A greater understanding of
cancer biology and major advances in biotechnology have resulted in the identification of a plethora of rationally designed, target-based anticancer
therapeutics, particularly those that inhibit malignant-cell signal transduction, ushering in new therapeutic opportunities and extraordinary developmental challenges. Because these agents seem to principally target malignant cells, it is expected that they will produce less toxicity at clinically effective doses than nonspecific
cytotoxic agents. The innate complexity of signaling networks, which have redundant relay systems that confer robustness, adaptability, and signaling diversity, also decreases the probability that any single therapeutic manipulation against any specific signaling
element will be highly successful when used alone, particularly in patients with solid
malignancies that have multiple relevant signaling aberrations. In addition, because the predominant
therapeutic effect of inhibitors of signal transduction processes in preclinical studies is a decreased rate of
tumor growth, it is anticipated that the predominant therapeutic outcome in the clinic will be similar; however, this end point is not readily detectable or quantifiable using traditional clinical evaluation methods. Furthermore, the results of preclinical and early clinical studies indicate that dose-toxicity relationships are not likely to be as steep as with nonspecific
cytotoxic agents. Therefore, both regulatory and clinical practice end points, such as time to
disease progression, disease-related symptoms, and quality of life, which are generally considered secondary for
cytotoxic agents, may evolve into primary end points. The cumulative results of developmental evaluations to date indicate that the development, evaluation, and general clinical use of rationally designed, target-based anticancer
therapeutics will require a radical departure from traditional paradigms to exploit the full potential of these new
therapies.