Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q

Lenalidomide as well as other immunomodulatory drugs (IMiDs) have achieved clinical efficacies in certain sub-types of hematologic malignancies, such as multiple myeloma, lower-risk myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)) and others. Despite superior clinical response to lenalidomide in hematologic malignancies, relapse and resistance remains a problem in IMiD-based therapy. The last ten years have witnessed the discovery of novel molecular mechanism of IMiD-based anti-tumor therapy. IMiDs bind human cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase complex. Binding of CRBN with IMiDs leads to degradation of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3) and casein kinase 1 alpha. We have found that lenalidomide-mediated degradation of IKZF1 leads to activation of the G protein-coupled receptor 68 (GPR68)/calcium/calpain pro-apoptotic pathway and inhibition of the regulator of calcineurin 1 (RCAN1)/calcineurin pro-survival pathway in MDS and acute myeloid leukemia (AML). Calcineurin inhibitor Cyclosporin-A potentiates the anti-leukemia activity of lenalidomide in MDS/AML with or without del(5q). These findings broaden the therapeutic potential of IMiDs. This review summarizes novel molecular mechanism of lenalidomide in myeloid malignancies, especially without del(5q), in the hope to highlight novel therapeutic targets

A Decision Support Tool for Appropriate Glucose-Lowering Therapy in Patients with Type 2 Diabetes

Abstract Background: Optimal glucose-lowering therapy in type 2 diabetes mellitus requires a patient-specific approach. Although a good framework, current guidelines are insufficiently detailed to address the different phenotypes and individual needs of patients seen in daily practice. We developed a patient-specific decision support tool based on a systematic analysis of expert opinion. Materials and Methods: Based on the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) 2012 position statement, a panel of 12 European experts rated the appropriateness (RAND/UCLA Appropriateness Method) of treatment strategies for 930 clinical scenarios, which were permutations of clinical variables considered relevant to treatment choice. These included current treatment, hemoglobin A1c difference from individualized target, risk of hypoglycemia, body mass index, life expectancy, and comorbidities. Treatment options included addition of a second or third agent, drug switches, and replacement by monotherapies if the patient was metformin-intolerant. Treatment costs were not considered. Appropriateness (appropriate, inappropriate, uncertain) was based on the median score and expert agreement. The panel recommendations were embedded in an online decision support tool (DiaScope(®); Novo Nordisk Health Care AG, Zürich, Switzerland). Results: Treatment appropriateness was associated with (combinations of) the patient variables mentioned above. As second-line agents, dipeptidyl peptidase-4 inhibitors were considered appropriate in all scenarios, followed by glucagon-like peptide-1 receptor agonists (50%), insulins (33%), and sulfonylureas (25%), but not pioglitazone (0%). Ratings of third-line combinations followed a similar pattern. Disagreement was highest for regimens including pioglitazone, sulfonylureas, or insulins and was partly due to differences in panelists' opinions and in drug availability and reimbursement across European countries (although costs were disregarded in the rating process). Conclusions: A novel decision support tool based on the ADA/EASD 2012 position statement and a systematic analysis of expert opinion has been developed to help healthcare professionals to individualize glucose-lowering therapy in daily clinical situations.status: publishe