Welcome to PeerView

The complexity of signaling transduction pathways is well illustrated by efforts to exert anti-tumor effects through inhibition of cyclooxygenase-2 (COX-2) and Ras kinase or Ras downstream substrates, such as Raf-1, MEK-1, or ERK 1. Anti-tumor effects have been observed with agents that work along these pathways in several types of solid tumors, but important questions remain about timing of therapy and how these drugs can be combined with existing therapies in second- or even first-line management.

Clinical benefit from inhibiting COX-2 and Ras kinase is expected as both are implicated in cell proliferation, malignant transformation, and abnormal apoptotic signaling. COX-2 is overexpressed in a wide variety of cancer types as well as in premalignant conditions, such as Barrett's esophagus and familial adenomatous polyposis (FAP). Ras kinase upregulation has been isolated as an early event in the cascade of signals leading to cell differentiation and transformation. Both COX-2 inhibitors and inhibitors of the Ras kinase pathway are in clinical trials, but results have been mixed, suggesting that patient selection, timing of the dose, or other factors may be important for optimal benefits.

"It may be useful to correlate response with pre- and post-treatment measures of COX-2 in order to better understand what type of effect we are achieving," reported Alan Sandler, MD, during the 20^th annual meeting of the Chemotherapy Foundation. Clinical trials with COX-2 inhibitors in addition to conventional chemotherapy in treatment-refractory patients with non-small cell lung cancer (NSCLC) have had modest but promising results.

Early Trial Data with COX-2 Inhibitors
In one trial that has enrolled 30 patients to date, a 400-mg twice-daily (BID) dose of the COX-2 inhibitor celecoxib has been combined with 75 mg/m² of docetaxel (Csiki I et al. Proc Am Soc Clin Oncol. 2002;21(suppl 1):297a. Abstract 1187). Of the 13 evaluable patients so far, 2 (15.3%) achieved a partial response. In another trial, 400 mg BID celecoxib was added to paclitaxel and carboplatin as neoadjuvant therapy in patients undergoing surgical resection (Altorki NK et al. Proc Am Soc Clin Oncol. 2002;21(suppl 1):26a. Abstract 101). There were 12 (75%) objective responses among 16 evaluable patients, 4 (25%) of whom achieved complete response and 8 (50%) had stable disease. According to Dr. Sandler, this rate of response compares favorably with the same neoadjuvant therapy without a COX-2 inhibitor.

"Another promising area is using COX-2 inhibitors to increase the effects of radiotherapy. Two animal models have already suggested that COX-2 inhibition can significantly inhibit tumor growth in this setting," Dr. Sandler reported. This benefit is predicted by the fact that COX-2 is upregulated by irradiation. Phase II clinical trials testing this combination are already underway at several institutions. Clinical effects have not yet been measured, but initial results from one pilot study suggest that the addition of COX-2 inhibition does not appear to increase the toxicity or radiation (Carbone D et al. Proc Am Soc Clin Oncol. 2002;21:318a. Abstract 1270).

Based on the importance of COX-2 upregulation to the development of malignancies, COX-2 inhibitors may also have a role in prevention of NSCLC, according to Dr. Sandler. This principle has already been applied in a premalignant condition. Polyp control in FAP is already a licensed indication for celecoxib. The drug has been shown to reduce polyp formation by 30% in patients with FAP (Steinbach G et al. N Engl J Med. 2000;342:1946-1952). Although FAP is a relatively rare genetically transmitted condition, it has been intensively studied for what it may reveal about the mechanisms by which polyps form in the colon and transform into malignant colorectal adenocarcinomas.

"FAP appears to provide insight into the biology of colorectal adenomas, and the activity of celecoxib in this disease has provided important support for the principles of COX-2 inhibition for clinical benefit," reported Andrew J. Danneberg, MD, Strang Cancer Prevention Center, Cornell University, New York, New York. He suggested that this experience has been a major impetus to pursue anti-tumor activity in other diseases with a premalignant phase characterized by overexpression of COX-2. This includes some oral lesions associated with head and neck cancers and Barrett's esophagus, which is associated with development of adenocarcinoma of the esophagus.

