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.

Figure 1

Regulation of hematopoiesis by cytokines. The process of differentiation of hematopoietic stem cells into mature blood cells is tightly regulated by the actions of both stimulatory and inhibitory cytokines.

Figure 2

Model for pathogenesis of MDS. A mutation or epigenetic alteration in hematopoietic stem cells (HSC), leads to generation of pro-inflammatory milieu in marrow microenvironment that can result in apoptotic cell death of normal HSCs. Inhibition of myelo-suppressive cytokine signaling cascades can stimulate hematopoietic activity in HSCs.

Figure 3

Mitogen activated protein kinases. These are evolutionarily conserved protein kinases that regulate many important physiological processes. The p38 MAP kinase regulates cell death and proliferation in hematopoietic cells.

Figure 4

TGF-β signaling pathway. TGF-β receptors after binding with the TGF-β ligand, forms a receptor- ligand complex. This dimerization activates the kinase domain of Type I receptor. The activated Type 1 receptor kinase further activates the downstream smad complexes to regulate gene transcription. LY2157299 inhibits the TGF-β receptor I kinase and can reverse the cellular effects of TGF- β signaling pathway in hematopoietic cells.