Imatinib as a Paradigm of Targeted Therapies

doi:10.1016/S0065-230X(04)91001-9

Advances in Cancer Research

Volume 91, 2004, Pages 1-30

https://doi.org/10.1016/S0065-230X(04)91001-9 Get rights and content

Abstract

Imatinib (Gleevec) exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of the BCR-ABL tyrosine kinase as a therapeutic target in chronic myeloid leukemia and the steps in the development of an agent to specifically inactivate this abnormality. The clinical trials results are reviewed along with a description of resistance mechanisms. 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 will be described. Issues related to clinical trials of molecularly targeted agents are discussed, including patient and dose selection. Last, the translation of this paradigm to other malignancies is explored.

Introduction

A wealth of knowledge has emerged regarding the molecular events involved in human cancer. A major priority is the translation of this growing body of knowledge into therapeutics targeted specifically to these pathways. Perhaps the best example in which an understanding of the molecular pathogenesis of a human malignancy has been translated into clinical reality is imatinib for chronic myeloid leukemia (CML). The success of imatinib has also exemplified how the confluence of several fields in cancer research can result in significant advances. These include the investigations of chromosomal or genetic changes in cancer, the study of transforming retroviruses leading to the discovery of oncogenes, the availability of molecular techniques to map genes, and the biochemical evaluation of protein phosphorylation leading to the discovery of tyrosine kinases. All of these have contributed to the identification of the BCR-ABL oncogene as the causative molecular abnormality of CML and the development of a drug designed to inactivate this enzyme. This review traces these discoveries and discusses some of the lessons learned in the clinical development of a molecularly targeted agent and the implications for translating this success to other malignancies.

Section snippets

Chronic Myeloid Leukemia: Clinical Features

CML is a clonal hematopoietic stem cell disorder with an annual incidence of 1 or 2 cases per 100,000 per year. The first description of CML was by two pathologists, Rudolf Virchow and John Hughes Bennett, in 1845 (Bennett 1845, Virchow 1845). Although a debate ensued as to whose description was first, Virchow acknowledged that Bennett's case report had predated his (Geary, 2000). Of note, these first accounts of CML occurred before staining methods for blood, which were not developed until the

Chemistry

Given the success of imatinib and the enormous interest in protein kinase inhibitors, it is easy to forget the degree of skepticism that kinase inhibitors faced from the scientific community and the pharmaceutical industry in the 1980s and 1990s. Much of this skepticism was due to the prevailing thought that inhibitors of ATP binding would lack sufficient target specificity to be clinically useful. However, in 1988, Yaish et al. published a series of compounds, known as tyrphostins that

Phase I Clinical Trials

A standard dose-escalation, phase I study of imatinib began in June 1998. The study population consisted of CML patients in chronic phase, refractory or resistant to IFN-α-based therapy or intolerant of this drug (Druker et al., 2001b). At later stages of the study, patients with CML in blast crisis and patients with Ph chromosome-positive ALL were also enrolled (Druker et al., 2001a). Imatinib was well tolerated, with the most common side effects including occasional nausea, periorbital edema,

Mechanisms of Relapse

Response rates to imatinib in chronic phase patients are quite high and thus far, responses have been durable. Response rates are also quite high in patients with advanced phase disease, but relapses, despite continued therapy with imatinib, have been common. This high response rate in advanced phase patients is encouraging as imatinib targets an early molecular change in a malignancy that presumably contains multiple molecular abnormalities. In all patients who have relapsed, the BCR-ABL

Structural Basis of Abl Inhibition By Imatinib

The catalytic domains of kinases include the ATP-binding lobe (P-loop), the catalytic site, and the activation loop (A-loop). In active kinases, the A-loop is in an “open” conformation, as it swings away from the catalytic center of the kinase (Fig. 8A). Whereas the conformation of the A-loop is structurally similar in kinases when they are in the active, open conformation, there are considerable differences between their inactive (closed) conformations.

The crystal structure of the catalytic

Gastrointestinal Stromal Tumors

In addition to inhibiting the ABL tyrosine kinase, imatinib inhibits the PDGFR and KIT tyrosine kinases. There are now several other cancers in which imatinib has shown clinical benefits that are based on the profile of kinases inhibited by imatinib and an understanding of the genetic defects causing various malignancies (Table II). One such disease is gastrointestinal stromal tumor (GIST). GISTs are mesenchymal neoplasms that can arise from any organ in the gastrointestinal tract or from the

Patient Selection

One of the goals of cancer research is to develop the ability to match the right patient with the right drug, based on specific knowledge of the genetic abnormalities of a tumor. The impact of this was clear in the clinical trials of imatinib. As an ABL inhibitor was being tested, enrollment was limited to patients with activated ABL driving their cancer, and these patients could be identified easily as they had the Ph chromosome or BCR-ABL.

In GIST, the situation was more complicated. In these

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 this agent. One of 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 also the

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Imatinib as a Paradigm of Targeted Therapies

Abstract

Introduction

Section snippets

Chronic Myeloid Leukemia: Clinical Features

Chemistry

Phase I Clinical Trials

Mechanisms of Relapse

Structural Basis of Abl Inhibition By Imatinib

Gastrointestinal Stromal Tumors

Patient Selection

Translating the Success of Imatinib to Other Malignancies

Blood

Blood

Biochim. Biophys. Acta

Blood

J. Biol. Chem.

Blood

Am. J. Pathol.

Blood

Blood

Hum. Pathol.

Blood Cells Mol. Dis.

Lancet

Cell

Cell

Blood

Hum. Pathol.

Cell

Am. J. Med.

Cell

Blood

Blood

Exp. Hematol.

J. Biol. Chem.

Blood

Blood

Adv. Virus Res.

Blood

Cancer Cell

Blood

Lancet

Eur. J. Cancer

Lancet

Lymphosarcoma: Virus-induced thymic-independent disease in mice

Cancer Res.

High incidence of BCR-ABL kinase domain mutations in CML patients with secondary resistance to imatinib

Hematol. J.

Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor β

N. Engl. J. Med.

Mutation in the ATP-binding site of BCR-ABL in a patient with chronic myeloid leukaemia with increasing resistance to STI571

Br. J. Haematol.

The chronic myelogenous leukemia-specific P210 protein is the product of the bcr⧸abl hybrid gene

Science

Case of hypertrophy of the spleen and liver in which death took place from suppuration of the blood

Edinb. Med. Surg. J.

Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148)

Clin. Cancer Res.

Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative

Cancer Res.

The Tel platelet-derived growth factor β receptor (PDGF-β-R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF-β-R kinase-dependent signaling pathways

Proc. Natl. Acad. Sci. USA

A novel Abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia

Nature

Unique forms of the Abl tyrosine kinase distinguish Ph1-positive CML from Ph1-positive ALL

Science

Expression of a distinctive BCR-ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL)

Science

Altered transcription of the c-abl oncogene in K-562 and other chronic myelogenous leukemia cells

Science

A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome

N. Engl. J. Med.

Induction of chronic myelogenous leukemia in mice by the P210bcr⧸abl gene of the Philadelphia chromosome

Science

Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-Abl proteins with similar in vitro kinase properties

Mol. Cell. Biol.

A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukemia

Nature

Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors

N. Engl. J. Med.

Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing M_r 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148)