Bedside to benchtop translational development: Targeting the S1P/ceramide axis may alleviate symptoms of chemical induced peripheral neuropathy.

Abstract

e15045 Background: Chemical Induced Peripheral Neuropathy (CIPN) is a debilitating and serious side-effect associated with many chemotherapeutic treatments. Often, CIPN is a dose-limiting toxicity, and its effects can be long-lasting in some patients. The pathology of CIPN is thought to involve not only cytotoxicity of neuronal cells, but also inflammation and immune responses. Hence, it is not surprising that the sphingolipid sphingosine-1-phosphate (S1P) is thought to be a key contributor to CIPN. Methods: BXQ-350, a nanovesicle comprised of recombinantly expressed Saposin C and dioleoylphosphatidylserine, has broad anticancer activity. It modulates sphingolipid metabolism and signaling, lowers S1P and increases pro-apoptotic ceramides, and induces an anti-tumoral immune response. BXQ-350 was investigated in a Phase 1 dose-escalation safety study of all-comer cancer patients with advanced solid malignancies, including high grade gliomas ( NCT02859857 )*. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetics, efficacy profile and to elucidate potential biomarkers. Results: Interestingly, several patients with established CIPN spontaneously reported improvement of their neuropathy-related symptoms following BXQ-350 administration. Plasma samples from those patients revealed changes in circulating levels of sphingolipids and cytokines, including reduction of circulating levels of S1P and of IL-6, IL-8, cytokines, following BXQ-350 dosing. These properties of BXQ-350 were subsequently investigated in a murine oxaliplatin-CIPN preclinical model; results showed a dose-dependent prevention/resolution of CIPN, which also correlated with decreasing systemic S1P levels. Additional plasma based CIPN specific biomarkers were investigated, and preclinical results suggest that BXQ-350 may also favorably inhibit specific immune cells that favor CPIN. Conclusions: These preclinical and clinical observations related to CIPN, coupled with the fact that BXQ-350 acts synergistically with many chemotherapies and radiation, warrant further its investigation into preventing or improving CIPN related symptoms in cancer patients. Clinical trial information: 02859857.