The selection of appropriate targets for intervention is the most critical component of the drug development process. Appropriate target selection is based on efficacy assessment as well as the potential negative effects of impacting the target (as discussed below). Indications of effectiveness fall into several major categories - knowledge of mechanisms, in vitro
and animal in vivo
experimental data, epidemiological case-control and cohort studies, and data from clinical trials, either early phase prevention trials or secondary endpoint analysis from trials performed for other indications (reviewed in ref. 7
). During each stage of drug development, but particularly at the juncture between preclinical and early clinical trials and then again at the juncture between early phase and definitive phase III clinical trials, it is necessary to review all the available data and to examine it for consistency. The quality and consistency of the available data help determine whether additional data needs to be obtained prior to clinical trials, or if sufficient knowledge is available to make the “go-no go” decision.
Understanding the mechanisms responsible for carcinogenesis at specific target organs is critical to designing the appropriate clinical intervention trials. However, despite the recent logarithmic increases in our knowledge, the detailed mechanisms giving rise to most human cancers are not well worked out. It is becoming clear that cancer represents a multitude of molecular processes with different pathogenetic mechanisms even within the same target organ. For instance, breast cancer classification has moved beyond the simple estrogen receptor-positive and estrogen receptor-negative categories, while a variety of molecular alterations, several of which can be specifically targeted for therapy, are known to lead to lung adenocarcinoma.8,9
This molecular complexity suggests that multiple strategies may well be needed to prevent different types of cancers and thus it becomes even more important to identify the individuals at high risk for specific molecular types of cancer.
The more dependent a cell is on a particular pathway for its growth and survival, the more likely that an intervention blocking the pathway will be effective. This is best illustrated by the tyrosine kinase inhibitor imatinib, which inhibits p210BCR-ABL
that causes chronic myelogenous leukemia (CML) and also inhibits c-Kit, which is involved in gastrointestinal stromal tumors (GIST) and small cell lung cancer (SCLC).10–12
In CML, p210BCR-ABL
is necessary and sufficient to cause the disease, and imatinib has striking efficacy, especially in the early chronic phase. In fact, chronic CML can be considered a premalignant phase of the leukemic process. However, imatinib’s efficacy decreases markedly with advancing disease, such as accelerated phase and blast crisis, both of which are characterized by the accumulation of additional mutations. Similarly, in GIST, c-Kit is mutated and imatinib is again very effective in the tumors with the appropriate mutations. However, in SCLC, although c-Kit is frequently expressed, activating mutations in c-kit exon 11 are not found while a multitude of other mutations in other genes do exist, and imatinib is inactive.13
Efficacy in blocking a single pathway only occurs when the cell is critically dependent on that pathway.
Thus, the better one understands the process of carcinogenesis and the molecular basis for the evolution of the neoplastic phenotype, the more likely will one be able to develop interventions to prevent and possibly even reverse neoplastic progression. The efficacy of an agent in preventing cancer will depend on how critical its target is to carcinogenesis (as exemplified by the role of imatinib in CML), whether the agent can be delivered at the time that its target drives the carcinogenic process, and the potency of the intervention. Because different aspects of carcinogenic progression may depend on different molecular abnormalities or signaling pathways, it is important to determine when specific abnormalities should be targeted. For instance, targeting the initial DNA damage from carcinogen exposure in tobacco smoke by blocking carcinogen metabolism may be very effective prior to the acquisition of much DNA damage, but is not likely to be effective once the damage already exists and cells have acquired multiple genetic lesions (e.g., after years of smoking). A priori, there is no reason to theorize that interventions that are effective during some phases of carcinogenesis will be effective during other stages, unless the target has a critical biological role during multiple stages of carcinogenesis. Finally, it is important to remember that phase III cancer prevention trials with tumor incidence endpoints generally test interventions for only a small number of years, so these trials are, by design, testing intervention efficacy on relatively advanced stages of premalignancy (). Consequently, an intervention that blocks early events in carcinogenesis, such as initiating DNA damage events, is highly unlikely to prevent cancer in a trial where the duration of the intervention is 3–5 years. In selecting targets for cancer prevention, the ability to design the appropriate clinical trials to demonstrate efficacy must be considered – if one cannot demonstrate preventive ability within the context of our currently available clinical trials resources (for instance, if the intervention must be delivered prior to all carcinogen exposure), the drug development process is likely to fail.
Timing of Clinical Trials During the Process of Carcinogenesis