Multimodal gene and targeted drug therapy for chronic myelogenous leukemia using BIM/MCL-1 chimeric nanoparticle: computational target analysis and therapeutic validation

Developing an efficient and safe therapy necessitates a mechanistic understanding of the complex underlying pathology and manipulation of the multiple pathways at the molecular and genetic level. Network-based simulation of chronic myeloid leukemia (CML), a relatively well-understood cancer model, revealed the dynamics of simultaneously expressing pro-apoptotic BIM (Bcl-2 interacting mediator of cell death) and silencing pro-survival MCL-1 (myeloid cell leukemia-1) in combination with the breakpoint cluster region (BCR)-Abelson (ABL)-targeted tyrosine kinase inhibitor dasatinib. Viral/nonviral chimeric nanoparticles (ChNPs) composed of a BIM-expressing adeno-associated virus (AAV) core and a degradable polymeric shell that encapsulates MCL-1 siRNA (BIM/MCL-1 ChNPs) selectively killed BCR-ABL + CML cells in combination with dasatinib. In a mouse CML model, the BIM/MCL-1 ChNPs and dasatinib combination therapy suppressed proliferation of BCR-ABL + hematopoietic cells and prevented leukemic infiltration of organs. The enhanced anti-leukemic effect was further pronounced in an acute phase model of the disease. This study investigated a strategy of developing a versatile and tunable multimodal therapy assisted by a computational toolset that analyzes the molecular foundation of a disease and predicts therapeutic response. The interdisciplinary approach developed and validated in this study can be used in discovering new therapies for cancer and other diseases.