Developments in targeted therapy of advanced gastrointestinal stromal tumors.
Gastrointestinal stromal tumors (GISTs) comprise a recently defined entity of the most common mesenchymal neoplasms of the gastrointestinal tract. Advances in the understanding of the molecular mechanisms of GIST pathogenesis have resulted in the development of a treatment approach which has become a model of targeted therapy in oncology. The introduction of imatinib mesylate (inhibiting KIT/PDGFRA (platelet-derived growth factor receptor-alpha) and their downstream signaling cascade) has revolutionized the therapy of advanced (inoperable and/or metastatic) GISTs. Imatinib has now become the standard of care in the treatment of patients with advanced GIST. However, a majority of patients eventually develop clinical resistance to imatinib. Over the last few years major progress has been made in elucidating the mechanism of disease progression (as secondary mutations in KIT and/or PDGFRA kinase domains) and resistance to imatinib. Currently, the sole approved second-line drug is sunitinib--a multitargeted agent, an inhibitor of tyrosine kinase, of KIT and PDGFRA/B and of the vascular endothelial growth factor receptors (VEGFRs)-1, -2 and 3, FMS-like tyrosine kinase-3 (FLT3), colony stimulating factor 1 receptor (CSF-1R), and glial cell-line derived neurotrophic factor receptor (REarranged during Transfection; RET). However, a number of new generation tyrosine kinase inhibitors, alone or in combination, are being evaluated at present alongside treatment options alternative to inhibiting the KIT signaling pathway (as heat shock protein 90 or mammalian target of rapamycin). This article discusses the factors relating to imatinib resistance as well as upcoming potentially effective treatment options for patients with progressive disease available in 2008 and those under investigation with more individualized treatment methods, which has been recently patented. This review focuses on the current achievements in targeted therapy of advanced GISTs, and how the insight into the resistance mechanisms may allow in the near future to treat patients with advanced GISTs.
Department of Soft Tissue/Bone Sarcoma and Melanoma, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. rutkowskip@coi.waw.pl
Piotr
P
Rutkowski
Małgorzata
M
Symonides
Marcin
M
Zdzienicki
Janusz A
JA
Siedlecki
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D000077210:Sunitinib
D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib