OncoloGIST, BioloGIST, RadioloGIST: the big impact on the field of oncology of a molecularly-targeted therapy designed to treat a rare disease

Abstract

The field of oncology is now in a period of enlightkeep KIT and other kinase signalling under close regenment, linking scientific and clinical progress. The basic principles of cancer biology, which have been systematically explored over the past three decades, are now being translated into effective, new clinical therapeutic strategies. The paradigm of this work has been the development of selective tyrosine kinase inhibiting agents, of which Imatinib (Glivec/Gleevec, made by Novartis Pharmaceuticals of Basel Switzerland) is the most studied and clinically developed example. Two papers, published in this issue of the European Journal of Cancer [1,2], further demonstrate the impact this agent has had on the fundamental principles of clinical investigation and translational research. Imatinib is a translational product of many decades of insightful work into the molecular biology of oncogenes, leukaemia and signal transduction. Drs Brian Druker, Nicholas Lyden, Alex Matter and colleagues at Novartis, in association with other investigators worldwide, proved the principle that inhibition of the uncontrolled tyrosine kinase activity of the chimeric BCRABL oncoprotein could lead to clinical and molecular remissions of leukaemias in which this oncoprotein was present. This has revolutionised the treatment of chronic myeloid leukaemia (CML) and molecularlyrelated haematological malignancies. The impact of Imatinib has been expanded beyond the BCR-ABL target. Specifically, insights were made from the laboratory study of Hirota and colleagues in Japan on a solid tumour, gastrointestinal stromal tumour (GIST) [3], a form of sarcoma totally unconnected with leukaemia or the oncogenic signalling of BCR-ABL. This group detected an uncontrolled mutant form of a completely different tyrosine kinase known as KIT. In their small, but important, study, they showed that most GIST cells had activated the KIT kinase in an uncontrolled manner. Normal cells ulatory supervision but, in GIST cells, this regulation does not exist. Clearly, this is analogous to the situation in CML, although involving an entirely different molecular pathway. Fortuitously, the same rationallydesigned agent, Imatinib, had the ability to inhibit mutated KIT in GIST as well as the BCR-ABL products in CML [4,5]. Investigators were able to test these hypotheses in the clinic with mutated KIT as the target. The observations have been extremely consistent across multiple studies which have all shown that Imatinib possesses an unprecedented efficacy against most GISTs [6–8]. The extrapolation of the key message of this work to other forms of cancer provides a message of hope, as well as a strategically important caveat: find the key pathogenomic difference between the cancer and normal cell, therapeutically target it, and one should be able to make clinically extraordinary advances against that form of cancer. This sounds simple and elegant. However, in truth, this process will continue to be a complex undertaking, since we can assure ourselves only occasionally that a specific molecular abnormality is truly a ‘key’ difference between the cancer and normal cell. Cancer cells have many differences that distinguish them from normal cells [9]. The difficulty is in identifying which of these many differences would be necessary and sufficient to target in order to see clinical benefits in our patients. In the paper by Verweij and colleagues, the success of the previously smaller study of the European Organisation for Research and Treatment of Cancer (EORTC) [7], which demonstrated the activity of Imatinib in GIST, is confirmed. However, these authors also caution that Imatinib is not a molecular panacea for all forms of cancer. Although there was a rationale for targeting forms of sarcoma other than GIST on the basis of the expression of the platelet-derived growth factor (PDGF) receptor, Imatinib showed little activity against other