Gastrointestinal stromal tumours (GISTs) are soft tissue tumours that originate from the precursors of the interstitial cells of Cajal (ICCs), the pacemaker cells of the gastrointestinal (GI) tract that regulate autonomous contractions. Although GISTs are rare tumours with an estimated annual incidence of about 15 cases per million, they comprise the most common non-epithelial malignancies of the digestive tract. It is of great importance to differentiate GISTs from leiomyomas and leiomyosarcomas upon diagnosis, because these tumours differ in their molecular pathology and clinical behaviour. The median age at diagnosis is approximately 60 and more than 40% of these tumours are overtly malignant with presence of metastasis. GISTs are most commonly found in the stomach (40%), the small intestine (30%) or the colon and rectum (10%), but in rare occasions they can also be found in the oesophagus, omentum, mesentery or the retro peritoneum.
Unlike epithelial tumours, which often grow within the intestinal lumen causing early erosion and ulceration of the lumen, GISTs tend to grow rather parallel to the intestinal lumen and between the intra-abdominal organs. This typical growth pattern causes ulceration of the overlying GI mucosa at a relatively late stage and explains why many GISTs are large in size at the time of diagnosis (median 8cm diameter). Large GISTs are often necrotic and haemorrhagic and may bleed into the abdominal cavity or intestinal lumen. About 30% of GISTs invade the surrounding structures at the time of presentation, which often hampers a complete surgical removal of the tumour. GISTs also easily spill into the abdominal cavity during surgery, which is associated with a high risk of tumour recurrence. Surgery has been the only effective treatment for GISTs for decades. Radiotherapy and conventional chemotherapy were usually not successful. Until recently, there was no effective treatment for metastatic or recurrent GISTs besides surgery and most patients with high risk GISTs usually died within the first two years after diagnosis; however, the growing insights into the molecular pathological mechanisms of GISTs have led to a revolution in cancer treatment.
S i g n a l T r a n s d u c t i o n
The majority of GISTs express the KIT transmembrane receptor tyrosine kinase (TK) for the stem cell factor (SCF), which is normally involved in haematopoiesis, gametogenesis and intestinal motility. In normal circumstances, the intracellular domain of this protein activates a signal transduction cascade upon binding of SCF to the extracellular domain. This signal transduction involves many messenger proteins that pass the signal from the cellular surface to the nucleus, where it finally results in cellular division. This strictly controlled mechanism regulates the normal growth and function of the cells of Cajal, which are responsible for gastric motility. Up to 90% of all malignant GISTs harbour gain-offunction mutations in the gene that encodes the KIT protein, which render the KIT protein constitutively active without the presence of its extracellular activator protein (SCF). About 8% of all GISTs harbour gain-of-function mutations in a similar receptor TK, the platelet-derived growth factor receptor alpha (PDGFRa), which belongs to the same family as the KIT protein. Most other tumours are the result of an accumulation of several gain-offunction mutations in similar proteins, together with loss-of-function mutations in genes that encode tumour suppressor proteins. The presence of only one mutation driving the growth of GISTs is rather exceptional and makes this tumour an ideal model for scientific research.
I m a t i n i b
In the past decade academic institutions, together with pharmaceutical companies, have developed antibodies and small molecule inhibitors that are able to interfere with growth factors, growth factor receptors and signal transduction proteins. Imatinib mesylate (also known as STI571, generic names Glivec® in Europe and Gleevec® in the US, developed by Novartis), was originally designed as a selective inhibitor of the oncoprotein BCR-ABL, which drives chronic myelogenic leukaemia (CML). Imatinib competes for ATP in the intracellular binding site of BCR-ABL and several tyrosine kinases, including KIT (see Figure 1). In CML it results in a high response rate and is now registered worldwide for first-line treatment. Imatinib also offers the first effective systemic treatment for GISTs. The drug is orally administered in well tolerated daily doses ranging from 400mg to 800 mg. In about two-thirds of GIST patients treated with Imatinib, a reduction in tumour volume of more than 50% can be achieved and in approximately 90% symptoms can be relieved. Response to Imatinib can occur rapidly, but regression can also be slow, particularly after an initial phase of rapid tumour regression. The median time to response is approximately 13 weeks. Trials comparing 12 or 24 months of adjuvant therapy after complete surgical resection are on-going. Responses lasting up to 48 months have been observed in patients with metastatic disease and it is strongly recommended not to interrupt Imatinib administration in these patients.
The response to treatment with Imatinib strongly depends on the type of KIT mutation. In a randomised phase II trial 84% of GIST patients with exon 11 mutation responded to Imatinib, compared with only 48% of patients with exon 9 mutation. Acquired resistance has also been observed in patients who initially responded to Imatinib. The underlying mechanisms of resistance to Imatinib are not yet clear.
O t h e r S i g n a l T r a n s d u c t i o n I n h i b i t o r s
Other small molecule inhibitors affecting similar TK receptors or downstream messenger proteins involved in signal transduction may be effective for the treatment of metastatic GISTs that are resistant to Imatinib. These compounds are best used in combination with Imatinib, because the majority of the cells of progressive tumours still respond to Imatinib. If administration of Imatinib to these patients is interrupted, this can result in a much faster progression. RAD001 (Novartis) is an inhibitor of the signal transduction protein mTOR, through which many Imatinib-resistant GISTs escape. In combination with Imatinib, a response of more than 30% can be observed in patients with Imatinib-resistant GISTs.
SU11248 (Pfizer) is a compound similar to Imatinib that inhibits the TKs KIT and PDGFRa, but also FLT3, a receptor for the vascular endothelial growth factor (VEGF), thereby adding an additional antiangiogenic effect. Tumours require angiogenesis (the formation of new blood vessels from the existing vasculature) to grow beyond a critical size and to metastasise. Anti-angiogenic compounds are promising for the future treatment of various types of cancer. SU11248 has been shown effective in the treatment of Imatinib-resistant GISTs. AMG706 (Amgen) is very similar to SU11248 and is currently also being tested in a phase II clinical trial for patients who were progressive under Imatinib treatment. PKC412 (Novartis) is an inhibitor of protein kinase C (PKC), a very important messenger protein in signal transduction. PKC412 is currently being tested in combination with Imatinib in phase I/II clinical trials. BMS-354825 (Bristol-Myers Squibb) inhibits KIT and PDGFRa TKs, but also the Src kinase, an important messenger protein in signal transduction. BMS-354825 is currently being evaluated in several phase I trials.
C o n c l u s i o n s a n d P e r s p e c t i v e s
Although GISTs are rather rare malignancies, their relatively simple molecular biological background has put them at the forefront of both fundamental and applied cancer research. A lot of new, specific therapies with signal transduction inhibitors are, or soon will be, tested in clinical trials. Combination treatments with different signal transduction inhibitors are preferred over single agent treatments. Scientific research will give further insights into the mechanisms that are responsible for resistance to Imatinib. This will allow future resistance predictions at an early stage and avoid therapeutic failure by combining the right compounds for the individual patient. The experience with signal transduction inhibitors for the treatment of GISTs opens new opportunities for the treatment of a large variety of cancers in the next decade. ¦