Soft tissue sarcomas in adults are rare malignancies with diverse histologies that have historically been classified together, mostly for convenience. In truth, however, these diseases are quite biologically distinct in their pathogenesis and clinical behavior. The molecular mechanisms underlying sarcoma development are for the most part still poorly understood; however, recent studies have begun to elucidate the gene mutations responsible for oncogenesis in some of the histologic subtypes, including the SYT-SSX fusion gene in synovial sarcoma and c-KIT in gastrointestinal stromal tumors (GIST).[1-3] Recent studies in GIST are worthy of discussion, as they have provided a long-awaited proof of principle for molecular targeting of aberrant cellular pathways in solid tumors.
Gastrointestinal Stromal Tumors
Unresectable or metastatic GIST is a fatal disease that is refractory to all chemotherapeutic interventions. KIT is a cell-surface transmembrane receptor that has tyrosine kinase activity and regulates cell proliferation and apoptosis. It was recently discovered that the c-KIT gene is mutated or dysregulated in nearly all patients with GIST; this leads to constitutive activation of KIT signaling, resulting in uncontrolled cell proliferation.
Imatinib mesylate (Gleevec, Glivec) is a selective inhibitor of several tyrosine kinases including KIT, bcr-abl, and platelet-derived growth factor receptor. In a recently reported phase II trial, 147 patients with recurrent or metastatic GIST treated with imatinib(Drug information on imatinib) had an overall response rate of 54%, with another 28% of patients achieving stable disease. Based on early results from this study, two large phase III trials were collaboratively developed and conducted in North America and Europe. Together, these studies accrued approximately 1,800 patients in less than 10 months.
These are remarkable achievements, demonstrating that rationally designed molecularly targeted agents may have significant efficacy when patients whose cancers possess the critical target are appropriately assessed and selected for therapeutic intervention. This also affirms the ability of the Cooperative Groups to rapidly conduct and complete important large-scale trials in these rare diseases.
The scientific success and clinical results of the investigations in GIST have generated renewed excitement in sarcoma research, culminating recently in a National Cancer Institute (NCI)-sponsored State-of-the-Science Meeting: "Soft Tissue Sarcoma: Building on Molecular and Clinical Progress." This conference brought together an international group of sarcoma experts from a wide variety of disciplines including biology, pathology, surgery, radiation oncology, imaging, and medical oncology. Among other issues, these experts considered and discussed opportunities and obstacles for: (1) continued identification of aberrant molecular pathways in sarcomas; (2) translating basic research into clinical investigation; and (3) identifying the questions that are of highest priority for clinical investigation. Interested individuals can review the proceeds and summary recommendations of this meeting on the Internet at www.webtie.org/SOTS/index.htm.