Mathematical modeling of eIF5B-mediated non-canonical translation initiation as a chemotherapeutic target

Abstract

Glioblastoma is an extremely aggressive brain cancer that has a median survival time of 15 months, and a 95% mortality rate within 5 years. Standard-of-care therapy has not changed in over 15 years, and has unfortunately been limited in success. Glioblastomas tend to grow rapidly, creating hypoxic conditions within their cells. Under these conditions, the alpha subunit of eIF2 is phosphorylated, resulting in its inability to deliver the initiator tRNA to the ribosome during canonical translation initiation. In healthy cells, if the stress persists and is not alleviated, this may trigger a form of programmed cell death known as apoptosis. However, cancer cells exploit a non-canonical translation initiation pathway that replaces eIF2 with eIF5B to deliver the tRNAi to the pre-initiation complex. Some anti-apoptotic proteins are translated using this pathway, such as X-linked inhibitor of apoptosis (XIAP). The XIAP mRNA contains an IRES element which allows it to be translated using this non-canonical pathway. XIAP is up-regulated in glioblastoma cells, and therefore the eIF5B-mediated non-canonical translation initiation pathway is a promising therapeutic target for those suffering from this deadly disease. In this thesis, ordinary differential equation (ODE) and delay-differential equation (DDE) models are assembled to analyze the canonical and non-canonical translation initiation pathways. Four inhibitor classes are proposed and examined for both pathways. Results are presented in the forms of sensitivity analyses, 3D surface plots and contour plots which allow us to determine several potentially therapeutically effective combinations of inhibitor concentrations and KD values for each mode of inhibition. The results indicate that a direct eIF5B inhibitor or non-canonical ternary complex inhibitor are the most promising therapeutic targets.