Sorafenib and Sunitinib: Novel Targeted Therapies for Renal Cell Cancer

Abstract and Introduction

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.

Introduction

In 2007, in the United States, 51,190 people are expected to be diagnosed with renal cell cancer (RCC), and 12,890 people are expected to die from it. Renal cell cancer is the seventh most common malignancy in men and the ninth most common in women. The disease is predominant in men (1.6:1): 31,590 cases are expected to be diagnosed in men and 19,600 in women in 2007. In addition, RCC is largely a disease of the elderly, with a median age at diagnosis of 65 years.^{[1, 2]}

The 5-year survival rate for patients with localized disease is approximately 90%, drops to 60% in patients with locally advanced disease, and declines again to 20% in those with metastatic disease.^[3] Unfortunately, an estimated 30% of patients are diagnosed with advanced disease, and about half the patients who are treated for localized disease relapse with metastatic disease.^[3] Thus, developing effective therapy for advanced RCC may prolong survival and decrease mortality rates.

In the middle to late 1980s, cytokine-based therapy with interferon alfa or aldesleukin became the first major treatment advance for metastatic RCC. During the past 5 years, however, researchers have made excellent progress in understanding RCC biology, providing insight into the treatment of this malignancy. These advances have led to the development of a new class of drugs: multiple-kinase inhibitors. The United States Food and Drug Administration (FDA) recently approved two multiple-kinase inhibitors—sorafenib and sunitinib—for treatment of advanced RCC.

Biology of Renal Cell Cancer

The most common histologic types of RCC are clear cell (75%), papillary (12%), chromophobe (4%), and oncocytoma (4%).^[3] Renal cell cancer occurs in sporadic and inherited forms and, in general, is caused by genetic mutations that silence or activate key genes to cause unregulated cell growth and metastases.

Inherited cancer syndromes occur in approximately 2% of patients with RCC.^[4] Most notably, von Hippel-Lindau (VHL) disease is associated with clear cell RCC, the most common histologic type. In this disease, which is inherited in an autosomal dominant manner, one VHL gene allele is mutated and the other is silenced. Of importance, the VHL gene is also mutated in most sporadic cases of clear cell RCC.^[3]

First identified in 1993, the VHL gene is a tumor suppressor gene located on chromosome 3p25-26.^[5] The VHL protein binds to hypoxia-inducible factor, a gene transcription factor that allows cell growth and survival in hypoxic conditions, and targets it for degradation. When VHL protein function is lost or inactivated, hypoxia-inducible factor-1a accumulates, even under normoxic conditions. This stimulates production of growth factors and carbonic anhydrase IX, which is a tissue hypoxia marker. Growth factors include vascular endothelial growth factor (VEGF), transforming growth factor-α (TGF-α), basic fibroblast growth factor, erythropoietin, and platelet-derived growth factor (PDGF). This promotes angiogenesis, tumor cell proliferation, and survival.^{[3, 6, 7]} Inhibition of the tyrosine kinases necessary for these growth factors to interact with their respective receptors is a potential target for anticancer therapy.

Ras protooncogenes, identified in the 1960s, were among the first protooncogenes discovered. The Ras gene family includes N-Ras (neuro-blastoma cell line), H-Ras (Harvey murine sarcoma virus), and K-Ras (Kirsten murine sarcoma virus), the most frequently activated oncogene. Ras proteins deliver signals from cell surface receptors, passing them from protein to protein along several different pathways.^[8]

The Ras-Raf/MEK (mitogen extracellular kinase)/ERK (extracellular signal-related kinase) pathway, a common downstream Ras signaling pathway present in all eukaryotic cells, is upregulated in approximately 30% of all human cancers.^[9] This pathway regulates tumor cell proliferation, angiogenesis, and metastasis by relaying extracellular signals to the nucleus by a cascade of specific phosphorylation events involving Ras, Raf, MEK, and ERK. The Raf kinases are the first signaling elements in the Ras-Raf/MEK/ERK pathway. Three Raf kinase isoforms exist: C-Raf, A-Raf, and B-Raf. Receptor tyrosine kinases, such as VEGF-R, PDGF-R, TGF-Rα, and epidermal growth factor receptor (EGF-R), regulate key cell functions such as proliferation, differentiation, and antiapoptotic signaling in the Ras signaling pathway. The VEGF, PDGF, TGF-α, and EGF act on tyrosine kinase receptors and promote angiogenesis and cell growth. Unregulated activation of Raf kinases and receptor tyrosine kinases, through mechanisms such as point mutations or overexpression, can induce Ras activation. This, in turn, activates the downstream Raf/MEK/ERK pathway (Figure 1).^{[8, 10]}

In addition, patients with hereditary papillary RCC have mutations in Met, a protooncogene belonging to the tyrosine kinase receptor super-family.^{[3, 5]} Met binds to its ligand, hepatocyte growth factor–scatter factor, and activates the Raf/MEK/ERK pathway. Overexpression of Met increases cellular processes, such as cell motility, proliferation, angiogenesis, and morphogenic differentiation.^[3] In addition, cytogenetic studies have implicated H-Ras point mutations, mitogen-activated protein (MAP) kinase activations, MEK overexpression, and C-Raf mutations in the pathobiology of RCC.^{[6, 11, 12]} Thus, developing tyrosine kinase inhibitors directed at inhibiting the Ras-Raf/MEK/ERK signaling pathway, and the other pathways activated by the absence of the VHL protein, is a rational strategy for treating RCC.