Table of Contents  

Druker: Imatinib (Glivec®) as a paradigm of targeted cancer therapies

Introduction – translational research

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 (Glivec®, Novartis Pharmaceuticals UK Ltd, Basel, Switzerland) 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. Translational research did not end with the clinical trials of imatinib, as there was still much to learn about resistance to imatinib, which led to the development of several additional inhibitors of the ABL kinase. As a result of these translational research efforts, CML has been converted from a routinely fatal disease to a manageable condition.

Clinical description of chronic myeloid leukaemia

Chronic myeloid leukaemia was first described by two pathologists, Dr Rudolf Virchow and Dr John Hughes Bennett, in 1845.1,2 These first accounts of CML occurred prior to staining methods for blood, which were not developed until the late 1800s. We now know that CML is a clonal haematopoietic stem cell disorder with an incidence of 1 to 2 cases per 100,000 per year and with no clear geographic variations in incidence.3 The only known risk factor for development of CML is exposure to radiation in high doses, which became evident from studies of survivors of the atom bomb explosions in Japan in 1945.4

The chronic, or stable, phase of CML is characterized by excess numbers of myeloid cells that differentiate and function normally. Between 90% and 95% of patients will be diagnosed in this phase of the disease. Historically, within an average of 4–6 years, the disease transforms through an ‘accelerated phase’ to an invariably fatal acute leukaemia, also known as blast crisis. Disease progression is probably the result of the accumulation of molecular abnormalities that lead to a progressive loss of the capacity for terminal differentiation of the leukaemic clone.5

Molecular pathogenesis of chronic myeloid leukaemia

In 1960, Peter Nowell and David Hungerford described a consistent chromosomal abnormality in CML patients which was thought to be a chromosomal deletion.6 This was the first example of a chromosomal abnormality linked to a specific malignancy and was named the Philadelphia (Ph) chromosome after the city in which it was discovered. In 1973, Dr Janet Rowley determined that the shortened chromosome 22, the so-called Ph chromosome, was the product of a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9:22)(q34;q11) (Figure 1).7 Throughout the 1980s, by mapping oncogenes to specific chromosomal locations, it was recognized that the c-ABL tyrosine kinase, which normally resides on chromosome 9, had been translocated to chromosome 22 in patients with CML.8 As the breakpoints on chromosome 22 clustered in a relatively small region that spanned 5.3 kb, this region was named the breakpoint cluster region, or BCR.9,10 Shortly thereafter, Shtivelman et al.11 showed that a chimeric mRNA, called BCR-ABL, which was larger than the normal c-ABL mRNA, was present in patients with CML.11 One year later, Owen Witte and David Baltimore demonstrated that a chimeric BCR-ABL protein was made and that it possessed tyrosine kinase activity.12,13 BCR-ABL has elevated tyrosine kinase activity compared with c-ABL and the kinase activity of BCR-ABL is essential for its ability to transform cells.14,15 In 1990, John Groffen’s laboratory and George Daley in David Baltimore’s laboratory put BCR-ABL into animal models and demonstrated that BCR-ABL is the sole oncogenic event that induces leukaemia,16,17 thus establishing BCR-ABL as a leukaemic oncogene.

FIGURE 1

Schematic diagram of the translocation that creates the Ph chromosome. The ABL and BCR genes reside on the long arms of chromosomes 9 and 22, respectively. As a result of the (9;22) translocation, a BCR-ABL gene is formed on the derivative chromosome 22 (the Ph chromosome).

7-3-1-fig1.jpg

Thus, the period from 1960 to 1990 identified BCR-ABL as an ideal therapeutic target in patients with CML. It is expressed in all patients with CML and it has been shown to be the cause of the disease. BCR-ABL functions as a constitutively activated tyrosine kinase and mutagenic analysis has shown that this activity is essential for the transforming function of the protein. For these reasons, an inhibitor of the BCR-ABL kinase would be predicted to be an effective and selective therapeutic agent for CML (Figure 2).

