Fingolimod and Ozanimod for the treatment and prevention of chemobrain

化疗引起的认知障碍是一种常见的神经毒性，影响50% 在接受广泛使用的化疗药物治疗的患者8中，包括紫杉烷(如紫杉醇)9-11和铂类- 以药物为基础的药物(如顺铂)。8、9、12没有FDA批准的干预措施。线粒体功能障碍和 中枢神经系统(CNS)中的神经炎症被认为是推动CiCi的机制，但这些机制是如何 仍然难以捉摸。6，13-15我们的初步研究涉及中枢神经系统鞘脂代谢的变化 和增加鞘氨醇-1-磷酸(S1P)的形成，为治疗干预提供了一个新的靶点 S1P1受体亚型(S1PR1)拮抗剂。 在顺铂致认知障碍的初步研究中，前额叶皮质(PFC)中S1P的增加 和海马区(主要的认知中枢)，S1PR1在此表达。这与 线粒体超氧化物歧化酶硝化与NOD-、LRR-和 吡咯结构域包含蛋白3(NLRP3)炎症体。MnSOD对过氧亚硝酸根(PN)介导的严密调控 硝化应激，16，17，但在PN.18-20硝化时也有80%失活。这种PN介导的过程具有 在许多疾病状态下与线粒体功能障碍有关。17-19，21-23NLRP3是白细胞介素1β的关键 (IL-1β)和IL-18成熟，认知障碍中24-26个强大的炎性细胞因子。27-31全身性。 口服生物利用型中枢神经系统渗透剂S1PR1功能拮抗剂FTY72032阻断MnSOD 硝化/失活、NLRP3激活和弱化CiCi而不影响运动活动 (初步数据)。这些发现非常令人兴奋，因为FTY720(Fingolimod)是FDA批准的多用途 具有良好安全性的硬化症。33-36化疗如何触发S1P/S1PR1信号尚不清楚，但 初步数据表明，可能与胶质细胞Toll样受体4(TLR4)有关。 我们假设化疗使TLR4参与在中枢神经系统中驱动S1P/S1PR1信号的作用 通过PN介导的线粒体功能障碍和NLRP3介导的神经炎症作用于CiCi(图1)。我们 将在幼稚和携带肿瘤的雄性和雌性小鼠身上测试这一假说。在目标1中，我们将调查 S1P/S1PR1信号在中枢神经系统中的分布，S1PR1的时间和细胞分布，并测试S1PR1是否 拮抗剂在不干扰抗肿瘤作用的情况下预防和逆转CiCi。在目标2中，我们将使用 用药理学和遗传学方法确定TLR4在鞘脂代谢和S1P中的作用 检测S1PR1抑制对线粒体功能障碍和NLRP3驱动的影响 神经炎。S1PR1拮抗剂预计不会干扰化疗效果；我们和其他人 已经表明这些药物可以阻止肿瘤细胞的生长、炎症和转移。 预计将提供改变范式的见解，从而在CiCi中建立S1PR1并加快翻译 对已获FDA批准作为化疗辅助药物(Fingolimod/OzAnimod)的药物进行调查。

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 platinum- based 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.