Glivec^® (imatinib), the first molecularly targeted cancer treatment, has revolutionised the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST). Glivec has shown the ability to act as a precise molecular tool with documented effectiveness and activity against both conditions. Glivec, which is better tolerated than previous treatment options, targets cancer growth by blocking specific aberrant tyrosine kinases that control pathways to proliferation.

Here, you’ll find detailed information about the science behind Glivec and how Glivec works to target CML and GIST.

To understand how Glivec works, it is necessary to start at the cellular level.

Healthy tissues require activation by specific extracellular signalling ligands to initiate replication. The activation gatekeepers are tyrosine kinase molecules, present either on the cell surface or in the cytoplasm. Cytokines or ligands initiate the signals to begin replication by binding to tyrosine kinases, activating their adenosine triphosphate (ATP) binding sites. These activation signals trigger a cascade of events that eventually lead to cell division. During the course of normal, controlled cell growth, when the activation signals stop, replication stops.

Many cancers, including CML and GIST, bypass the need for a signalling ligand (also known as cytokine-independent signalling). Membrane-bound tyrosine kinases (TK) and nonreceptor TK molecules in the signalling chain mutate and become constitutively active, resulting in uncontrolled cell division. By blocking ATP binding sites on specific mutant tyrosine kinases, Glivec directly interferes with the downstream propagation of signals to the nucleus, inhibiting the growth of tumour cells. Glivec has also demonstrated activity in blocking the signalling pathways tumours exploit to enhance their microenvironment to further support growth.

Glivec was first approved in May of 2001, for the treatment of CML, a life-threatening form of cancer that accounts for about 15%-20% of all adult leukaemias^{48, 49}. Leukaemias account for 300,000 new cases (~3% of all new cancer cases) each year and 220,000 deaths worldwide⁵⁰.

Unrestricted cell division and extended cell survival are the hallmark features of cells found in patients with CML. CML is characterised by an abnormal chromosome, the Philadelphia (Ph) chromosome, detected in approximately 95% of patients with CML⁵¹. The Ph chromosome results from an exchange of genetic material, or translocation, between chromosomes 22 and 9. The resulting BCR-ABL fusion gene of the Ph chromosome codes for a protein that is a constitutively activated tyrosine kinase, resulting in the uncontrolled blood cell proliferation characteristic of CML.

The hybrid oncoprotein BCR-ABL influences cell growth through 3 mechanisms^{51, 52}:

• Increased signal transduction, activation of proliferation pathways, and increased cytokine-independent growth
• Inhibition of pathways that normally lead to apoptosis
• Alterations of pathways and other cytoskeletal processes that result in the failure of CML cells to organise, adhere, and transfer signals within bone marrow

ATP molecules bind to a site in the BCR-ABL kinase and drive the continuous signalling for cell propagation. Glivec is designed to selectively bind to the BCR-ABL ATP-binding pocket. By binding to this active site, Glivec switches off downstream signalling, cells stop proliferating, and apoptosis ensues.

Glivec was first approved for the treatment of GIST in February 2002. The epidemiology of GISTs is still not completely known, since historically, GIST was misdiagnosed or went undiagnosed⁵³. This formerly "rare" disease is now recognized as having a much higher incidence than previously thought. Under the current, widely accepted definition of GIST, European studies and US estimates are in agreement: the incidence of GIST is in the range of 10-20 cases per million^54-56.

In the majority of GISTs, the interstitial cells of Cajal, which mediate peristalsis in the upper intestine, undergo uncontrolled growth. Growing tumours stimulate angiogenesis or formation of new blood vessels via production of cytokines, such as vascular endothelial growth factor (VEGF). Cells located within the growing blood vessels then secrete other cytokines, including platelet-derived growth factors (PDGFs). These bind to associated PDGF receptors on pericytes, resulting in increased vascular and endothelial cell stability.

Approximately 95% of GISTs stain positive for KIT (CD117) in immunohistochemical tests⁵⁷. About one third of the remaining GISTs are found to have abnormal PDGFRα⁵⁸. These 2 proteins are responsible at the molecular level for GIST tumorigenesis.

The ligands stem-cell factor (or steel factor) and PDGF bind to the tyrosine kinase receptors (TKRs) KIT and PDGFRα, respectively. During normal cell growth, binding of these ligands to their respective receptors leads to phosphorylation in intracellular domains of the receptors. The resulting intracellular signalling leads to cell growth, changes in cell morphology, and prevention of apoptosis when new cells are needed^{59, 60}.

In GIST, constitutive activity of KIT and PDGFRα is associated with mutations in the genes that encode these TKRs. GISTs expressing activating mutations in either of these TKRs have a similar oncogenic phenotype. Constitutive TKR activation in the absence of ligand binding leads to abnormal ligand-independent cell growth, changes in cell morphology, and prevention of apoptosis^{35, 58, 60, 61}.

ATP molecules bind to mutated KIT and PDGFRα receptors and drive the continuous signalling for cell propagation. Glivec is designed to selectively bind to the mutated KIT and ATP-binding pocket. By binding to this active site, Glivec switches off downstream signalling, cells stop proliferating, and apoptosis ensues.

Since the development of Glivec in the early 1990s as a potent inhibitor of the BCR-ABL kinase, researchers have demonstrated the importance of other molecular targets in haematological malignancies other than CML, as well as in many solid tumours. Over time, researchers have also discovered that Glivec has activity against additional kinase targets. Glivec is a highly potent yet selective kinase inhibitor that spares kinase-mediated signal transduction essential for normal cell growth (eg, epidermal growth factor, insulin, insulin-like growth factor I).

In addition to inhibiting ABL and BCR-ABL at concentrations in the micromolar range, Glivec blocks receptor tyrosine kinase family members, including PDGFRα, PDGFRβ, and KIT, the receptor for stem-cell factor or steel factor. Glivec also inhibits the macrophage colony-stimulating factor c-Fms, as well as ARG, another protein-tyrosine kinase structurally related to ABL.

Find out about the Human Impact of Glivec.