Sorafenib and Sunitinib: Novel Targeted Therapies for Renal Cell Cancer

Abstract

Renal cell cancer (RCC) is a relatively uncommon malignancy, with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High-dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low-dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia-inducible factor and the Ras-Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first- and second-line therapy in patients with cytokine-refractory metastatic RCC who have clear-cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression-free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first- and second-line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand-foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.

Residual renal function after partial or radical nephrectomy for renal cell carcinoma

“…However, since there is some creatinine secretion, this leads to an overestimation of GFR at low levels of renal function. 7 125 I-Iothalamate, 51 Cr-EDTA or 99m Tc-DTPA are radioactive markers that can be used in combination with renal imaging to determine (split) GFR. 7 Finally, there is substantial interest in cystatin C to estimate GFR; however, this has not yet entered clinical practice.…”

“…This has been reported for sorafenib, sunitinib and temsirolimus. [51][52][53][54] A recent review has indi- cated that in case of sunitinib to treat RCC, the incidence of renal dysfunction can be as high as 66%. 55 Moreover, several cases have now been described where VEGF inhibitors have caused thrombotic microangiopathy.…”

Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors

“…Key words: VEGF, VEGF Trap, endothelial cells, signal transduction, angiogenesis, biomarker, p-ERK, p-STAT3, p-AKT number of common tumor types, resulting in its approval for the treatment of metastatic colorectal, non-small cell lung, breast and renal cell cancers and progressive glioblastoma, usually in combination with chemotherapy or biological agents. [29][30][31][32][33] Sunitinib is an inhibitor of VEGFR2 that also targets other receptor tyrosine kinases, 28,34 and has been approved for the treatment of metastatic renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). 1,34,35 VEGF Trap (aflibercept, Regeneron and Sanofi-Aventis), a soluble chimeric decoy receptor for VEGF that fuses portions of human VEGFR1 and VEGFR2 with the Fc region of human IgG1, binds all isoforms of VEGF-A, VEGF-B and PlGF.…”

“…[29][30][31][32][33] Sunitinib is an inhibitor of VEGFR2 that also targets other receptor tyrosine kinases, 28,34 and has been approved for the treatment of metastatic renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). 1,34,35 VEGF Trap (aflibercept, Regeneron and Sanofi-Aventis), a soluble chimeric decoy receptor for VEGF that fuses portions of human VEGFR1 and VEGFR2 with the Fc region of human IgG1, binds all isoforms of VEGF-A, VEGF-B and PlGF. 36 Its affinity for murine and human VEGF makes it useful for studying therapeutic effects in tumors of mouse as well as human origin.…”

UHRF1 is a novel molecular marker for diagnosis and the prognosis of bladder cancer

“…These two drugs are tyrosine kinase inhibitors that have antitumor activity in advanced renal cell carcinoma. They may improve the mortality rates of this cancer, although these drugs have side effects, such as hand -foot syndrome, rash, fatigue, hypertension, and diarrhoea (Grandinetti and Goldspiel, 2007). Current diagnosis mainly relies on ultrasound and computed tomographic-scan.…”