Targeting Metastatic Colorectal Cancer in 2008: A Long Way From 5-FU

Alexandra Pohl, MD
Postdoctoral Research Fellow

Wu Ahang, MD
Research Scientist

Yan Ning, MD, PhD
Research Scientist

Philipp C. Manegold, MD
Postdoctoral Research Fellow

Georg Lurje, MD
Postdoctoral Research Fellow

Heinz-Josef Lenz, MD, FACP
Professor of Medicine and Preventive Medicine
Division of Medical Oncology
Sharon A. Carpenter Laboratory
USC/Norris Comprehensive Cancer Center
Keck School of Medicine
Los Angeles, California
ABSTRACT: Colorectal cancer is one of the leading causes of cancer-related death worldwide, with almost 20% of all patients presenting with metastatic disease at the time of their diagnosis. The treatment regimens and options of metastatic colorectal cancer have significantly changed in the last 10 years, leading to an improvement of response rates to about 50%, progression-free survival of about 10 months, and overall survival reaching over 2 years. Beside US Food and Drug Administration approval of the cytotoxic agents irinotecan (Camptosar), oxaliplatin (Eloxatin), and capecitabine (Xeloda), the increasing understanding of molecular pathways that comprise the cell cycle, apoptosis, angiogenesis, and invasion has provided novel targets in cancer therapy. The biologic agent bevacizumab (Avastin), an inhibitor against vascular endothelial growth factor, and cetuximab (Erbitux) and panitumumab (Vectibix), monoclonal antibodies to epidermal growth factor receptor, have demonstrated their efficacy in clinical trials. This article reviews the mechanisms of action and possible markers of resistance, and summarizes data on the clinical efficacy of targeting agents.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. With an estimated 153,760 newly diagnosed cases and 52,180 cancer-related deaths in the United States for 2007, it will remain the second leading cause of cancer-related death.[1] Almost 20% of these patients will present at the time of diagnosis with metastatic disease (mCRC).[2] For nearly 35 years, the standard chemotherapeutic regimen for treating metastatic colorectal carcinoma consisted only of fluorouracil (5-FU), with an overall response rate of 10% and a median survival of 10 months.[3,4] With the addition of leucovorin to 5-FU, the response rate improved to 23%.[5] During the past 10 years, with the addition of the cytotoxic agents irinotecan (Camptosar) and oxaliplatin (Eloxatin), a substantial change in response rate, progression-free survival, and overall survival occurred.

Furthermore, the increasing understanding of molecular pathways that characterize the cell cycle, apoptosis, angiogenesis, and invasion has provided novel targets in cancer therapy.[6] The biologic agents bevacizumab (Avastin) as an inhibitor against vascular endothelial growth factor (VEGF), and cetuximab (Erbitux), a monoclonal antibody to the epidermal growth factor receptor (EGFR), received US Food and Drug Administration (FDA) approval for the treatment of metastatic CRC.

This article reviews the mechanisms of action, promising new agents, and markers of resistance, and summarizes data on the clinical efficacy of targeting agents.

Targeting VEGF
The revelation that tumor growth is angiogenesis-dependent identified new targets for anticancer treatment.[7,8] The promotion of new blood vessel formation is a tightly regulated complex, working via secretion of proangiogenic factors by tumor cells and adjacent stromal cells that activate endothelial cells.[9] Among these, the most prominent proangiogenic factors are VEGF, platelet-derived growth factor (PDGF), and angiopoietin-1.[9]

VEGF is a heparin-binding glycoprotein family that includes six members, referred to as VEGF-A through VEGF-E and PDGF.[10] VEGF is the most critical regulator for the development of neoangiogenesis and functions as an endothelial cell mitogen. It increases microvascular permeability, induces endothelial cell migration and division, reprograms gene expression, promotes endothelial cell survival, prevents senescence, and induces angiogenesis and lymphangiosis.[11]

VEGF-A through -E and PDGF act through specific binding to three different cell membrane receptors (VEGFR-1, -2, and-3), which consist of an extracellular domain, a transmembrane domain, and an intracellular region containing a tyrosine kinase domain. Binding of a ligand to its receptor induces the activation of the tyrosine kinase domain, which initializes the activation of intracellular signaling transduction pathways that are involved in regulation of cellular proliferation and survival, such as the raf/MEK, ERK, AKT, mTOR, IGFIR, and PI3K pathways.[12]

High VEGF serum levels have been found to be associated with poor outcome in cancer patients.[13,14] Numerous angiogenesis inhibitors (eg, bevacizumab, sunitinib [Sutent], vatalanib) have been developed in the clinic as antiangiogenic approaches to therapy. Inhibition of VEGF-A by bevacizumab in patients with mCRC appears to be the most promising such strategy so far.