Imatinib mesylate (Gleevec/Glivec, Novartis, Basel, Switzerland), formerly called STI571, is a specific and potent inhibitor of the BCR-ABL tyrosine kinase, the molecular hallmark of chronic myeloid leukaemia. Several clinical trials have demonstrated the efficacy of imatinib in different phases of this disease. On the other hand, imatinib is also active against other tyrosine kinases, such as ABL, the stem cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this regard, imatinib has already shown a remarkable activity in patients with hypereosinophilic syndrome and gastrointestinal stromal tumours. Imatinib is an example of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a molecular-targeted therapy.

The International Conference on Molecular Targets and Therapeutics, jointly sponsored by the American Association for Cancer Research (AACR), National Cancer Institute (NCI) and European Organization for Research and Treatment of Cancer (EORTC), was held in Boston on November 17-21, 2003. It offered updates of the latest developments and emerging trends in anti-cancer research. One of the most exciting areas was the development of molecular target-specific therapeutics that have the potential to maximize therapeutic benefit while minimizing toxicity to normal cells. Signifying the coming of age of tumour-specific targets and agents was the recurring theme, to urgently develop and validate biomarker assays as surrogate endpoints; both for showing that targeted agents act as expected and for providing proof of concept in the scientific rationale of new agents. Given the dominance of protein tyrosine kinase inhibitors in small-molecule drug design, a strong case was made for the implementation of phospho-proteomics or signal transduction signatures and pharmaco-proteomics or chemotherapeutic scans in phase I/II trials–or for the future “Nanolab”, eloquently described by Leroy Hood. However, molecular targeted agents-other than imanitib (Gleevec)–have yet to enter broad clinical use and several presentations described efforts for improving classical (cytotoxic) chemotherapeutic agents by targeting them selectively to tumour cells.

 

Novotny JR, Rosenthal C, Elmaagacli AH, Dürig J, Beelen DW, Dührsen U. Disease- or therapy-related bone marrow damage cannot be overcome by changes in stem cell source or dose in allogeneic transplantation. Eur J Haematol 2004: 73: 1-9. Copyright Blackwell Munksgaard 2004.Abstract: Objective: To test whether the functional impairment of the host bone marrow (BM) microenvironment pre-existing at the time of transplantation could be overcome by the increased content of immature cells in allogeneic peripheral blood stem cell transplantation (PBSCT) when compared with bone marrow transplantation (BMT). Methods: Cobble stone area forming cells (CAFC) were assayed in normal BM and BM after allogeneic BMT and PBSCT after stable engraftment. Groups were compared by two-tailed t-test. Results: While BM from 11 normal controls contained an average of 778.8 CAFC-d35 per 10(6) low density bone marrow cells (LDBMC, range 453-1231 per 10(6) LDBMC), BM from patients after BMT contained an average of 123.7 CAFC-d35 per 10(6) LDBMC (range 38-257) per 10(6) LDBMC. BM from patients transplanted with PBSC after myeloablative conditioning contained 128.3 (range 46-305) CAFC-d35 per 10(6) LDBMC (P = 0.89 compared with BMT). Similar results were obtained when patients after PBSCT with non-myeloablative conditioning were included (P = 0.62 compared with BMT). CAFC numbers in patients transplanted in early stages of myeloid leukaemia (acute myeloid leukaemia first remission, chronic myeloid leukaemia first chronic phase) were significantly higher than CAFC numbers in patients transplanted in more advanced stages (P = 0.008) or myelodysplastic syndrome (P = 0.023). The lowest CAFC numbers were found in two cases of retransplantation. Conclusion: Our findings indicate that the functional state of the BM microenvironment rather than stem cell dose or source is limiting for the homing and engraftment of immature haemopoietic cells in clinical transplantation.

 

Monotherapy of chronic myeloid leukemia (CML) with imatinib mesylate has been cast into shadow by the evolution of clinical resistance during therapy. Resistance to imatinib can arise by multiple mechanisms including amplification or mutation of Bcr-Abl, and continuity of imatinib therapy is probably a poor option for either of these patient groups. Recently, however, a structurally distinct new class of drugs, the pyrido[2,3-d]pyrimidines, has been described, and these compounds are predicted to make different molecular contacts in the Abl kinase domain. These drugs potently target both the Bcr-Abl and Src-family kinase activities, both of which are thought to be relevant to survival of the leukemic cell. We asked whether these drugs could selectively induce cell death in murine cell line models of CML cells sensitive and resistant to imatinib by different mechanisms. We show that whereas the pyrido[2,3-d] pyrimidines are indeed highly potent in suppressing proliferation of Bcr-Abl-overexpressing imatinib-resistant cells, they are almost completely ineffective against cells expressing the T315I mutant. This implies that despite structural differences from imatinib, these drugs are unlikely to be useful in patients expressing this mutant Bcr-Abl protein, but may be effective in cases where selection of cells overexpressing the oncoprotein leads to refractoriness to imatinib.Leukemia advance online publication, 17 June 2004; doi:10.1038/sj.leu.2403416