Effect of BXQ-350, a novel sphingolipid metabolism modulator, on neuronal environments through modulation of gene pathways.

e24058 Background: Chemotherapeutic Induced Neuropathy (CIPN) remains an obstacle for the successful completion of chemotherapeutic courses. Patients have had to stop first line treatment courses such as FOLFOX due to complications that arise from CIPN. Finding suitable treatments to allow for the progression of these courses has been a focus of the industry for some time. BXQ-350, a novel protein-lipid small molecule, is currently in Phase 2 clinical trials to determine its efficacy as an anti-CIPN and anti-cancer adjuvant for Oxaliplatin and FOLFOX treatment. Preclinical data shows BXQ-350 anti-CIPN effects. However, those effects do not appear to directly counteract Oxaliplatin treatment insults. Instead, BXQ-350 upregulates homeostatic neuronal genes of dorsal root ganglions (DRGs) in response to chemotherapeutic insults. Methods: The company Transpharmation treated 48 mice intro-peritoneally with 2mg/kg or 10mg/kg BXQ-350, 10mg/kg Oxaliplatin, and/or vehicle over 14 days. Dorsal root ganglia were isolated from 45 of the treated mice, 10 from the control group, 12 from the BXQ-350 and combo groups, and 11 from the Oxaliplatin group, and sent to Nanostring to run gene analysis on. A suite of genes deemed to be implicated in CIPN were investigated looking at the differences in RNA levels between mice DRGs from the BXQ-350 alone, BXQ-350/Oxaliplatin, Oxaliplatin alone, and vehicle alone groups. RNA differential analysis was performed using Nanostring’s nCounter3 and Rosalind, a bioinformatics platform. Results: BXQ-350 positively impacted several pathways known to promote healthy neurons that are affected by CIPN. Two pathways implicated are the axon guidance and synaptic plasticity which help regulate the neurotransmitter response to stimuli. Following BXQ-350 dosing, multiple genes were upregulated from homeostatic pathways that are shown to promote axon guidance and plasticity. CIPN has been known to cause reactive oxygen species build up in neurons leading to inflammation and cell death. BXQ-350 indirectly regulates genes from pathways responsible for ROS creation and alleviation. In response to inflammation, BXQ-350 downregulates several inflammatory pathways. Conclusions: CIPN is a dangerous side effect of chemotherapy that causes patients to discontinue treatment courses. BXQ-350 has been shown to reduce the burden of CIPN in vivo and in vitro . Instead of directly counteracting the effects of specific chemotherapeutics, BXQ-350 promotes several pathways that regulate neuronal health, cleaning up neurons and promoting homeostatic neuronal environments.