Enhances GBM therapeutic efficacy while mitigating GBM-mediated neurotoxicity with BMX-001 (Radiation Medicine and Markey Cancer Center Collaborative Bench to Bedside pilot)

Enhances GBM therapeutic efficacy while mitigating GBM-mediated neurotoxicity with BMX-001 Glioblastoma multiforme (GBM) is the most lethal brain cancer with a mean survival of nearly 15 months after therapy, and therapy induced cognitive impairment (TICI) is a common observation in GBM patients. Greater understanding of mechanisms underlying tumor- and therapy-associated TICI are needed to improve the quality of life of GBM patients. Recent findings of our team, compared to non-cancerous control cells indicated that: (a) virulent cancer cells have elevated indices of oxidative damage, including the lipid peroxidation product, 4-hydroxynonenal (HNE); (b) pro-inflammatory cytokines, exemplified by tumor necrosis factor-alpha (TNFα), are elevated following redox cycling-associated chemotherapeutic agent treatment; (c) TNFα translocates from periphery to brain to lead to increased oxidative damage, mitochondrial dysfunction, apoptosis, and cognitive impairment; and (d) extracellular vesicles (EV), containing higher levels of HNE-bound proteins are released from target tissues of chemotherapy. Using a cell-specific EV assay, our preliminary data and those of others determined that higher levels of EV occur with GBM patients compared to non-cancer patients. Since reactive oxygen species (ROS) also act as signaling stimuli involved in cellular functions, including EV production, together with the information above, we postulate that GBM-derived, HNE-modified EV are pivotal to signaling processes that are increased by GBM therapy, promoting neurotoxicity and cognitive impairment. In addition, we aim to advance our preliminary findings by exploiting the high ROS property of GBM cells to lead to their selective death. Specifically, following exposure to standard of care therapy, we will use a novel redox active antioxidant BMX-001, to drive GBM cells to an even higher redox state, thereby leading to apoptosis. The redox states of glial and neuronal cells also are elevated by BMX-001, but because their baseline redox states are not significantly elevated, these cell types are not forced into apoptosis. In contrast, BMX-001 will mitigate GBM-mediated neurotoxicity by restoring redox homeostasis in glia cells and neuron cells, therefore, selectivity of neuron protection is achieved. Completion of this project will provide innovative and significant insights into the basis for advocating use of redox-active antioxidants (exemplified by BMX-001) as an adjuvant therapy to improve the quality of life of GBM patients.