Severe clinical toxicities are correlated with survival in patients with advanced renal cell carcinoma treated with sunitinib and sorafenib

Fiore, Frédéric Di; Rigal, Olivier; Ménager, C.; Michel, Pierre; Pfister, Christian

doi:10.1038/bjc.2011.507

Cited by 47 publications

(31 citation statements)

References 13 publications

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“…2,7 Previous studies showed that some of these AEs have predictive value for the efficacy of sunitinib treatment. [8][9][10] The aim of this retrospective study was to systematically analyze the relationship between treatment efficacy and AEs, including the correlations with on-or off-target and the total number of AEs with treatment outcome.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Survival: A New Phenomenon Connected to Adverse Events of First-Line Sunitinib Treatment in Advanced Renal Cell Carcinoma

Nagyiványi

Budai

Bíró

et al. 2016

Clinical Genitourinary Cancer

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Section: Introductionmentioning

confidence: 99%

Synergistic Survival: A New Phenomenon Connected to Adverse Events of First-Line Sunitinib Treatment in Advanced Renal Cell Carcinoma

Nagyiványi

Budai

Bíró

et al. 2016

Clinical Genitourinary Cancer

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“…Severe adverse events of Grades 3 and 4 have been shown to be associated with survival in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib and sorafenib, categorized as multitargeted tyrosine kinase inhibitors (1). In particular, hypertension (HT), which is one of the common adverse events associated with sunitinib, was shown to be associated with the clinical outcome in patients with mRCC treated with this drug (2).…”

Section: Introductionmentioning

confidence: 99%

Hand-Foot Skin Reaction is Associated with the Clinical Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Sorafenib

Nakano

Kono

Kubo

et al. 2013

Japanese Journal of Clinical Oncology

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Background: To elucidate whether Hand -Foot skin reaction could become a biomarker of clinical outcome in patients with metastatic renal cell carcinoma treated with sorafenib, we retrospectively examined the association between the Hand -Foot skin reaction and the clinical outcome in metastatic renal cell carcinoma patients treated with sorafenib. Methods: Thirty-six Japanese metastatic renal cell carcinoma patients treated with sorafenib were enrolled and divided into the groups with or without Hand -Foot skin reaction. Patient characteristics, best tumor response, progression-free survival and adverse events were investigated and compared between these two groups. Results: A sorafenib-induced Hand -Foot skin reaction in metastatic renal cell carcinoma patients was observed at a significantly higher rate in patients in the favorable-risk group in the Memorial Sloan-Kettering Cancer Center risk classification, and with Eastern Cooperative Oncology Group Performance Status of one or less, prior nephrectomy, higher hemoglobin, lower lactate dehydrogenase and lower C-reactive protein. The mean best tumor response was significantly better in the group with Hand -Foot skin reaction (216.7%) than that in the group without it (17.9%; P , 0.001). The median progression-free survival was significantly longer in the group with Hand -Foot skin reaction (4.6 months) than that in the group without it (1.5 months; P ¼ 0.002). In multivariate analysis, only Hand -Foot skin reaction was shown to be a predictive factor of progression-free survival (hazard ratio 0.312, P ¼ 0.010). Conclusions: A sorafenib-induced Hand -Foot skin reaction in metastatic renal cell carcinoma patients emerged at a significantly higher rate in patients in the favorable-risk group in the Memorial Sloan-Kettering Cancer Center risk classification and was significantly associated with best tumor response and progression-free survival, suggesting that Hand -Foot skin reaction might be an independent predictive factor for clinical outcome in metastatic renal cell carcinoma patients treated with sorafenib.

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“…In some cells, 24 h might be enough to sufficiently reduce Mcl-1 protein levels such that ABT alone can induce apoptosis. In these scenarios, however, there is likely to be a trade-off between drug efficacy and toxicity [31]. …”

Section: Discussionmentioning

confidence: 99%

VHL-deficient renal cancer cells gain resistance to mitochondria-activating apoptosis inducers by activating AKT through the IGF1R-PI3K pathway

2016

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We previously developed (2-deoxyglucose)-(ABT-263) combination therapy (2DG-ABT), which induces apoptosis by activating Bak in the mitochondria of highly glycolytic cells with varied genetic backgrounds. However, the rates of apoptosis induced by 2DG-ABT were lower in von Hippel-Lindau (VHL)-deficient cancer cells. The re-expression of VHL protein in these cells lowered IGF1R expression in a manner independent of oxygen concentration. Lowering IGF1R expression via small interfering RNA (siRNA) sensitized the cells to 2DG-ABT, suggesting that IGF1R interfered with the activation of apoptosis by the mitochondria. To determine which of the two pathways activated by IGF1R, the Ras-ERK pathway or the PI3K-AKT pathway, was involved in the impairment of mitochondria activation, the cells were treated with a specific inhibitor of either PI3K or ERK, and 2DG-ABT was added to activate the mitochondria. The apoptotic rates resulting from 2DG-ABT treatment were higher in the cells treated with the PI3K inhibitor, while the rates remained approximately the same in the cells treated with the ERK inhibitor. In 2DG-ABT-sensitive cells, a 4-h 2DG treatment caused the dissociation of Mcl-1 from Bak, while ABT treatment alone caused the dissociation of Bcl-xL from Bak without substantially reducing Mcl-1 levels. In 2DG-ABT-resistant cells, Mcl-1 dissociated from Bak only when AKT activity was inhibited during the 4-h 2DG treatment. Thus, in VHL-deficient cells, IGF1R activated AKT and stabilized the Bak-Mcl-1 complex, thereby conferring cell resistance to apoptosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-016-5260-2) contains supplementary material, which is available to authorized users.

show abstract

Severe clinical toxicities are correlated with survival in patients with advanced renal cell carcinoma treated with sunitinib and sorafenib

Cited by 47 publications

References 13 publications

Synergistic Survival: A New Phenomenon Connected to Adverse Events of First-Line Sunitinib Treatment in Advanced Renal Cell Carcinoma

Synergistic Survival: A New Phenomenon Connected to Adverse Events of First-Line Sunitinib Treatment in Advanced Renal Cell Carcinoma

Hand-Foot Skin Reaction is Associated with the Clinical Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Sorafenib

VHL-deficient renal cancer cells gain resistance to mitochondria-activating apoptosis inducers by activating AKT through the IGF1R-PI3K pathway

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