Challenges of developing therapeutics that target signal transduction in patients with gynecologic and other malignancies.
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.
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA. erowinsk@saci.org
Eric K
EK
Rowinsky
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015507:Drugs, Investigational / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D018579:Patient Selection; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome; D018631:ras Proteins / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C546842:MTOR protein, human; C508053:ERBB2 protein, human