Gastrointestinal stromal tumors and the evolution of targeted therapy.
Gastrointestinal stromal tumors (GISTs) historically have differed from other soft-tissue sarcomas in demonstrating a particularly grim prognosis. GISTs have an extraordinarily high rate of recurrence after surgical resection and are highly resistant to radiation and standard chemotherapy. The discovery that constitutive activation of the c-kit gene drives malignant behavior in GISTs exposed a weakness that was soon exploited through the application of the novel targeted therapy imatinib, a small-molecule tyrosine kinase inhibitor of Bcr-Abl, KIT, and the platelet-derived growth factor receptor-alpha and -beta. Imatinib had shown unparalleled results in patients with advanced chronic myelogenous leukemia (remission rates approaching 98%), and the first GIST patients treated with imatinib demonstrated dramatic response rates unseen with other therapeutic modalities. Thousands of patients worldwide with advanced GIST have been treated with imatinib, with the demonstration of significant response rates, prolongation of survival, and improvement in quality of life. Studies of imatinib in both the neoadjuvant and adjuvant settings are now being conducted to evaluate whether low rates of cure with surgical resection alone can be improved. Additionally, multiple new targeted agents are being tested in patients with imatinib-resistant GIST. The gains that have been made in the treatment of GIST through the use of imatinib have helped to open the door to a new era of development of targeted therapeutic agents in oncology. Whether this new era of targeted therapy will provide the same advances in more common malignancies will be determined only through the ongoing application and development of clinical trials.
Sanborn
Rachel E
RE
Oregon Health and Science University Cancer Institute, Portland, Oregon 97239, USA.
Blanke
Charles D
CD
D001549:Benzamides; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy / Q000379:methods / Q000639:trends; D016503:Drug Delivery Systems / Q000379:methods / Q000639:trends; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D016044:Fusion Proteins, bcr-abl