Signal transduction inhibitors in treatment of myelodysplastic syndromes

Abstract

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.

Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia

“…Our findings of elevated Smad2/3 activation, erythroid hyperplasia, and inhibition of erythroid differentiation in Hbb th1/th1 mice are consistent with reports of constitutive overactivation of Smad2/3 in erythroid tissue from patients with MDS, 16 another disease characterized by erythroid hyperplasia and abortive maturation. [33][34][35] We hypothesize that one or more TGFb superfamily ligands that activate the Smad2/3 pathway negatively regulate terminal erythroid differentiation, perhaps by promoting erythroid expansion during ineffective erythropoiesis, and that RAP-536 exerts beneficial effects in b-thalassemic mice by blunting elevated activity in this inhibitory pathway.…”

TGF-β signaling in the control of hematopoietic stem cells

“…Excessive activation of inhibitory pathways, such as TGF-b, has been proposed to amplify the inefficient blood production inherent to MDS. 113 For example, SMAD2 is upregulated and overactivated in CD34 1 BM progenitors from MDS patients. Importantly, pharmacologic inhibition of the TGF-b pathway in vivo, using a small-molecule inhibitor of ALK5, alleviates anemia in a mouse model of MDS.…”

Recent developments in myelodysplastic syndromes

“…124 ARRY-614, a dual p38 mitogenactivated protein kinase/Tie2 kinase inhibitor, has been associated with hematologic improvements in patients for whom hypomethylating agents have failed yet who still meet IPSS criteria for lowerrisk disease; a few other kinase inhibitors are also being studied despite the relative rarity of activating kinase mutations in MDS. 125 Finally, advances in HSCT may make this potentially curative approach available to a wider variety of patients and improve outcomes. Greater use of cord blood or haploidentical donors, use of novel reduced-intensity conditioning approaches in older patients and those with comorbidities, and graft manipulation with post-HSCT azacitidine or with specific immunotherapies all may increase the rate of HSCT use.…”