Targeted therapy for metastatic renal cell carcinoma

Abstract

Metastatic renal cell carcinoma (RCC) has historically been refractory to cytotoxic and hormonal agents; only interleukin 2 and interferon alpha provide response in a minority of patients. We reviewed RCC biology and explored the ways in which this understanding led to development of novel, effective targeted therapies. Small molecule tyrosine kinase inhibitors, monoclonal antibodies and novel agents are all being studied, and phase II studies show promising activity of sunitinib, sorafenib and bevacizumab. The results of phase III studies will determine the role of these agents in metastatic RCC. British Journal of Cancer (2006) Malignant renal cell carcinoma (RCC) accounts for 2 -3% of cancer incidence and results in over 100 000 worldwide deaths annually. In developed nations the average age-adjusted incidence of RCC is approximately 12/100 000 in men and 5/100 000 in women. RCC is the most lethal urologic cancer and the sixth leading cause of cancer deaths in the developed nations. For reasons that are unclear, RCC age-adjusted incidence has been rising for the past 30 years within the US and most European nations at an annual rate of approximately 3% (Chow et al, 1999). For those who present with metastasis, the overall clinical course of RCC varies; approximately 50% of patients survive o1 year and 10% survive for over 5 years . For those who present with early stage disease, radical nephrectomy is the treatment of choice; however, 30% of these patients will relapse and develop future metastasis. Chemotherapy has consistently been an ineffective form of treatment for RCC (Motzer et al, 1996), and until recently, the only effective treatment for metastatic disease was cytokine-based immunotherapy with interferon (IFN)-a or interleukin (IL)-2, which have a response rate of approximately 15% (Rosenberg et al, 1987). Recent advances in understanding the biology and genetics of RCC have led to several novel targeted approaches for the treatment of metastatic RCC, with higher response rates.

A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma

“…So far, the best objective responses have been seen with sunitnib (40%) and combination therapy of bevacizumab and erlotinib (25%) with median disease-free periods of 8.7 and 11.1 months, respectively. The 2-year survival with sunitinib is 40%, which is comparable to the 42% 2-year survival for patients treated with ABR-214936 in this study Patel et al, 2006). However, the majority of patients still progress following these antiangiogenic therapies; thus, although it is an improvement on the response rate achieved with IFN-a or IL-2 there is still a requirement for further development of novel therapies.…”

“…One future direction for the development of RCC therapy currently under investigation is targeted antiangiogenic agents (de Gramont and Van Cutsem, 2005;Patel et al, 2006). This includes receptor tyrosine kinase inhibitors and antibodies directed against growth factors such as vascular endothelial growth factor, either singly or in combination.…”

Treatment of metastatic renal cancer with capsid-modified oncolytic adenoviruses

“…Unfortunately, radiotherapy, chemotherapy, or hormonal therapies have little effect in this disease, and therefore, it is the sixth leading cause of cancer deaths in developed nations (3). Immunomodulating agents, such as IFN-a and interleukin 2, have shown antitumor activity in 7% to 15% of patients according to a metaanalysis (4), but metastatic disease can be cured only very rarely (5).…”

Activated extracellular signal‐regulated kinase is an independent prognostic factor in clinically confined renal cell carcinoma

“…11 Therefore the utility of tumor biomarkers that not only identify high-risk patients but also have value in guiding treatment decisions for RCC is increasingly realized. 4,[12][13][14] The epidermal growth factor receptor (EGF-R)/ Ras/extracellular signal-regulated kinase (ERK) axis is shown to be mutationally activated or overexpressed in a significant number (>30%) of all cancers. 15 Once activated (phosphorylated), the terminal protein kinases, ERK-1/2, are translocated to the nucleus, whereupon an extensive array of transcription factors are activated, including among others Elk-1, Fos, and Stat-3.…”