FIGURE 2

(a) The constitutively active BCR-ABL tyrosine kinase functions by transferring phosphate from adenosine triphosphate (ATP) to tyrosine residues on various substrates to cause excess proliferation of myeloid cells characteristic of CML. (b) Imatinib (STI571) blocks the binding of ATP to the BCR-ABL tyrosine kinase, thus inhibiting kinase activity.

7-3-1-fig2a.jpg7-3-1-fig2b.jpg

Development of an ABL-specific tyrosine kinase

Given the success of imatinib and the large number of protein kinase inhibitors that are currently available, it is easy to forget the degree of scepticism that kinase inhibitors faced from the scientific community and the pharmaceutical industry in the 1980s and 1990s. Much of this scepticism was due to the prevailing thought that inhibitors of ATP binding would lack sufficient specificity to be useful clinically. Another concern was the belief that tyrosine kinase inhibitors would be extremely toxic owing to the finding that some of the early tyrosine kinase null animals had an embryonic lethal phenotype.18 From a clinical oncology viewpoint, there was considerable scepticism that targeting of a single molecular defect would be sufficient to treat highly heterogeneous cancers. Lastly, the pharmaceutical industry was concerned that it would never make sufficient profits to justify drug development efforts, given the relatively small size of the CML patient population. All of these concerns were obviously overcome with the development of imatinib, including the profitability of the drug, but given that this was the first kinase inhibitor developed, it is worth recalling some of these hurdles.

Working in Dr Thomas Roberts’ laboratory at the Dana-Farber Cancer Institute (Boston, MA, USA), I developed the antiphosphotyrosine antibody, 4G10.19 This antibody allowed the detection of the activity of tyrosine kinases, tyrosine phosphorylation, and was essential to detecting the ability of chemical compounds to inhibit tyrosine kinases. This antibody was used by Nicholas Lydon’s group at Ciba-Geigy (Basel, Switzerland), one of the few drug companies interested in developing kinase inhibitors. While the Ciba-Geigy group was working to identify kinase inhibitors, I decided to combine my emerging expertise in tyrosine kinase signalling with my background in oncology and established model systems to study BCR-ABL signalling.

By 1993, Nicholas Lydon’s group had developed several inhibitors of the platelet-derived growth factor receptor (PDGFR) tyrosine kinase, and several of these also inhibited the ABL tyrosine kinase.20 Nicholas sent me a variety of compounds for testing and my laboratory, now at the Oregon Health & Science University (Portland, OR, USA), identified STI571 (imatinib) as the compound that was the most specific at killing BCR-ABL-expressing cells in vitro and in vivo.21 We also demonstrated that imatinib had potent activity against KIT,22 with minimal activity against a broad range of other tyrosine and serine/threonine kinases, demonstrating that it had a high level of selectivity.23 Imatinib ultimately emerged as the lead compound for preclinical development based on its selectivity against CML cells in vitro and its drug-like attributes, including pharmacokinetic and formulation properties.24

Clinical trials of imatinib

Having designed the clinical trials of imatinib, I then served as the principal investigator on a series of studies, the first of which was a standard dose-escalation phase I study that began in June 1998. The study population consisted of patients with CML in the chronic phase who were refractory or resistant to interferon-alpha-based therapy, or intolerant of this drug. Once doses of 300 mg and above were obtained, significant therapeutic benefits were observed while side-effects were relatively minimal. The common side-effects included occasional nausea, periorbital oedema and muscle cramps. In this study, 53 of 54 (98%) patients who were treated with imatinib doses of 300 mg and above achieved a complete haematological response, and with 1 year of follow-up only one of these patients relapsed.25 The phase I study was expanded to patients with myeloid blast crisis, and 21 of 38 (55%) patients who were treated with doses of > 300 mg per day responded, with 18% having responses lasting beyond 1 year.26

These remarkable phase I data led to rapidly accruing phase II clinical trials that were conducted at 30 sites in six countries. These clinical trials confirmed the results seen in the phase I studies and led to US Food and Drugs Administration (FDA) approval of imatinib in May 2001, less than 3 years after the start of the phase I study. Among chronic-phase patients who were resistant to, or intolerant of, interferon-alpha, 95% achieved a complete haematological response and 60% a major cytogenetic response, defined as a reduction in the percentage of Ph chromosome-positive metaphases to < 35%. With a median follow-up of 29 months, only 13% of these patients relapsed.27 The estimated rates of freedom from progression to accelerated phase and blastic phase and of overall survival at 6 years were 61% and 76%, respectively.28 In accelerated-phase and blast crisis patients, the response rates were also quite high, but relapses were much more common, with the majority of blast crisis patients relapsing during the first year of therapy.29,30

