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.

摘要 乳腺癌是美国女性中第二常见的癌症，大多数病例都被诊断出来 在绝经后妇女中处于早期和可治疗阶段。大多数肿瘤是激素受体。 阳性和患者接受芳香酶抑制剂(AI)的内分泌辅助治疗以延长疾病- 自由存活率和复发时间。不幸的是，AI相关肌肉骨骼症状(AIMSS) 由于关节疼痛和肌肉僵硬/酸痛是人工智能的常见副作用，它导致大约1- 四分之三的患者停止治疗。AIMSS的确切机制尚不清楚，也没有 治疗被批准用于预防或治疗。显然迫切需要确定和验证 新的目标，以促进有效和安全的新治疗方法的开发。这项提案将重点放在 一个很有希望的靶点：鞘氨醇-1-磷酸-1受体(S1PR1)。我们的初步数据显示 S1P首次参与反复口服阿司匹林引起的AIMSS相关效应 来曲唑，一种广泛使用的人工智能，在雌性小鼠身上。来曲唑治疗增加腰椎S1P水平 雌性去卵巢小鼠脊髓。此外，来曲唑诱导的AIMSS相关症状有 与对照组相比，在CNS细胞谱系中缺乏S1PR1的条件性缺失小鼠中完全缺失。 FTY720是FDA批准的S1PR1/3/4/5激动剂前药，其疗效随后被评估为 在我们的模型中有可能进行治疗。口服FTY720逆转来曲唑诱导的痛样行为 并以剂量和时间依赖的方式出现功能损害。FTY720的治疗也很迅速 在中枢S1PR1信号失敏，提示功能拮抗剂的作用机制。 总之，我们的初步结果表明，S1PR1是一种很有前途的治疗新靶点 AIMSS的成员。该项目将检验S1PR1激活主要在星形胶质细胞中起作用的中心假设 来曲唑诱导的AIMSS相关症状及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的竞争性拮抗是否会缓解和 预防来曲唑诱导的AIMSS相关症状。目标2将确定S1PR1是否选择性地 激动剂ponesimod将通过脱敏或下调S1PR1在功能上拮抗SPR1。 中枢神经系统以缓解和预防AIMSS症状。我们还将确保这些S1PR1配体不会 干扰来曲唑在体内外乳腺癌模型中的抗芳香酶活性。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/巨噬细胞)中的作用 来曲唑诱导的AIMSS。总体而言，本项目旨在阐明靶受体类型、细胞类型(S)和 S1PR1调节剂逆转AIMSS的药理机制 开发基于S1PR1的药物治疗癌症辅助剂的这种副作用的理论基础 治疗。