Editorial [ Hot Topic: Highlights on Important Signaling Pathways as Drug Targets in Hematological Malignancies (Guest Editors: H. Serve and H.C. Hasselbalch) ]

摘要

In recent years, the dramatic progress in basic cancer research has finally reached clinical practice. Five years after the introduction of imatinib for the treatment of Bcr-Abl driven diseases, several novel targeted treatment modalities have been introduced into clinical medicine. For various reasons, hematological malignancies remain amongst the most promising candidates to be successfully treated by such modalities. This Theme Issue, entitled “Highlights on Important Signaling Pathways in Hematological Malignancies” describes some of the reasons, why this hope for our patients is realistic, especially for those suffering from Ph-negative myeloproliferative disorders. Here, major breakthroughs have been the discovery of various activating tyrosine kinases, including the most recent finding of a single, recurrent point mutation in the Janus kinase 2 (JAK2) in the large majority of patients with polycythemia vera, but also in about 50 % of patients with essential thrombocythemia and idiopathic myelofibrosis. Among other questions, Reiter and co-workers address this surprising result of a single mutation causing a variety of related diseases in their description of tyrosine kinases as therapeutic targets in Bcr-Abl negative chronic myeloproliferative disorders.nnHowever, the future will not only be bright. We will also have to face that the astounding success of imatinib in the treatment of chronic myeloid leukemia will not be easily copied to the other, often more complex, fully malignant and multigenic hematological malignancies. Here, it will be important to identify the pathways into the disease, to define their contribution to the initiation, progression and maintenance, to define molecular targets, and finally to combine specific therapeutic modalities with our cytotoxic armamentarium. It Is the second purpose of this Theme Issue to describe recent progress along these lines.nnIn a comprehensive review, Morgan et al. thoroughly describe the Ras-signaling pathway and ways of therapeutic interference with this pathway by inhibition of the mevalonate pathway in malignant hematological diseases, including farnesyl transferase inhibitor (FTI) treatment. The mevalonate pathway as a novel therapeutic target in polycythemia vera and related diseases is separately described by Hasselbalch & Riley who focus on the potential beneficial effects of statins and zoledronic acid in these disorders. This novel concept is based upon in vitro and in vivo studies showing that statins - in addition to the well-known cholesterol lowering effect – display anticancer potential as evidenced by their antiproliferative, proapoptotic, and antiangiogeneic properties. Furthermore, statins also have antithrombotic effects. All these drug effects may be beneficial in clonal myeloid diseases that feature myeloproliferation, myeloaccumulation (decreased apoptosis), increased angiogenesis and thrombotic complications.........