Sorafenib in Advanced Clear-Cell Renal-Cell Carcinoma

Escudier, Bernard; Eisen, Tim; Stadler, Walter M.; Szczylik, Cezary; Oudard, Stéphane; Siebels, M.; Négrier, Sylvie; Chevreau, Christine; Solska, E; Desai, Apurva A.; Rolland, Frédéric; Demkow, Tomasz; Hutson, Thomas E.; Gore, Martin; Freeman, Scott; Schwartz, Brian; Shan, Minghua; Simantov, Ronit; Bukowski, Ronald M.

doi:10.1056/nejmoa060655

Cited by 4,475 publications

(3,241 citation statements)

References 19 publications

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“…If such vascular subtleties are not recapitulated in transplant tumor models representing a particular organ‐specific cancer, then targeted antiangiogenic drugs may fail to accurately demonstrate their effects and limitations. Additionally, there is clinical evidence for intrinsic resistance (Bergers and Hanahan, 2008) to pharmacological inhibition of the predominant VEGF signaling pathway, seen for example in the progression‐free and overall survival plots of renal cancer patients receiving the VEGF pathway inhibitors bevacizumab (Yang et al., 2003), sunitinib (Motzer et al., 2007) and sorafenib (Escudier et al., 2007), wherein some ostensibly similar patients do not respond at all to the antiangiogenic therapy, and rather continue progressing, apparently refractory to the anti‐angiogenic therapies (Albiges et al., 2011; Garcia et al., 2010; Rini et al., 2008). …”

Section: Variability and Dynamics Of Stromal Cell Componentsmentioning

confidence: 99%

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

2012

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It is a time of great promise and expectation for the applications of knowledge about mechanisms of cancer toward more effective and enduring therapies for human disease. Conceptualizations such as the hallmarks of cancer are providing an organizing principle with which to distill and rationalize the abject complexities of cancer phenotypes and genotypes across the spectrum of the human disease. A countervailing reality, however, involves the variable and often transitory responses to most mechanism‐based targeted therapies, returning full circle to the complexity, arguing that the unique biology and genetics of a patient's tumor will in the future necessarily need to be incorporated into the decisions about optimal treatment strategies, the frontier of personalized cancer medicine. This perspective highlights considerations, metrics, and methods that may prove instrumental in charting the landscape of evaluating individual tumors so to better inform diagnosis, prognosis, and therapy. Integral to the consideration is remarkable heterogeneity and variability, evidently embedded in cancer cells, but likely also in the cell types composing the supportive and interactive stroma of the tumor microenvironment (e.g., leukocytes and fibroblasts), whose diversity in form, regulation, function, and abundance may prove to rival that of the cancer cells themselves. By comprehensively interrogating both parenchyma and stroma of patients' cancers with a suite of parametric tools, the promise of mechanism‐based therapy may truly be realized.

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Section: Variability and Dynamics Of Stromal Cell Componentsmentioning

confidence: 99%

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

2012

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“…Common side effects of Sor are cutaneous like hand–foot syndrome or rash and gastrointestinal like diarrhoea or nausea, as well as alopecia and fatigue. These side effects limit the patient's ability to receive full‐dose Sor treatment 18, 19…”

Section: Introductionmentioning

confidence: 99%

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Toledo

Penna

Oliva

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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BackgroundThe effectiveness of drugs aimed at counteracting cancer cachexia is generally tested in pre‐clinical rodent models, where only the tumour‐induced alterations are taken into account, excluding the co‐presence of anti‐tumour molecules that could worsen the scenario and/or interfere with the treatment.MethodsThe aim of the present investigation has been to assess the efficacy of a multifactorial treatment, including formoterol and megestrol acetate, in cachectic tumour‐bearing rats (Yoshida AH‐130, a highly cachectic tumour) undergoing chemotherapy (sorafenib).ResultsTreatment of cachectic tumour‐bearing rats with sorafenib (90 mg/kg) causes an important decrease in tumour cell content due to both reduced cell proliferation and increased apoptosis. As a consequence, animal survival significantly improves, while cachexia occurrence persists. Multi‐factorial treatment using both formoterol and megestrol acetate is highly effective in preventing muscle wasting and has more powerful effects than the single formoterol administration. In addition, both physical activity and grip strength are significantly improved as compared with the untreated tumour‐bearing animals. The effects of the multi‐factorial treatment include increased food intake (likely due to megestrol acetate) and decreased protein degradation, as shown by the reduced expression of genes associated with both proteasome and calpain proteolytic systems.ConclusionsThe combination of the two drugs proved to be a promising strategy for treating cancer cachexia in a pre‐clinical setting that better resembles the human condition, thus providing a strong rationale for the use of such combination in clinical trials involving cachectic cancer patients.

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“…Surgical resection is curative for most localized RCCs, but in cases of metastatic or recurrent disease conventional therapies including chemotherapy, radiotherapy and immunotherapy have generally had only limited success in a small proportion of patients. Recently, sorafenib and sunitinib, two orally delivered multitargeted receptor tyrosine kinase inhibitors, were approved as a new treatment for advanced RCC (Escudier et al, 2007;Motzer et al, 2007). Studies of such agents encourage the use of new targeted therapies to improve outcomes for patients with RCC.…”

Section: Introductionmentioning

confidence: 99%

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

et al. 2008

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The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P ¼ 0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P ¼ 0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of b-catenin. Knockdown of CXXC4 induced the nuclear translocation of b-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

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Sorafenib in Advanced Clear-Cell Renal-Cell Carcinoma

Cited by 4,475 publications

References 19 publications

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

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