A phase III study in newly diagnosed chronic-phase patients comparing imatinib with standard therapy with interferon-alpha plus cytarabine (Ara-C) was opened at 177 centres in 16 countries and accrued over 1000 patients in a 7-month period. A total of 553 patients were randomized to each of the two treatments, imatinib at 400 mg per day or interferon-alpha plus Ara-C. There were no significant differences in prognostic features on the two arms. With a median follow-up of 19 months, patients randomized to imatinib had significantly better results than patients treated with interferon-alpha plus Ara-C in all parameters measured, including rates of complete haematological response (97% vs. 56%, P < 0.001), major and complete cytogenetic responses (85% and 74% vs. 22% and 8%, P < 0.001), discontinuation of assigned therapy caused by intolerance (3% vs. 31%) and progression to accelerated phase or blast crisis (3% vs. 8%, P < 0.001) (Figure 3A).31 The substantial superiority of imatinib resulted in study results being disclosed early and most patients being crossed over to the imatinib arm. Accordingly, this study is now a long-term follow-up study of patients who received imatinib as initial therapy.

FIGURE 3

Phase III results of imatinib for newly diagnosed patients with CML. (a) Results for newly diagnosed patients in the chronic phase with a median follow up of 18 months. (b) A 5-year survival curve for newly diagnosed patients with chronic phase CML treated with imatinib. Overall survival among patients treated with imatinib is shown based on an intention-to-treat analysis.32

7-3-1-fig3a.jpg7-3-1-fig3b.jpg

In the most recent update of this phase III study, the overall survival for newly diagnosed chronic-phase patients treated with imatinib at 5 years is 89% (Figure 3B). An estimated 93% of imatinib-treated patients remain free from disease progression to the accelerated phase or blast crisis. An additional 6% of patients have shown some evidence of loss of response to imatinib, but their disease has not progressed to the accelerated phase or blast crisis.32 Most of the side-effects of imatinib are mild to moderate, with the most common being oedema, muscle cramps, diarrhoea, nausea, skin rashes and myelosuppression. Thus, imatinib therapy has substantially increased survival for patients with CML while simultaneously offering a generally well-tolerated oral therapy. Despite the fact that the most patients randomized to imatinib achieve a complete cytogenetic response, the majority of these patients have detectable leukaemia as analysed by reverse transcriptase-polymerase chain reaction (RT-PCR) for BCR-ABL.33 Thus, most patients treated with imatinib have persistent disease at the molecular level, although among the fraction of patients whose transcript levels are persistently undetectable, 40% have been able to discontinue therapy for up to 3 years without relapsing.34

Mechanisms of relapse

Although most patients with chronic-phase CML treated with imatinib have well-controlled disease, some patients have relapsed and/or progressed to accelerated phase or blast crisis.32 Most patients with advanced phases of CML respond initially to imatinib but subsequently relapse.25,29,30 Therefore, the mechanisms of relapse emerged as a major question.

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. Patients with persistent inhibition of the BCR-ABL kinase would be predicted to have additional molecular abnormalities besides BCR-ABL driving the growth and survival of the malignant clone. In contrast, patients with persistent BCR-ABL kinase activity or reactivation of the kinase would be postulated to have resistance mechanisms that either prevent imatinib from reaching the target or render the target insensitive to imatinib. In the former category are mechanisms such as drug efflux or protein binding of imatinib and in the latter category would be mutations of the BCR-ABL kinase that render BCR-ABL insensitive to imatinib or amplification of the BCR-ABL protein.

