sirolimus and Guillain-Barre-Syndrome

Waldenström's macroglobulinemia is a rare B-cell malignancy defined by medullar infiltration by clonal lymphoplasmocytic cells and monoclonal IgM secretion. Treatment is reserved for symptomatic patients. The main first-line treatment strategies combine immunotherapy (principally the anti-CD20 monoclonal antibody rituximab) with chemotherapeutic agents, including alkylating agents, purine analogs and/or bortezomib. The overall response rate to these conventional treatments is between 70 and 90%, but a cure cannot be expected. For patients with relapsed or refractory disease, drugs that were not used for first-line treatment and other agents such as immunomodulators can be tried, but the response rate is generally lower and the responses are shorter lived. Recently, advances in our understanding of the biology of Waldenström's macroglobulinemia have led to the development of new drugs targeting hyperactive pathways. This review focuses on current treatment options and on new therapeutic developments.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Comorbidity; Disease Progression; Everolimus; Forecasting; Guillain-Barre Syndrome; Hematopoietic Stem Cell Transplantation; Histone Deacetylase Inhibitors; Humans; Immunologic Factors; Immunotherapy; Incidence; Lenalidomide; Myelin-Associated Glycoprotein; Protein Kinase Inhibitors; Pyrazines; Rituximab; Salvage Therapy; Sirolimus; Thalidomide; Transplantation, Autologous; Treatment Outcome; Waldenstrom Macroglobulinemia; Watchful Waiting

AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolic and immune functions mainly through the inhibition of the mechanistic target of rapamycin (mTOR)-dependent anabolic pathways and the activation of catabolic processes such as autophagy. The AMPK/mTOR signaling pathway and autophagy markers were analyzed by immunoblotting in blood mononuclear cells of 20 healthy control subjects and 23 patients with an acute demyelinating form of Guillain-Barré syndrome (GBS). The activation of the liver kinase B1 (LKB1)/AMPK/Raptor signaling axis was significantly reduced in GBS compared to control subjects. In contrast, the phosphorylated forms of mTOR activator AKT and mTOR substrate 4EBP1, as well as the levels of autophagy markers LC3-II, beclin-1, ATG5, p62/sequestosome 1, and NBR1 were similar between the two groups. The downregulation of LKB1/AMPK signaling, but not the activation status of the AKT/mTOR/4EBP1 pathway or the levels of autophagy markers, correlated with higher clinical activity and worse outcomes of GBS. A retrospective study in a diabetic cohort of GBS patients demonstrated that treatment with AMPK activator metformin was associated with milder GBS compared to insulin/sulphonylurea therapy. In conclusion, the impairment of the LKB1/AMPK pathway might contribute to the development/progression of GBS, thus representing a potential therapeutic target in this immune-mediated peripheral polyneuropathy.

Topics: AMP-Activated Protein Kinases; Beclin-1; Down-Regulation; Guillain-Barre Syndrome; Humans; Insulins; Metformin; Proto-Oncogene Proteins c-akt; Retrospective Studies; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases