Signal transduction inhibitors in treatment of myelodysplastic syndromes

Journal of Hematology & Oncology

Amit Verma⁴  Ulrich Steidl¹  Ira Braunschweig³  Tatiana Carrillo³  Dale Wyville³  Carolina Schinke¹  Ionnis Mantzaris¹  Oleg Gligich²  Lohith Bachegowda¹ 

[1] Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10467, USA;Jacobi Medical Center, 1400 Pelham Pkwy S, New York, NY 10461, USA;Division of Oncology, Montefiore Medical Center, 110, E 210 Street, Bronx, NY 10467, USA;Medicine/Oncology, Developmental & Molecular Biology, 1300 Morris Park Ave, Bronx, NY 10461, USA

关键词: mTOR;    Mek;    ON- 01910.Na;    GSTP 1–1;    FTI;    EGFR;    ALK;    TGF-β;    Cytokines;    Signal transduction inhibitors;    Myelodysplastic syndrome;   

Others  :  804553
DOI  :  10.1186/1756-8722-6-50

 received in 2013-04-30, accepted in 2013-05-29,  发布年份 2013

【 摘 要 】

Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-β, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-β signaling has been therapeutically targeted by small molecule inhibitor of the TGF-β receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-β receptor kinase inhibition, members of TGF-β super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.

【 授权许可】

   
2013 Bachegowda et al.; licensee BioMed Central Ltd.

【 图 表 】

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