Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma

Motzer, Robert J.; Hutson, Thomas E.; Tomczak, Piotr; Michaelson, M. Dror; Bukowski, Ronald M.; Rixe, Olivier; Oudard, Stéphane; Négrier, Sylvie; Szczylik, Cezary; Kim, Sindy T.; Chen, Isan; Bycott, Paul; Baum, Charles M.; Figlin, Robert A.

doi:10.1056/nejmoa065044

Cited by 5,350 publications

(4,187 citation statements)

References 29 publications

Supporting

106

Mentioning

3,811

Contrasting

Unclassified

161

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

Section: Variability and Dynamics Of Stromal Cell Componentsmentioning

confidence: 99%

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

2012

View full text Add to dashboard Cite

show abstract

“…These drugs are particularly effective in VEGF-driven tumours such as clear-cell renal cancer. Indeed sunitinib monotherapy doubles progression-free survival and extends overall survival in this disease and is now standard first-line therapy (Motzer et al, 2007(Motzer et al, , 2009. Despite these impressive results, variation in response between individuals occurs and, more importantly, resistance to therapy invariably develops (Motzer et al, 2009;Rini and Atkins, 2009).…”

Section: Introductionmentioning

confidence: 99%

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

et al. 2010

View full text Add to dashboard Cite

The vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor sunitinib has been approved for first-line treatment of patients with metastatic renal cancer and is currently being trialled in other cancers. However, the effectiveness of this anti-angiogenic agent is limited by the presence of innate and acquired drug resistance. By screening a panel of candidate growth factors we identified fibroblast growth factor 2 (FGF2) as a potent regulator of endothelial cell sensitivity to sunitinib. We show that FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib and that FGF2 can suppress sunitinib-induced retraction of tubules. Importantly, these effects of FGF2 were ablated by PD173074, a small molecule inhibitor of FGF receptor signalling. We also show that FGF2 can stimulate pro-angiogenic signalling pathways in endothelial cells despite the presence of sunitinib. Finally, analysis of clinical renal-cancer samples demonstrates that a large proportion of renal cancers strongly express FGF2. We suggest that therapeutic strategies designed to simultaneously target both VEGF and FGF2 signalling may prove more efficacious than sunitinib in renal cancer patients whose tumours express FGF2.

show abstract

“…Results in randomised studies in renal cell carcinoma with the broadspectrum TKIs sunitinib and sorafenib have resulted in their regulatory approval for this disease (Escudier et al 2007;Motzer et al, 2007). Most other TKIs so far have either only been tested in smaller phase I and II studies, or have failed to show meaningful effects in larger randomised phase III studies (Koehne et al, 2006).…”

mentioning

confidence: 99%

Vascular disrupting agents in clinical development

2007

View full text Add to dashboard Cite

Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific anticancer drugs has been developed. These so-called vascular disrupting agents (VDAs) target the established tumour vasculature and cause an acute and pronounced shutdown of blood vessels resulting in an almost complete stop of blood flow, ultimately leading to selective tumour necrosis. As a number of VDAs are now being tested in clinical studies, we will discuss their mechanism of action and the results obtained in preclinical studies. Also data from clinical studies will be reviewed and some considerations with regard to the future development are given.

show abstract

Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma

Abstract: Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa (ClinicalTrials.gov numbers, NCT00098657 and NCT00083889 [ClinicalTrials.gov]).

Cited by 5,350 publications

References 29 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

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

Vascular disrupting agents in clinical development

Contact Info

Product

Resources

About