Early Trial Data with Ras Inhibitors
Therapies directed at the Ras pathway of signal transduction are at an even earlier stage of clinical testing with several agents proposed that affect different targets along this pathway. These include BAY 433-9006, an inhibitor for Raf kinase (a downstream Ras effector) and inhibitors of farnesyl transferase, an enzyme that participates in the production of Ras. Both these agents have shown signs of activity in patients with advanced malignancies in phase I clinical trials (Figure 1).

Source: Adapted with permission of Bristol-Myers Squibb Oncology.

"In the 163 patients treated with BAY 433-9006, there have been a substantial number of tumor regressions in cancers of the liver, ovary, cervix, kidney, and colorectum. The objective response rate overall has been 20%, and the toxicities were mild to moderate," reported Eric K. Rowinsky, MD, director of clinical research, Institute for Drug Development Cancer Therapy and Research Center, San Antonio, Texas. The main toxicities in these trials were hand-foot syndrome in 50% and diarrhea in 28%, but the initial results provide a "proof of principle" that Raf inhibition is a legitimate molecular target for cancer control.

Results with inhibition of farnesyl transferase have been less predictable. Some of the best therapeutic results in phase I trials have been achieved in malignancies in which evidence of Ras upregulation is least well established. However, as more is learned about the interrelationship of molecular signals within cancer cells, growing evidence suggests that farnesyl transferase may act on proteins outside of those commonly associated with the Ras pathway. As a result, there is growing suspicion that farnesyl transferase may be a good target, but not for the reasons initially proposed.

"We think that the conceptions of signal transduction may be too simplistic. These are probably not linear pathways easily interrupted by inhibiting one enzyme but a network in which inhibition of one signal may not be enough," Dr. Rowinsky suggested.

In addition, there may be heterogeneity in key signaling events even among patients with the same types of cancers. This heterogeneity would explain the rather large differences in response rates observed in individuals exposed to the same targeted biological therapies or even the same chemotherapies. Several centers are now looking at ways to identify novel molecular biomarkers that can aid in the clinical decision-making process. Reporting on such an effort underway at his institution, Heinz-Josef Lenz, MD, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, suggested that certain biomarkers of gene expression that relate to essential target enzymes may be critical to directing cancer therapy.

"We and others have found that gene expression of specific enzymes, such as thymidine phosphorylase and thymidylate synthase helps identify those patients whose colorectal tumors are more likely to respond to fluoropyrimidine-based therapy," Dr. Lenz said. "With emerging technology to reliably measure gene expression, these types of measures may be used to select therapies, particularly in second-line therapy when there is a strong risk of resistance."

Although this work is largely being applied to conventional chemotherapies, the same principles may apply to molecular targeted therapy. Interest in this area is driven by a growing conviction that even similar tumors may not share the same molecular genetic profile. According to Dr. Rowinsky, cancers may develop from a vast number of aberrations in normal cell biology, which creates the need for therapies targeted to the specific characteristics of an individual tumor.

Key Points In Focus:

Clinical trials have confirmed activity for agents targeted at COX-2 and Ras signal transduction pathways, both of which are implicated in malignant transformation.
There is growing interest in the potential of COX-2 inhibitors to prevent cancer in patients with pre-malignant conditions in which this enzyme is upregulated. Prevention of the formation of adenomatous polyps in FAP supports the principle of this type of intervention.
The complexity of signal transduction leading to malignancy suggests that inhibition of one factor may be insufficient. Moreover, the likelihood of heterogeneity in the pathogenic events leading to malignancy (even in patients with the same cancer type) suggests that the optimal use of targeted therapy is for specific abnormalities in individual patients.

--[ TOP ]--