Preclinical Models for Drug Selection in Myeloproliferative Neoplasms
- PDF / 186,901 Bytes
- 8 Pages / 595.276 x 790.866 pts Page_size
- 6 Downloads / 222 Views
MYELOPROLIFERATIVE DISORDERS (JJ KILADJIAN, SECTION EDITOR)
Preclinical Models for Drug Selection in Myeloproliferative Neoplasms Niccolò Bartalucci & Costanza Bogani & Alessandro M. Vannucchi
Published online: 22 October 2013 # Springer Science+Business Media New York 2013
Abstract The discovery that an abnormally activated JAKSTAT signaling pathway is central to the pathogenesis of myeloproliferative neoplasms has promoted the clinical development of small-molecule JAK2 inhibitors. These agents have shown remarkable efficacy in disease control, but do not induce molecular remission; on the other hand, interferon holds the promise to target the putative hematopoietic progenitor cell initiating the disease. The presence of additional molecular abnormalities indicates a high molecular complexity of myeloproliferative neoplasms, and the need for simultaneously targeting different targets. Several drugs are currently under study as single agents and in combination. This review briefly describes the several in vitro and in vivo models of myeloproliferative neoplasms that are being used as preclinical models for drug development. Keywords Myeloproliferative neoplasms . JAK2 mutation . Animal models . JAK2 inhibitors . Myelofibrosis . Hematologic malignancy
Introduction Philadelphia chromosome-negative chronic myeloproliferative disorders, renamed myeloproliferative neoplasms (MPN) according to the 2008 revised World Health Organization classification [1, 2], include polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis, either primary (PMF) or developing as the late evolution of a preexisting PV
or ET (post-PV, post-ET MF). These disorders have remained without molecular information or effective therapies for more than 50 years since the initial description by Dameshek in the 1950s [3]. It was in 2005 that the first recurrent molecular lesion, a missense mutation in the JAK2 gene (JAK2V617F), was discovered [4–7] in >95 % of patients with PV and about 60 % of those with ET and PMF, pointing to abnormally activated JAK-STAT signaling as the putative main pathogenetic abnormality and, conceivably, a target for therapy [8, 9••]. In 2011 the Food and Drug Administration approved ruxolitinib, a JAK1 and JAK2 small-molecule inhibitor, for the treatment of MF [10••, 11••], and several other JAK2 inhibitors are currently under evaluation in clinical trials [12]. These agents, with some differences in terms of potency and side effects, have shown remarkable efficacy in reducing the splenomegaly and improving the symptomatic burden of the disease, and two pivotal phase 3 trials have provided some evidence that treatment with ruxolitinib improves survival [10••, 11••]. However, JAK2 inhibitors have uniformly failed to induce molecular remission, as shown by the modest and erratic reduction in the burden of JAK2V617F-mutated cells, which on the one hand has tempered enthusiasm for the view that JAK2 inhibitors could reproduce the extraordinarily successful story of BCR/ABL inhibitors and on the other has promp
Data Loading...
