sunitinib in RCC; thus, it may be useful to consider the expression levels of GLI2 in addition to conventional prognostic parameters when selecting m-ccRCC patients likely to benefit from treatment with sunitinib.

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Progression-free survival of the 39 patients with metastatic clear cell renal cell carcinoma treated with sunitinib.
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f1-mco-0-0-950: Progression-free survival of the 39 patients with metastatic clear cell renal cell carcinoma treated with sunitinib.

Mentions: During the follow-up period of 15.1 months from the initiation of sunitinib treatment, 26 patients (66.7%) showed disease progression and the median duration of PFS was 13.2 months. As shown in Fig. 1, the 1- and 2-year PFS rates were 55.5 and 31.0%, respectively. To identify parameters associated with PFS in m-ccRCC patients treated with sunitinib, uni- and multivariate analyses were performed using the Cox proportional hazard regression model. Of the 9 molecular markers analyzed in the present study, the expression levels of GLI2, VEGFR1 and VEGFR2 were identified as significant predictors of PFS by univariate analysis (Table II). In Fig. 2, the PFS curves according to the expression status of GLI2, VEGFR1 and VEGFR2 are presented in addition to the representative immunohistochemical images for the expression levels of these molecular markers. In addition to these molecular markers, the MSKCC and baseline C-reactive protein (CRP) levels were also significantly correlated with PFS among several conventional factors examined. Furthermore, multivariate analysis of these 5 significant predictors of PFS on univariate analysis revealed that only the expression status of GLI2 was independently correlated with the other factors included (Table II).


GLI2 expression levels in radical nephrectomy specimens as a predictor of disease progression in patients with metastatic clear cell renal cell carcinoma following treatment with sunitinib
Progression-free survival of the 39 patients with metastatic clear cell renal cell carcinoma treated with sunitinib.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4998152&req=5

f1-mco-0-0-950: Progression-free survival of the 39 patients with metastatic clear cell renal cell carcinoma treated with sunitinib.
Mentions: During the follow-up period of 15.1 months from the initiation of sunitinib treatment, 26 patients (66.7%) showed disease progression and the median duration of PFS was 13.2 months. As shown in Fig. 1, the 1- and 2-year PFS rates were 55.5 and 31.0%, respectively. To identify parameters associated with PFS in m-ccRCC patients treated with sunitinib, uni- and multivariate analyses were performed using the Cox proportional hazard regression model. Of the 9 molecular markers analyzed in the present study, the expression levels of GLI2, VEGFR1 and VEGFR2 were identified as significant predictors of PFS by univariate analysis (Table II). In Fig. 2, the PFS curves according to the expression status of GLI2, VEGFR1 and VEGFR2 are presented in addition to the representative immunohistochemical images for the expression levels of these molecular markers. In addition to these molecular markers, the MSKCC and baseline C-reactive protein (CRP) levels were also significantly correlated with PFS among several conventional factors examined. Furthermore, multivariate analysis of these 5 significant predictors of PFS on univariate analysis revealed that only the expression status of GLI2 was independently correlated with the other factors included (Table II).

View Article: PubMed Central - PubMed

ABSTRACT

The aim of the present study was to investigate the role of the Hedgehog signaling pathway in the progression of metastatic clear cell renal cell carcinoma (m-ccRCC) as well as the molecular targets of sunitinib, an inhibitor of multiple tyrosine kinases. A total of 39 patients subjected to radical nephrectomy who were diagnosed with m-ccRCC and were subsequently treated with sunitinib were enrolled in the present study. The expression levels of the Hedgehog signaling proteins (GLI1, GLI2, cyclin D1, cyclin E and transforming growth factor-β) and major molecular targets of sunitinib [vascular endothelial growth factor receptor (VEGFR)-1 and −2, and platelet-derived growth factor receptor-α and -β] in primary RCC specimens were assessed by immunohistochemical staining. The expression levels of GLI2, VEGFR-1, VEGFR-2 and pre-treatment C-reactive protein as well as the Memorial Sloan-Kettering Cancer Center risk were identified as significant predictors of progression-free survival (PFS). Of these, only GLI2 expression was independently correlated to PFS according to multivariate analysis. Furthermore, treatment with sunitinib resulted in a marked inhibition of GLI2 expression in the parental human RCC ACHN cell line, but not in ACHN cells with acquired resistance to sunitinib. These findings suggested that GLI2 may be involved in the acquisition of resistance to sunitinib in RCC; thus, it may be useful to consider the expression levels of GLI2 in addition to conventional prognostic parameters when selecting m-ccRCC patients likely to benefit from treatment with sunitinib.

No MeSH data available.


Related in: MedlinePlus