(573f) Combined Gene and Chemotherapy for Cancer: Interdisciplinary Multimodal Approaches to Effective, Safe, and Diverse Therapies

Most therapies tackle a single pathological target such as an effector protein or a abnormal genetic pathway, often resulting in limited, ancillary therapeutic effects. For example, cancers arise from complex molecular causes, making them difficult to treat by a single modal therapy. In order to rebalance the broken molecular homeostasis in chronic myelogenous leukemia (CML) as a simple, well-documented model, pro-apoptotic and pro-survival genes were simultaneously expressed and silenced in a CML cell, respectively, using a viral/nonviral chimeric nanoparticles (ChNPs) that were composed of the BIM-expressing adeno-associated virus (AAV) core and MCL-1 siRNA-encapsulating, acid-degradable polymeric shell. While BIM/MCL-1 ChNPs genetically rebalance the pathological genetic pathways, a targeted chemotherapeutics for CML, dasatinib, was additionally administered. The result demonstrated synergistically enhanced anti-leukemic effects by the combined multimodal gene and chemotherapy in vitro and in vivo, especially in a rapidly progressing disease stage of blast crisis. A computational simulation via multi-omics network analyses using machine learning also predicted the synergistically augmented apoptosis by the combined multimodal gene and chemotherapy. This study demonstrates the critical roles of engineering therapies that address the complex nature of a disease by integrating interdisciplinary principles.