Page 73 - Haematologica-5

haematologica | 2018; 103(5)
DCC-2618: a new drug against mastocytosis
was found to inhibit the proliferation of neoplastic bone marrow cells obtained from a patient with ASM (Table 1 and Online Supplementary Figure S6B). In addition, DCC- 2618 was found to block the growth of bone marrow cells obtained from patients with secondary hypereosinophilic syndromes (Online Supplementary Table S1 and Online Supplementary Figure S6B).
DCC-2618 inhibits growth of human endothelial cells
Increased bone marrow angiogenesis has been impli- cated in the pathogenesis of SM.41 To investigate potential effects of DCC-2618 on angiogenesis, we explored drug effects on growth of HUVEC and the microvascular endothelial cell line HMEC-1. As assessed by 3H-thymi- dine uptake, DCC-2618 and its metabolite were found to inhibit the proliferation of HUVEC and HMEC-1 cells in a dose-dependent manner (Online Supplementary Figure S7). DCC-2618 exerted stronger effects on HUVEC (707±224 nM) than on HMEC-1 cells (3.7±2.2 μM).
Discussion
Due to the poor response to conventional drugs, treat- ment of patients with advanced SM is still a major chal- lenge in clinical practice. Despite the availability of new
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drugs the prognosis of these patients remains poor with short survival times.10,16,28,29 Research is, therefore, seeking new effective drugs and novel treatment concepts. DCC- 2618 is a novel switch-control type II blocker that exerts inhibitory effects on KIT D816V, other KIT mutants, and several other critical target kinases, such as FLT3, PDGFRA and KDR.35 We here describe that DCC-2618 inhibits the proliferation of nine different human MC lines, with lower IC50 values obtained in HMC-1.1 cells and ROSAKIT WT cells than in KIT D816V-positive HMC-1.2 and ROSAKIT D816V cells. In addition, DCC-2618 was found to block the proliferation of primary neoplastic MC obtained from patients with ASM or MCL. Moreover, DCC-2618 exerted major antineoplastic effects on AHN cells and endothelial cells, all of which may be relevant in the pathogenesis of advanced SM. Based on these obser- vations DCC-2618 is a novel emerging drug candidate for advanced SM. Indeed, clinical trials with DCC-2618 have been started recently.
The multi-kinase inhibitor midostaurin (PKC412) is effective against the D816V-mutated variant of KIT and has shown promising results in patients with advanced SM in a global phase II trial, with an overall response rate of 60%.28 In addition, midostaurin was found to suppress mediator-related symptoms and IgE-dependent histamine release from basophils.28,42 However, despite clinical effi-
Figures 4. Effects of DCC-2618 on anti-IgE-induced histamine release from normal basophils. (A) Primary blood basophils from healthy donors were incubated in control medi- um (0 μM) or in various concentrations of DCC-2618, as indicated, at 37°C for 30 min. Thereafter, cells were incubated in control buffer or in buffer containing anti-IgE antibody E-124.2.8 (1 μg/mL) at 37°C for 30 min. After incubation, cells were centrifuged at 4°C, and cell-free supernatants and cell suspensions recovered and examined for histamine- content by radioimmunoassay. Histamine release was calculated as percent of total hista- mine and is expressed as percent of control. Results represent the mean±S.D. of four inde- pendent experiments. Asterisk (*): P<0.05 compared to control medium. (B) HMC-1 cells were cultured in the presence or absence of DCC-2618 (HMC-1.1: 25 nM; HMC-1.2: 500 nM) over a 6-day period. Spontaneous release of tryptase from HMC-1.1 and HMC-1.2 cells was measured by determining tryptase concentrations in cell-free supernatants and lysates. Tryptase release is expressed as percent of total (intra- and extra-cellular) tryptase. Results represent the mean±S.D. of three independent experiments. Asterisk (*): P<0.05.
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