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

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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.