Targeting Sphingosine-1-phosphate (S1P1) receptors for the treatment of Aromatase Inhibitors-induced Musculoskeletal Symptoms

靶向 1-磷酸鞘氨醇 (S1P1) 受体治疗芳香酶抑制剂引起的肌肉骨骼症状

• 批准号: 10668781
• 负责人: M. Imad Damaj
• 金额: $ 61.39万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-21 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668781
• 关键词: Acute; Adherence; Adjuvant; Adjuvant Therapy; Affinity; Agonist; Aromatase; Aromatase Inhibitors; Arthralgia; Astrocytes; Behavior; Breast Cancer Model; Breast Cancer Treatment; Breast Cancer cell line; Breast Cancer therapy; Cell Lineage; Chronic; Data; Development; Diagnosis; Disease-Free Survival; Dose; Down-Regulation; Effectiveness; Endocrine; Ensure; Estrogen receptor positive; FDA approved; Fatigue; Female; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; In Vitro; Inflammatory; Joints; Knockout Mice; Letrozole; Ligands; Lumbar spinal cord structure; Macrophage; Malignant Neoplasms; Mediating; Mediator; Microglia; Modeling; Mus; Muscle; Musculoskeletal; Myalgia; Neurons; Oral; Oral Administration; Pain; Patients; Pharmaceutical Preparations; Play; Postmenopause; Prevention; Prevention strategy; Prodrugs; Receptor Activation; Receptor Signaling; Recurrence; Role; Sphingosine-1-Phosphate Receptor; Spinal; Symptoms; Syndrome; System; Testing; Time; Toxic effect; United States; Validation; Vertebral column; Woman; antagonist; cancer type; cell type; comparison control; conditional knockout; cytokine; desensitization; design; effective therapy; efficacious treatment; functional disability; genetic approach; hormone receptor-positive; in vivo; inhibitor therapy; malignant breast neoplasm; mortality; mouse model; multiple sclerosis treatment; muscle stiffness; new therapeutic target; novel; novel therapeutics; overexpression; pharmacologic; pre-clinical; prevent; protein activation; receptor; receptor expression; receptor function; side effect; sphingosine 1-phosphate; therapy development; tumor

Summary Breast cancer is the second most common cancer among women in the U.S., with most cases diagnosed among postmenopausal women at an early and treatable stage. The majority of tumors are hormone-receptor positive and patients receive adjuvant endocrine treatment with aromatase inhibitors (AI) to prolong disease- free survival and time-to-recurrence. Unfortunately, AI-associated musculoskeletal symptoms (AIMSS) such as joint pain and muscle stiffness/achiness is a common side-effect of AIs, which causes approximately one- fourth of patients discontinue their therapy. The precise mechanisms of AIMSS are unknown and no therapies are approved for prevention or treatment. There is clearly an urgent need to identify and validate novel targets to facilitate development of new treatments that are effective and safe. This proposal focuses on a promising target: the sphingosine-1-phosphate type-1 receptor (S1PR1). Our preliminary data suggest for the first time that S1P contributes to AIMSS-related effects produced by repeated oral administration of letrozole, a widely used AI, in female mice. Letrozole treatment increased levels of S1P in the lumbar spinal cord in female ovariectomized mice. Furthermore, letrozole-induced AIMSS-related symptoms were completely absent in conditional null mice lacking S1PR1 in CNS cell lineages compared to control mice. The effect of FTY720, which is an FDA-approved S1PR1/3/4/5 agonist prodrug, was then assessed as a potential treatment in our model. Oral FTY720 administration reversed letrozole-induced pain-like behaviors and functional impairment in a dose- and time-dependent manner. Treatment with FTY720 also rapidly desensitized S1PR1 signaling in the CNS, suggesting a functional antagonist mechanism of action. Collectively, our preliminary results suggest that S1PR1 represents a promising novel target for the treatment of AIMSS. This project will test the central hypothesis that S1PR1 activation, mainly in astrocytes, contributes to letrozole-induced AIMSS-related symptoms and that competitive or functional antagonism of S1PR1 alleviates these effects. Aim 1 will determine whether competitive antagonism of S1PR1 will alleviate and prevent letrozole-induced AIMSS-related symptoms. Aim 2 will determine whether the S1PR1-selectively agonist, ponesimod, will functionally antagonize SPR1 by desensitization or downregulation of S1PR1 in the CNS to alleviate and prevent AIMSS symptoms. We will also ensure that these S1PR1 ligands do not interfere with the anti-aromatase activity of letrozole in in vitro and in vivo breast cancer models. Aim 3 will determine the role of S1PR1 in specific cell types (astrocytes, neurons, and microglia/macrophages) in letrozole-induced AIMSS. Overall, this project aims to elucidate the target receptor type, cell type(s) and pharmacological mechanism responsible for S1PR1 modulator-induced reversal of AIMSS, thereby providing a rationale for development of S1PR1-based medications to treat this side effect of cancer adjuvant treatment.

概括 乳腺癌是美国女性第二常见的癌症，大多数情况被诊断出 在绝经后妇女中，在早期可治疗的阶段。大多数肿瘤是激素受体 阳性和患者接受芳香酶抑制剂（AI）的辅助内分泌治疗，以延长疾病 - 自由生存和时间的时间。不幸的是，AI相关的肌肉骨骼症状（AIMS）此类 由于关节疼痛和肌肉刚度/成就是AI的常见副作用，这会导致大约1- 四分之一的患者停止治疗。目标的确切机制是未知的，没有 疗法被批准用于预防或治疗。显然迫切需要识别和验证 促进有效且安全的新疗法的开发的新颖目标。该提案重点是 在有希望的靶标上：1-磷酸1型1受体（S1PR1）。我们的初步数据暗示 S1P首次对AIMSS相关的效应造成 letrozole是雌性小鼠中广泛使用的AI。 letrozole治疗增加了腰椎的S1P水平 雌性卵巢切除小鼠的绳子。此外，letrozole引起的与AIMS相关的症状是 与对照小鼠相比，在中枢神经系统细胞谱系中缺乏S1PR1的条件零小鼠中完全不存在。 然后将FTY720的效果（是FDA批准的S1PR1/3/4/5 Agonist前药）作为一个评估 我们模型中的潜在处理。口服FTY720给药逆转了letrozole引起的类似疼痛的行为 和功能障碍以剂量和时间依赖的方式。 FTY720的治疗也很快 中枢神经系统中的S1PR1信号传导脱敏，表明功能性拮抗作用机理。 总的来说，我们的初步结果表明S1PR1代表了治疗的有前途的新目标 目标。该项目将测试中心假设，即S1PR1激活主要在星形胶质细胞中贡献 letrozole引起的与AIMS相关的症状以及S1PR1的竞争性或功能对抗 减轻这些影响。 AIM 1将确定S1PR1的竞争对抗是否会减轻和 防止letrozole引起的与AIMS相关的症状。 AIM 2将确定S1PR1 - 选择性是否 ponesimod激动剂将通过脱敏或下调S1PR1在功能上与SPR1进行拮抗。 中枢神经系统减轻和预防目标症状。我们还将确保这些S1PR1配体不会 干扰letrozole在体外和体内乳腺癌模型中的抗芳香酶活性。目标3意志 确定S1PR1在特定细胞类型（星形胶质细胞，神经元和小胶质细胞/巨噬细胞）中的作用 letrozole引起的目标。总体而言，该项目旨在阐明目标受体类型，细胞类型和 负责S1PR1调节器引起的目标逆转的药理机制，从而提供 开发基于S1PR1的药物来治疗癌症佐剂的副作用的基本原理 治疗。