scio-469 and Myelodysplastic-Syndromes

The management strategy for patients with myelodysplastic syndromes (MDS) has evolved from sole reliance on supportive measures to active treatment guided by disease risks. Recent progress in understanding the molecular pathogenesis of MDS has accelerated the discovery of new therapeutic targets, and consequently launched the development of several novel therapeutics that are currently in varied stages of clinical testing. One such agent is lenalidomide, which has shown remarkable effectiveness in the cytogenetically defined subset of MDS with the chromosome 5q31 deletion. The advent of new and effective targeted therapeutics may beneficially affect outcomes of an ever-increasing number of patients with MDS. This discussion summarizes the preliminary results of selected novel therapeutics.

Topics: Amifostine; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Enzyme Inhibitors; Glutathione; Humans; Immunosuppressive Agents; Indoles; Myelodysplastic Syndromes

Topics: Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Female; Humans; Indoles; Male; Middle Aged; Mitogen-Activated Protein Kinase 14; Myelodysplastic Syndromes; Protein Kinase Inhibitors

The myelodysplastic syndromes (MDSs) are collections of heterogeneous hematologic diseases characterized by refractory cytopenias as a result of ineffective hematopoiesis. Development of effective treatments has been impeded by limited insights into any unifying pathogenic pathways. We provide evidence that the p38 MAP kinase is constitutively activated or phosphorylated in MDS bone marrows. Such activation is uniformly observed in varied morphologic subtypes of low-risk MDS and correlates with enhanced apoptosis observed in MDS hematopoietic progenitors. Most importantly, pharmacologic inhibition of p38alpha by a novel small molecule inhibitor, SCIO-469, decreases apoptosis in MDS CD34+ progenitors and leads to dose-dependant increases in erythroid and myeloid colony formation. Down-regulation of the dominant p38alpha isoform by siRNA also leads to enhancement of hematopoiesis in MDS bone marrow progenitors in vitro. These data implicate p38 MAPK in the pathobiology of ineffective hematopoiesis in lowrisk MDS and provide a strong rationale for clinical investigation of SCIO-469 in MDS.

Topics: Aged; Aged, 80 and over; Apoptosis; Bone Marrow; Down-Regulation; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Hematopoiesis; Humans; Indoles; Isoenzymes; Male; Middle Aged; Myelodysplastic Syndromes; Myeloid Progenitor Cells; Neoplastic Stem Cells; p38 Mitogen-Activated Protein Kinases; Risk Factors; RNA, Small Interfering; Tumor Cells, Cultured

Myelodysplastic syndromes (MDS) are common causes of ineffective hematopoiesis and cytopenias in the elderly. Various myelosuppressive and proinflammatory cytokines have been implicated in the high rates of apoptosis and hematopoietic suppression seen in MDS. We have previously shown that p38 MAPK is overactivated in MDS hematopoietic progenitors, which led to current clinical studies of the selective p38alpha inhibitor, SCIO-469, in this disease. We now demonstrate that the myelosuppressive cytokines TNFalpha and IL-1beta are secreted by bone marrow (BM) cells in a p38 MAPK-dependent manner. Their secretion is stimulated by paracrine interactions between BM stromal and mononuclear cells and cytokine induction correlates with CD34+ stem cell apoptosis in an inflammation-simulated in vitro bone marrow microenvironment. Treatment with SCIO-469 inhibits TNF secretion in primary MDS bone marrow cells and protects cytogenetically normal progenitors from apoptosis ex vivo. Furthermore, p38 inhibition diminishes the expression of TNFalpha or IL-1beta-induced proinflammatory chemokines in BM stromal cells. These data indicate that p38 inhibition has anti-inflammatory effects on the bone marrow microenvironment that complements its cytoprotective effect on progenitor survival. These findings support clinical investigation of p38alpha as a potential therapeutic target in MDS and other related diseases characterised by inflammatory bone marrow failure.

Topics: Aged; Bone Marrow; Cytokines; Humans; Indoles; Inflammation; Inflammation Mediators; Interleukin-1beta; Myelodysplastic Syndromes; p38 Mitogen-Activated Protein Kinases; Paracrine Communication; Protein Kinase Inhibitors; Tumor Necrosis Factor-alpha

Topics: Angiogenesis Inhibitors; Antimetabolites, Antineoplastic; Azacitidine; Clinical Trials, Phase III as Topic; Decitabine; Enzyme Inhibitors; Humans; Indoles; Lenalidomide; Myelodysplastic Syndromes; Predictive Value of Tests; Thalidomide; Treatment Outcome