Targeted Agents for the Treatment of Advanced Renal Cell Carcinoma

Abstract

Renal cell carcinoma (RCC) is a highly treatment-resistant tumor type; however, advances in elucidating the molecular pathophysiology underlying RCC has led to the identification of promising targets for therapeutic intervention. In clear-cell RCC, mutations to the von Hippel-Lindau (VHL) gene results in the up regulation of many proteins necessary for tumor growth and survival--such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF), which are involved in tumor-initiated angiogenesis. Carbonic anhydrase IX and signaling via the epidermal growth factor receptor (EGFR) are involved in tumor cell proliferation and are also up regulated by mutation in the VHL gene. The intracellular messenger pathways phosphoinositide 3-kinase (PI3K) and Raf/MEK/ERK act as convergence points for positive growth signaling; the Raf/MEK/ERK pathway is also implicated in apoptosis. Several agents in development target VEGF (bevacizumab), the VEGF receptor (PTK787, SU11248, VEGF-trap, and BAY 43-9006), the PDGF receptor (SU11248 and BAY 43-9006), or the EGF receptor (gefitinib, cetuximab, ABX-EGF, and erlotinib). The intracellular Raf/MEK/ERK signaling cascade has been targeted at either the level of Raf (BAY 43-9006, ISIS 5132) or MEK (CI-1040, PD184352 and ARRY-142886), and PI3K signaling is disrupted by CCI-779. WX-G250 targets the G250 antigen, and PS-341 disrupts the 26S proteasome mediating the degradation of intracellular proteins. Given that multiple pathways contribute to tumor growth, anti-tumor activity may be increased by agents targeting multiple pathways, or by combining agents to allow horizontal or vertical inhibition of multiple pathways.

Calcitonin targets extracellular signal-regulated kinase signaling pathway in human cancers

“…In addition, the activated MAPK or increased levels of MAPK expression have been detected in a variety of human tumors (Oka et al 1995, Sivaraman et al 1997, Hoshino et al 1999, Kim et al 1999, Ahmed et al 2002, Satyamoorthy et al 2003, Liang et al 2005, Takata et al 2005. Thus, the MAPK signaling pathway is a potential target in cancer therapy (Duesbery et al 1999, Tecle et al 1999, Fang & Richardson 2005, Staehler et al 2005.…”

ZD6474 induces growth arrest and apoptosis of human leukemia cells, which is enhanced by concomitant use of a novel MEK inhibitor, AZD6244

“…Additional investigations revealed that ZD6474 blocked the downstream signaling pathways including extracellular signalregulated kinase (ERK) signaling in EOL-1 cells (Figure 1b). Further studies examined the antileukemic activity of AZD6244 (ARRY-142886), 3 a novel inhibitor of mitogen-activated protein kinase /ERK signaling. The drug synergistically enhanced the .…”

“…[1][2][3][4] Clinical trials with VEGF inhibition in a variety of malignancies are ongoing. The best-studied and most advanced approach to VEGF inhibition is the recombinant humanized monoclonal antibody bevacizumab (BV -1 mM) or control diluent.…”

Exploitation of Aberrant Signalling Pathways as Useful Targets for Renal Clear Cell Carcinoma Therapy

“…In single-agent EGFR inhibitor trials, gefitinib (a selective EGFR TKI) and cetuximab (a recombinant mousehuman mAb) were administered as monotherapy. Neither agent demonstrated a complete or partial response (Staehler et al, 2005). In a randomized phase II trial, clear cell RCC patients received either bevacizumab or bevacizumab plus the EGFR inhibitor erlotinib.…”