Synergistic Effects of Bortezomib-OV Therapy and Anti-Invasive Strategies in Glioblastoma: A Mathematical Model

Recent experimental studies have demonstrated the great potential of combination therapies, using oncolytic viruses (OVs) in conjunction with proteasome inhibitor, bortezomib (BTZ), for the treatment of glioblastoma. So, we have developed a mathematical model of combination (bortezomib+OV) therapy, including intracellular signaling network (proteasome-NKkB-Bcl2-Bax) which mediate anti-apoptosis, apoptosis, and necroptosis of tumor cells. In addition, a challenging tumor microenvironment (TME) such as gray matter and dense ECM structure in brain, has been shown to regulate tumor invasion. But the critical role of TME in such therapies has not been studied in the context of combination therapies. We show (i) how the intracellular signaling regulates tumor cell killing in the combination therapy, (ii) that the TME plays a significant role in controlling the anti-tumor efficacy in Bortezomib-OV combination therapies and generating various spatial patterns of tumor growth. The simulation results show the possibility of development of new tumor treatment options within TME and new anti-invasion strategy.