To examine BCR-ABL kinase activity, my laboratory developed an assay that looked at the phosphorylation state of the Crk-like protein (CRKL),25 which we had previously shown is the major tyrosine-phosphorylated protein in CML patient samples.35 Using this assay, it was determined that the majority of patients who respond to imatinib and then relapse had reactivation of the BCR-ABL tyrosine kinase.36 In these studies, more than 50% of patients had BCR-ABL point mutations scattered throughout the ABL kinase domain (Figure 4).37,38 Other patients had amplification of BCR-ABL at the genomic or transcript level. In contrast, in patients with primary resistance, i.e. patients who do not respond to imatinib therapy, BCR-ABL-independent mechanisms are most common.39

FIGURE 4

Schematic diagram of point mutations in the ABL kinase domain. The ABL kinase domain, from amino acids 240 to 500, is shown with the ATP binding domain (P), the catalytic domain (C) and the activation loop (A). The numbers below the kinase domain are amino acids that are mutated in patients who relapsed during therapy with imatinib. The vertical lines above the kinase domain indicate the number of times each amino acid has been found to be mutated.23

7-3-1-fig4.jpg

Second-generation BCR-ABL inhibitors

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. Thus, a second generation of drugs was generated that had the ability to inhibit the most common imatinib-resistant mutations. One such drug, nilotinib (Tasinga®, Novartis Pharmaceuticals UK Ltd, Basel, Switzerland), is a structurally modified form of imatinib that binds more tightly to the ABL kinase than imatinib.40 Dasatinib (Sprycel®, Bristol–Myers Squibb Pharmaceuticals Ltd, NY, USA) and bosutinib (Bosulif®, Pfizer Ltd, NY, USA) belong to a structurally unique class of ABL kinase inhibitors. They are also more potent than imatinib at inhibiting the ABL kinase, but, owing to their binding mode to the ABL kinase, they inhibit more kinases than imatinib or nilotinib.41,42 All of these second-generation drugs inhibit the majority of imatinib-resistant mutations with the exception of ABL T315I. This threonine residue lies at the entry to the ATP binding site and is also known as the gatekeeper residue. A bulkier isoleucine residue at this position prevents the binding of all four of these kinase inhibitors. Ponatinib (Iclusig®, ARIAD Pharma UK Ltd, Cambridge, MA, USA) was developed as a compound to circumvent resistance to ABL T315I and inhibits all known imatinib-resistant mutations.43

All four of these compounds, dasatinib, nilotinib, bosutinib and ponatinib, progressed rapidly through clinical trials, and all are FDA approved for patients with resistance or intolerance to imatinib. All show significant activity and good durability of responses in patients with relapsed, chronic-phase disease.4449 There have been four randomized studies comparing imatinib with newer agents in patients newly diagnosed with CML, one each of imatinib to nilotinib and bosutinib, and two comparing dasatinib and imatinib.5055 A few generalities emerge from these studies. All therapies are extremely effective with excellent progression-free survival. The newer, more potent, tyrosine kinase inhibitors induce faster cytogenetic and molecular responses, but only the imatinib compared with nilotinib study has translated this into a small, but statistically significant, difference in progression-free survival at 3 years. In the other studies there was either no difference or a trend to improved progression-free survival, but no studies have shown a significant difference in overall survival. As most relapses on imatinib occur in the first 3 years, it is unlikely that additional follow-up will lead to significant changes in these data. Currently, imatinib, nilotinib and dasatinib are approved for newly diagnosed patients with chronic-phase disease and there is no strong rationale for choosing among the three. The exception is in patients whose disease is more biologically advanced as defined by a combination of features that generate a Sokal risk score. Historically, this score predicted time to disease progression to advanced phase disease. In the era of tyrosine kinase inhibitor therapy, patients with a higher-risk Sokal score respond less well to imatinib and would therefore be candidates for therapy with nilotinib or dasatinib.

Imatinib and gastrointestinal stromal tumour

In addition to its activity in CML, imatinib is also a highly active agent for the treatment of gastrointestinal stromal tumours (GISTs). GISTs are mesenchymal neoplasms that can arise from any organ in the gastrointestinal tract, or from the mesentery or omentum, with an annual incidence of approximately 5000 cases in the USA. Although GISTs morphologically resemble leiomyosarcomas and nerve sheath tumours, they are a distinct entity. The majority of GISTs express KIT, and in 90% of cases KIT activation is linked to somatic mutations, usually involving exon 9 or 11.56,57 Published data suggest that the response rate of GISTs to single- or multiagent chemotherapy is less than 5%.

