Multifunctional protein nanomedicine constructs to overcome CML drug resistance

Abstract

Drug resistance is a critical issue impeding the success of cancer therapy. A typical model of drug resistance induced therapy failure is the case of chronic myeloid leukemia (CML), a hematological malignancy affecting the myeloid progenitors of blood. In CML, the primary oncogene responsible for leukemiogenesis is BCR-ABL, which is translated in to BCR-ABL fusion protein exhibiting constitutive tyrosine kinase activity. The small molecular inhibitor, imatinib had shown excellent response in chronic phase patients. However, a certain population of patients shows refractoriness to imatinib due to the point mutations in the kinase domain and/or BCR-ABL amplification. Later, newer and more effective inhibitors were developed to overcome the drug resistance. However, those drugs also had limited success. Recent line of evidences suggests that, in addition to the aberrations in primary oncogene BCR-ABL, activation of secondary kinases also play significant roles in CML drug resistance. Accordingly, in this thesis, we have focused on the alternative mechanisms of drug resistance in CML and developed novel protein nanomedicines against key mechanistic pathways of resistance, which are otherwise less explored in the clinics as therapeutic targets. Molecular characterization of refractory CML patient samples and in vitro generated model refractory cell line K562R showed that, in addition to BCR-ABL, STAT5 was also consistently up-regulated in refractory patients compared to the drug sensitive patients. Another interesting observation was that, refractory cells showed over-expression of iron transport protein transferrin receptors (TfR1), in a correlative manner with increase in drug resistance and STAT5 expression. Based on these inputs, we developed transferrin conjugated albumin nanoparticles loaded with STAT5 inhibitor sorafenib (Tf-nAlb-Soraf) for the targeted inhibition of aberrant STAT5 through TfR1 targeted drug delivery. This transferrin conjugated albumin-bound sorafenib nanomedicine (Tf nAlb-Soraf), prepared u