Multimodal gene and targeted drug therapy for chronic myelogenous leukemia: Computational target analysis and therapeutic validation
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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 and silencing pro-survival MCL-1 in combination with the BCR-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) synergistically and 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 synergistic 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.
Abstract Figure
Graphical abstractsummarizing the study design and approach. A schematic representation of the integrated in silico and in vivo pipeline utilized in the study. The workflow begins with in silico simulations, including Boolean network modeling and protein-protein interaction (PPI) network analyses, leading to target discovery, optimized nanoparticle design, and validation in pathological contexts. This was followed by therapeutic efficacy assessments of BIM/MCL-1 ChNPs and their combination with dasatinib in BCR-ABL+ leukemia models in vitro and in vivo.