Given the sensitivity of KIT to imatinib, GISTs were another rational tumour for clinical trials for 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.58,59 These clinical trials served as the basis for the FDA approval of imatinib for GIST and have resulted in a significant improvement in overall survival for patients with this disease. They have also led to further explorations of the utility of imatinib in the adjuvant and neoadjuvant setting, as the recurrence rate of GISTs after surgery is quite high. Again, substantial improvements in outcomes have been observed in these indications.

Activity of imatinib in other diseases

There are several other diseases for which 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 PDGFR. Another disease in which ABL is targeted by imatinib is BCR-ABL-positive acute lymphoblastic leukaemia. Imatinib has significant activity in these patients, but responses to single agent therapy are generally transient.60 Data from paediatric clinical trials have shown that combinations of imatinib with standard chemotherapy reverse the negative prognosis conveyed by the presence of the Ph chromosome.61 Besides GIST, in which KIT is the therapeutic target, a low percentage of patients with melanoma harbour KIT mutations and respond dramatically to imatinib.62

Translocations involving the platelet-derived growth factor receptor-beta (PDGFRB) gene have been identified in several myeloproliferative and myelodysplastic syndromes. The most common of these translocations, t(5;12)(q33;p13), is seen in a subset of patients with chronic myelomonocytic leukaemia (CMML) and results in fusion of the EVT6 (TEL) and PDGFRB genes.63 Patients with CMML containing the (5;12) translocation have been treated with imatinib and significant responses have been observed.64,65 PDGFRB is also activated by a chromosomal translocation in dermatofibrosarcoma protuberans (DFSP). DFSP is a low-grade sarcoma of the dermis that often recurs after surgical excision. These tumours are characterized by a (17;22) translocation involving the COL1A1 and PDGF-B genes, resulting in overproduction of the fusion COL1A1–PDGF-BB ligand and consequent hyperactivation of PDGFRB,66 thus making this disease a rational choice for treatment with imatinib.67,68

The activity of imatinib in hypereosinophilic syndrome serves as an interesting example. Imatinib was tried empirically in this disorder and dramatic results were observed.69 Investigations of the molecular basis for the activity of imatinib in this disease demonstrated that an intrachromosomal deletion on chromosome 4 resulted in a fusion between a gene of unknown function, FIP1L1, and a truncated platelet-derived growth factor receptor-alpha gene (PDGFRA) in a large percentage of patients with this disorder.70,71 The resulting FIP1L1–PDGFRA fusion protein is a constitutively activated tyrosine kinase that is imatinib sensitive, thus accounting for the responsiveness of this disease to imatinib. The important message from this example is that careful study of responding patients can yield significant insights into disease pathogenesis.

Translating the success of imatinib to other malignancies

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 critical to the success of imatinib. One is these is that BCR-ABL tyrosine kinase activity has clearly been demonstrated to be critical to the pathogenesis of CML. Thus, not only was the target of imatinib known, but the target was discovered to be a critical factor required for the development of CML. Another important feature is that, as with most malignancies, treatment earlier in the course of the disease yields better results. Specifically, the response rate and durability of responses has been greater in chronic-phase patients than in blast-phase patients. Thus, 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. An equally as important issue is the selection of patients for clinical trials based on the presence of an appropriate target. Again, in the CML experience, patients with activation of BCR-ABL were easily identifiable by the presence of the Ph chromosome. When all of these elements are put together – a critical pathogenetic target that is easily identifiable early in the course of the disease – 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.

Conflicts of interest

Oregon Health & Science University has clinical trials contracts with Novartis, Bristol–Myers Squibb and ARIAD to pay for patient costs, nurse and data manager salaries, and institutional overheads. Brian Druker does not derive salary, nor does his laboratory receive funds, from these contracts. Brian Druker serves as a consultant to MolecularMD (www.molecularmd.com). Oregon Health & Science University and Brian Druker have a financial interest in MolecularMD. This potential individual and institutional conflict of interest have been reviewed and managed by Oregon Health & Science University.

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