Imatinib (Glivec®, Novartis Pharmaceuticals, Basel, Switzerland) exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. The identification of the breakpoint cluster region–Abelson murine leukaemia viral oncogene homologue 1 (BCR–ABL) tyrosine kinase as a therapeutic target in chronic myeloid leukaemia and the steps in the development of an agent to specifically inactivate this abnormality will be described. The unprecedented results of clinical trials will be reviewed along with a description of resistance mechanisms and the development of novel tyrosine kinase inhibitors to circumvent resistance. As imatinib also inhibits the tyrosine kinase activity of KIT and the platelet-derived growth factor receptors, the extension of imatinib to malignancies driven by these kinases is described. Finally, the application of the paradigm of targeting molecular pathogenetic events to other malignancies is explored.
At the core of translational research is the definition of a clinical entity, followed by an understanding of its molecular pathogenesis and then development of a specific therapy based on this understanding. The development of imatinib for chronic myeloid leukaemia (CML) is an outstanding example of this paradigm of translational research, beginning with the clinical description of CML in 1845, the recognition of the BCR–ABL tyrosine kinase as the causative molecular event in CML and, ultimately, the development of an effective inhibitor of the BCR–ABL kinase. With imatinib, the overall survival rate for newly diagnosed chronic-phase patients at 5 years is 89%, with mild to moderate side-effects.
Although most patients with chronic-phase CML treated with imatinib have well-controlled disease, some patients have relapsed. One of the most useful categorizations of relapse mechanisms has been to separate patients into two categories, those with persistent inhibition of the BCR–ABL kinase and those with reactivation of the BCR–ABL kinase at relapse. From these studies, it was determined that the majority of patients who respond to imatinib and then relapse have reactivation of the BCR–ABL tyrosine kinase. Further studies showed that more than 50% of patients have BCR–ABL point mutations scattered throughout the ABL kinase domain.
Much like the original paradigm, whereby an understanding of the molecular pathogenesis of CML led to the development of imatinib, the understanding of the mechanism of resistance to imatinib led to the rapid development of new drugs to circumvent resistance. Therefore, a second generation of drugs was generated that had the ability to inhibit the most common imatinib-resistant mutations. As a result of these translational research efforts, CML has been converted from a routinely fatal disease to a manageable condition.
There are several other diseases where imatinib has shown clinical benefits that are based on an understanding of the molecular pathogenesis of the disease and knowledge of the targets of imatinib: ABL, KIT and platelet-derived growth factor receptor. One remarkable example has been gastrointestinal stromal tumours (GISTs). GISTs are mesenchymal neoplasms that can arise from any organ in the gastrointestinal tract or from the mesentery or omentum. Historically, the response rate of GISTs to single- or multi-agent chemotherapy was less than 5% and survival time with metastatic disease was less than 1 year. The majority of GISTs express KIT and, in 90% of cases, KIT activation is linked to somatic mutations. Given the sensitivity of KIT to imatinib, GISTs were a logical choice for clinical trials of this agent. In these clinical trials, the objective response rate to imatinib as a single agent in patients with advanced GIST was 53–65% with another 19–36% of patients having disease stabilization. Most importantly, imatinib resulted in a significant improvement in overall survival for patients with this disease.
The clinical trials with imatinib are a dramatic demonstration of the potential of targeting molecular pathogenetic events in a malignancy. As this paradigm is applied to other malignancies, it is worth remembering that BCR–ABL and CML have several features that were crucial to the success of imatinib. One of these is that BCR–ABL tyrosine kinase activity has clearly been demonstrated as crucial to the pathogenesis of CML. Therefore, not only was the target of imatinib known, but the target is a critical factor required for the development of CML. Another important feature is that, as with most malignancies, treatment earlier in the course of disease yields better results. Specifically, the rate and durability of responses have been greater in chronic-phase patients than in blast-phase patients. Therefore, for maximal utility as a single agent, the identification of crucial early events in malignant progression is the first step in reproducing the success with imatinib in other malignancies. Equally important is the selection of patients for clinical trials based on the presence of an appropriate target. Again, in CML, patients with activation of BCR–ABL were easily identifiable by the presence of the Philadelphia chromosome. When all of these elements are put together, a critical pathogenetic target that is easily identifiable early in the course of the disease and remarkable results with an agent that targets this abnormality can be achieved. The obvious goal is to identify these early pathogenetic events in each malignancy and to develop agents that specifically target these abnormalities.
Conflict of interest
Oregon Health & Science University (OHSU) has clinical trial contracts with Novartis, Bristol-Myers Squibb and ARIAD to pay for patient costs, nurse and data manager salaries and institutional overheads. Brian J Druker does not derive a salary nor does his laboratory receive funds from these contracts. Brian J Druker serves as a consultant to MolecularMD. OHSU and Brian J Druker have a financial interest in MolecularMD. This potential individual and institutional conflict of interest has been reviewed and managed by OHSU.