Bortezomib (PS-341) may be a potential treatment for GRMD?

Golden retriever muscular dystrophy (GRMD) is a genetic myopathy corresponding to Duchenne muscular dystrophy (DMD) in humans. Muscle atrophy is known to be associated with degradation of the dystrophin-glycoprotein complex (DGC) via the ubiquitin-proteasome pathway.

In a recently published study, the investigators looked at the effect of bortezomib treatment on the muscle fibers of GRMD dogs. The Dogs treated with the proteasome inhibitor bortezomib (TD- Treated) were compared with control dogs (CD). Pharmacodynamics were evaluated by measuring the inhibition of 20S proteasome activity in whole blood after treatment.Immunohistochemical studies were performed on muscle biopsy specimens to evaluate the rescue of dystrophin and dystrophin-associated proteins in the muscles of GRMD dogs treated with bortezomib. Skeletal tissue from TD had lower levels of connective tissue deposition and inflammatory cell infiltration than CD as determined by histology, collagen morphometry and ultrastructural analysis. The CD showed higher expression of phospho-NF?B and TGF-?1, suggesting a more pronounced activation of anti-apoptotic factors and inflammatory molecules and greater connective tissue deposition, respectively. Immunohistochemical analysis demonstrated that dystrophin was not present in the sarcoplasmic membrane of either group. However, bortezomib-TD showed higher expression of?- and?-dystroglycan, indicating an improved disease histopathology phenotype. Significant inhibition of 20S proteasome activity was observed 1 hour after bortezomib administration in the last cycle when the dose was higher. Proteasome inhibitors may thus improve the appearance of GRMD muscle fibers, lessen connective tissue deposition and reduce the infiltration of inflammatory cells. In addition, proteasome inhibitors may rescue some dystrophin-associated proteins in the muscle fiber membrane.

Bosutinib (SKI-606) is the third-generation tyrosine kinase inhibitor of Bcr-Abl, the constitutively active tyrosine kinase resulting from the Philadelphia chromosome abnormality in CML. Bosutinib also inhibits kinases in the Src family, including Src, Lyn, and Hck. According to many research reports, Bosutinib is active against many imatinib-resistant mutations (16 of 18 imatinib-resistant forms of Bcr-Abl in murine myeloid cell lines), but not active against the T315I and V299L mutations.

According to clinicaltrials.gov, there are 3 ongoing trials on Bosutinib:

BELA: Bosutinib (BOS) versus imatinib (IM) in patients (pts) with newly diagnosed chronic phase chronic myeloid leukemia (CP CML)

Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias.

Compare Bosutinib To Imatinib In Subjects With Newly Diagnosed Chronic Phase Philadelphia Chromosome Positive CML