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大常见癌症，大多数病例均已确诊 处于早期和可治疗阶段的绝经后妇女。大多数肿瘤是激素受体肿瘤 阳性且患者接受芳香酶抑制剂（AI）辅助内分泌治疗以延长疾病- 自由生存和复发时间。不幸的是，人工智能相关的肌肉骨骼症状（AIMSS） 因为关节疼痛和肌肉僵硬/酸痛是人工智能的常见副作用，这会导致大约一 四分之一的患者停止治疗。 AIMSS 的确切机制尚不清楚，也没有 疗法被批准用于预防或治疗。显然迫切需要识别和验证 促进开发有效且安全的新疗法的新目标。该提案重点 一个有希望的目标：1-磷酸鞘氨醇1型受体（S1PR1）。我们的初步数据表明 S1P 首次通过重复口服产生 AIMSS 相关效应 来曲唑是一种在雌性小鼠中广泛使用的人工智能。来曲唑治疗增加腰椎 S1P 水平 雌性卵巢切除小鼠的脐带。此外，来曲唑诱导的 AIMSS 相关症状是 与对照小鼠相比，CNS 细胞谱系中缺乏 S1PR1 的条件无效小鼠中完全不存在。 FTY720 是 FDA 批准的 S1PR1/3/4/5 激动剂前药，其效果随后被评估为 我们模型中的潜在治疗方法。口服 FTY720 逆转来曲唑诱导的疼痛样行为 和功能损害以剂量和时间依赖性的方式。 FTY720治疗也很快 中枢神经系统中的 S1PR1 信号传导脱敏，表明其存在功能性拮抗剂作用机制。 总的来说，我们的初步结果表明 S1PR1 代表了一个有前途的新治疗靶点 AIMSS 的。该项目将测试中心假设，即 S1PR1 激活（主要在星形胶质细胞中）有助于 来曲唑诱导的 AIMSS 相关症状以及 S1PR1 的竞争性或功能性拮抗作用 减轻这些影响。目标 1 将确定 S1PR1 的竞争性拮抗作用是否会减轻并 预防来曲唑引起的 AIMSS 相关症状。目标2将确定S1PR1是否选择性地 激动剂 ponesimod 将通过 S1PR1 脱敏或下调来功能性拮抗 SPR1 CNS 缓解和预防 AIMSS 症状。我们还将确保这些 S1PR1 配体不会 在体外和体内乳腺癌模型中干扰来曲唑的抗芳香酶活性。目标3将 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 来曲唑诱导的 AIMSS。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 调节剂诱导 AIMSS 逆转的药理学机制，从而提供 开发基于 S1PR1 的药物来治疗癌症佐剂的这种副作用的理由 治疗。