Fingolimod and Ozanimod for the treatment and prevention of chemobrain

Chemotherapy-induced cognitive impairment (chemobrain; CICI) is a common neurotoxicity affecting >50% of patients8 treated with widely used chemotherapeutics, including taxanes (e.g., paclitaxel)9-11 and platinumbased agents (e.g., cisplatin).8,9,12 There are no FDA-approved interventions. Mitochondrial dysfunction and neuroinflammation in the central nervous system (CNS) are mechanisms thought to drive CICI, but how these are triggered remains elusive.6,13-15 Our preliminary studies implicate CNS alterations of sphingolipid metabolism and increased sphingosine-1-phosphate (S1P) formation, offering a novel target for therapeutic intervention with S1P1 receptor subtype (S1PR1) antagonists. In preliminary studies of cisplatin-induced cognitive impairment, S1P increased in the prefrontal cortex (PFC) and hippocampus (key centers of cognition) where S1PR1 was expressed. This was associated with mitochondrial superoxide dismutase (MnSOD) nitration and inactivation and activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. MnSOD tightly regulates peroxynitrite (PN)-mediated nitroxidative stress,16,17 but is also inactivated >80% when nitrated by PN.18-20 This PN-mediated process has been linked to mitochondrial dysfunction in many disease states.17-19,21-23 NLRP3 is critical for interleukin-1β (IL1β) and IL18 maturation,24-26 powerful inflammatory cytokines in cognitive impairment.27-31 Systemic administration of the orally bioavailable, CNS penetrant S1PR1 functional antagonist FTY72032 blocked MnSOD nitration/inactivation, NLRP3 activation and attenuated CICI without adversly affecting locomotor activity (preliminary data). These findings are very exciting, since FTY720 (fingolimod) is FDA-approved for multiple sclerosis with good safety profiles.33-36 How chemotherapy triggers S1P/S1PR1 signaling is not known, but preliminary data suggest glial cell toll-like receptor 4 (TLR4) as a likely link. We hypothesize that chemotherapy engages TLR4 to drive S1P/S1PR1 signaling in the CNS that contributes to CICI through PN-mediated mitochondrial dysfunction and NLRP3-mediated neuroinflammation (Fig. 1). We will test this hypothesis in naïve and tumor-bearing male and female mice. In Aim 1, we will investigate S1P/S1PR1 signaling in the CNS, temporal and cellular distribution of S1PR1 and test whether S1PR1 antagonists prevent and reverse CICI without interfering with antitumor effects. In Aim 2, we will use pharmacological and genetic approaches to define the role of TLR4 in sphingolipid metabolism and S1P formation during CICI and test the impact of S1PR1 inhibition on mitochondrial dysfunction and NLRP3-driven neuroinflammation. S1PR1 antagonists are not expected to interfere with chemotherapy efficacy; we and others have shown that these drugs block tumor cell growth, inflammation and metastasis.37-43 Our studies are anticipated to provide paradigm-shifting insights that establish S1PR1 in CICI and expedite translational investigation of medicines that are already FDA approved (fingolimod/ozanimod) as adjunct to chemotherapy.