Welcome to PeerView

Significant advances have been made in our understanding of the molecular events that are involved in the development of human cancers. There are a number of signal transduction pathways that are critical for the ongoing growth and proliferation of certain tumors. In addition, there is growing evidence that many of these same signaling pathways are intimately involved with other critical cellular events, including DNA repair, cell survival signals, invasion, metastasis, and angiogenesis. In addition, these pathways may play an essential role in mediating sensitivity to chemotherapy and radiation therapy.

In this issue of PeerView/inFocus^TM, Dr. Leonard Saltz, from the Memorial Sloan-Kettering Cancer Center, provides a nice overview of the progress that has been made in targeting the epidermal growth factor receptor (EGFR) in the treatment of advanced colorectal cancer (CRC). As outlined, there are several reasons as to why this pathway has become the most actively investigated area of drug development in CRC for the past few years. First, preclinical laboratory studies have documented that this signaling pathway plays a key role in regulating tumor cell growth, DNA repair and survival, invasion and metastasis, and the process of angiogenesis. Second, increased expression of the EGFR is observed in up to 75% of all patients with advanced CRC. Third, expression of this receptor is associated with disease progression, poor treatment outcome, and poor survival.

One approach to inhibit the EGFR pathway involves the development of monoclonal antibodies that are directed against the cell surface receptor. These antibodies act to inhibit the binding of the natural ligands of the EGFR, thereby preventing the ability of the receptor to dimerize with either its own receptor (homodimerization) or with other related cell surface receptors (heterodimerization). This dimerization step is felt to be critical for activation of the intracellular signaling events triggered by the EGFR. There are 3 monoclonal antibodies currently in clinical trials in the US, and they include cetuximab, ABG-EGF, and EMD72000. The most mature clinical data, to date, has been generated with the chimeric monoclonal antibody cetuximab. As a single agent, this antibody gives a 10%-12% response rate in patients with advanced CRC. Of note, when combined with irinotecan in patients who had shown evidence of disease progression on prior irinotecan therapy, a 23% objective response rate was observed. These promising results have led to the design of additional clinical trials to confirm the activity of cetuximab in previously treated patients. In addition, studies are now underway to combine cetuximab with other standard treatment regimens in previously untreated patients with advanced disease.

An alternative approach to target the EGFR pathway has been to develop small molecule inhibitors of the tyrosine kinase domain of the receptor. The 2 agents that have received the most attention include the quinazoline compounds gefitinib (ZD-1839) and erlotinib (OS-I774). However, as single agents, their clinical activity in advanced CRC has been quite modest, with no documented responses observed to date. At present, efforts are focused on designing novel combination regimens that incorporate either one of these small molecules with standard agents for treating advanced CRC.

Several issues remain unresolved and future challenges must be addressed as we develop therapeutic approaches to target the EGFR pathway. First, the optimal method for measuring EGFR status remains unclear. At present, immunohistochemical staining of tissues is the preferred method. However, as in the case of human epidermal growth factor receptor 2 (HER-2)/neu expression, it is conceivable that a reverse transcriptase polymerase chain reaction (RT-PCR)-based method to evaluate mRNA expression or a method to measure DNA expression may be more quantitative and reliable. Second, it has yet to be established whether EGFR status in a given tumor accurately predicts response to EGFR-targeted therapy. The third important issue relates to whether all EGFR-directed therapies have the same clinical activity and whether they can be used interchangeably. The simplistic view would be that this is true. However, growing clinical evidence indicates that the monoclonal antibody cetuximab has single-agent activity in advanced CRC in sharp contrast to the small molecule inhibitors ZD-1839 and OSI-774, which clearly do not. It remains to be determined whether other monoclonal antibodies will show the same level of activity as cetuximab, although it is quite likely that they may not, given their rather different molecular structures. Finally, significant efforts are being made to combine each of the EGFR inhibitors with standard chemotherapy regimens. The challenge, however, will be to identify the optimal sequence of administration as well as duration of treatment so as not to negate the clinical activity of standard chemotherapy.

The role of cyclooxygenase-2 (COX-2) as a novel target for cancer therapy is reviewed by Dr. Alan Sandler from Vanderbilt University. This enzyme is overexpressed in several premalignant disorders as well as in a wide range of human cancers, including colorectal adenomas, CRC, hepatocellular cancer, non-small cell lung cancer, and pancreatic cancer. Preclinical laboratory studies have documented that COX-2 overexpression plays a critical role in tumorigenesis through activation of the prostaglandin pathway. In addition, the COX-2 signaling cascade activates processes that are involved in invasion and metastasis as well as angiogenesis. With regard to CRC, studies have shown that the expression of COX-2, either at the mRNA or protein level, is elevated in up to 80%-85% of CRC tumors, but is low to undetectable in corresponding normal colonic mucosa. In addition, recent studies suggest that COX-2 expression is higher in more aggressive tumors than those that are confined to the mucosa.

COX-2-selective non-steroidal anti-inflammatory agents have been developed which specifically target COX-2. These agents exhibit anticancer activity by activating cell cycle arrest and apoptosis, thereby leading to inhibition of tumor cell growth. In addition, they display anti-metastatic and anti-angiogenic activity. Celecoxib and rofecoxib are the 2 COX-2 inhibitors that have received the most clinical attention to date. While they each target COX-2, there is emerging evidence to suggest that they may not exhibit the same level of clinical activity. In fact, the experimental data suggests that celecoxib may be a more potent anticancer agent. In addition, the safety profiles of these 2 agents appear to be different, with a higher incidence of cardiovascular and renal toxicity being observed for rofecoxib.

At present, efforts are focused on combining celecoxib with standard chemotherapy regimens both for advanced CRC as well as for the adjuvant therapy of early-stage disease. The clinical experience, thus far, suggests that celecoxib can be safely administered with standard anticancer regimens such as irinotecan, 5-fluorouracil/leucovorin (5-FU/LV; IFL) or with the oral 5-FU prodrug capecitabine. Perhaps of greater interest is that celecoxib appears to reduce the incidence and severity of toxicities associated with irinotecan and capecitabine, namely diarrhea and the hand-foot syndrome, but does not adversely affect their clinical efficacy. Clearly, further studies are needed to confirm these preliminary findings.

--[ TOP ]--