Welcome to PeerView

Extensive evidence indicates that drugs that inhibit transduction of signals for tumor cell proliferation are clinically viable therapeutic options. This has been shown repeatedly with monoclonal antibodies targeted at cell surface receptors, inhibitors of intracellular enzymes, and inhibitors of proteins important to cell migration or gene transduction. Several agents are now in phase III trials, including those that inhibit epidermal growth factor pathways of tumor cell proliferation. These are expected to expand therapeutic options, particularly in advanced cancers for treatment-experienced patients showing little or no response to current therapies.

The development of targeted therapies comes at an opportune time, according to Roy Herbst, MD, who spoke at the 20^th annual meeting of the Chemotherapy Foundation. Although he was referring to lung disease, he could have spoken for a large number of solid tumors when he said, "we have reached the ceiling for cytotoxic chemotherapy." A series of incremental improvements with chemotherapy with regards to important end points, such as prolonging the time to progression, have occurred over the past 2 decades. However, the 1-year survival rate in non-small cell lung cancer (NSCLC) now appears stalled at about 25%.

Targeted Therapy Defined
The definition of targeted therapy varies. To some clinical researchers, a therapy is targeted if the effects are more specific to a tumor cell than a normal cell. However, due to enormous advances in identifying the signaling pathways responsible for tumor cell proliferation, a more widespread definition of targeted therapy is one that interferes with a specific process in tumor cells to induce death or, at the very least, prevent growth.

A variety of targeted therapies have been developed. First, monoclonal antibodies exclusively target a specific receptor. A prominent example of this mechanism is antibodies that target the epidermal growth factor receptor (EGFR). These cell surface receptors signal several important downstream events critical to tumor cell proliferation. Second, enzyme inhibitors are designed to interrupt a chain of events. Among these, inhibitors of tyrosine kinase or Raf-1 kinase interrupt the critical process of transmitting signals for tumor growth. Third, some cytotoxic agents appear to function by triggering a specific anti-proliferative signal, such as the cytotoxic agent thalidomide, which appears to interrupt angiogenic signaling and promotes apoptosis (Figure 1).

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

Phase I and II trials on the activity of targeted therapies have been completed, and results are encouraging. Many of these agents are now being evaluated in phase III trials for their potential as adjuncts to conventional chemotherapy. The potential for additive or even synergistic effects is substantial. However, the ultimate role of targeted therapies may be when they are used in combination with one another. The reason is that there appear to be redundancies in various critical signaling pathways.

"It may be naīve to think that targeting of one pathway in the vast network will be enough," commented Eric K. Rowinsky, MD, director of clinical research, Institute for Drug Development Cancer Therapy and Research Center, San Antonio, Texas. He indicated that the anti-tumor effects of targeted therapy have been highly encouraging. However, he also suggested that major improvements in survival are likely to require therapies that target multiple signaling pathways.

Targeted therapies have been tested in patients with advanced cancer. Clinical response rates have been variable. However, a small number of patients have shown dramatic tumor regression, reinforcing the overall importance of targeting specific signaling pathways. So far, no single signaling pathway has been found to be so essential to tumor survival that any targeted therapy could be poised to serve as a magic bullet for cancer cure, with the exception of imatinib in chronic myelogenous leukemia. However, it is now clear that inhibition of cellular signal transduction can inhibit mechanisms used by tumor cells for growth and proliferation, invasion, and metastasis.

Combination Therapies May Delay Disease Progression
The targeted therapies "will allow us to continue to chip away" at solid tumors, according to Edward S. Kim, MD, Department of Thoracic/Head and Neck Medical Oncology, M. D. Anderson Cancer Center, Houston, Texas. Referring to plans to combine targeted therapies, such as anti-EGFR agents with cytotoxic agents, he anticipates that these drugs will "allow us to add a few weeks here and a few weeks there to delay progression and increase our long-term survival". This appears to be the goal of introducing these agents into currently available regimens. The ultimate direction of this research is to understand tumor cell signaling sufficiently to be able to halt tumor growth completely.

"What about the biological combinations? I think this is an intriguing place for this science to go," Dr. Herbst reported. He indicated that biologic agents offer enormous promise for both combination with conventional cytotoxic agents in advanced disease and for future use in novel applications. Dr. Herbst is already planning a phase I trial that combines a tyrosine kinase inhibitor and another anti-angiogenic drug for lung cancer patients.

Key Points In Focus:

Targeted therapies that interfere with signal transduction critical to tumor cell proliferation have been developed, with multiple studies showing that these agents are active in advanced carcinoma and are likely to expand therapeutic options.
Monoclonal antibodies and small molecules that exclusively target EGFR; inhibitors of enzymes, such as tyrosine kinase; and chemotherapies with anti-angiogenic effects, such as thalidomide, have all reached phase III testing and may soon be granted regulatory approval.
Targeted therapies are expected to be integrated into existing cytotoxic drug regimens to achieve additive or even synergistic benefits, but their ultimate role may be in potent combinations to inhibit multiple signaling pathways to achieve greater activity.
Targeted therapies may have a role as part of adjuvant therapy or as part of chemoprevention strategies in high-risk patients.

--[ TOP ]--