Targeting Sphingosine-1-Phosphate Axis with FTY720/Fingolimod as a Novel Therapy for Triple-Negative Breast Cancer and Chemotherapy-Induced Pain
Abstract
Breast cancer is a leading cause of cancer-associated death in women in the US. Most of these deaths result from uncontrolled metastatic disease as current therapies are not completely effective in the treatment of metastatic breast cancer. Triple-negative breast cancer (TNBC) is more aggressive and metastatic than other types of breast cancer and has a poorer prognosis. Moreover, treatment options are limited because the “triple-negative” refers to the absence of three receptor proteins normally required for breast cell growth. In the absence of these receptors, common treatments, such as hormonal therapy and drugs that target estrogen, progesterone, and HER-2 are ineffective. Thus, less targeted chemotherapies are typically used, including taxanes such as Taxol (paclitaxel) and platinum-based drugs such as Paraplatin (carboplatin). Indeed, combination therapy with these two drugs is now part of a common treatment regimen for TNBC. However, there are two problems with these drugs: they are not 100% effective and they can have devastating, dose-limiting side effects. Both paclitaxel and carboplatin can lead to neurotoxic side effects commonly known as chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by pain and loss of sensation in the hands and feet. CIPN is one of the most disabling and demoralizing problems for cancer survivors as it can significantly diminish the quality of life of cancer patients and be so severe that it limits or even causes termination of treatment. Current CIPN treatments include anti-depressants, opioids, and cannabinoids. However, these treatments do not address the root causes of CIPN and may reduce the efficacy of chemotherapy. Moreover, they often fail to provide pain relief for a large number of patients and have many unwanted side effects including addiction. A better understanding of the molecular underpinnings leading to neuropathic pain is essential for the development of effective, non-narcotic therapeutic approaches that target CIPN before it develops. The fundamental basis of this proposal is the growing evidence from our lab that sphingosine-1-phosphate (S1P), a bioactive sphingolipid signaling molecule formed inside cells by enzymes called sphingosine kinases, regulates many physiological processes involved in breast cancer progression, metastasis, and CIPN. Moreover, we found that the orally available drug used for treatment of multiple sclerosis, FTY720 (fingolimod/Gilenya), also has multiple anti-cancer activities and simultaneously prevents formation and actions of S1P via its receptor, S1PR1. In mouse breast cancer models, treatment with FTY720 reduced tumor progression and metastasis and enhanced sensitivity of TNBC to chemotherapies. As administration of clinically relevant doses of FTY720 also markedly suppressed CIPN in mice, in this proposal we will examine the intriguing hypothesis that targeting the S1P/S1PR1 axis with FTY720 combined with chemotherapy is a multipronged approach to enhance the anti-cancer effects of paclitaxel and carboplatin and also suppress CIPN. Another novel aspect of this proposal is unraveling the cellular and molecular mechanisms that lead to CIPN focused on the key roles of S1P in astrocytes in regulating neuroinflammation and synaptic plasticity. Our work will reveal new molecular and cellular insights of the S1P/S1PR1 axis as a linchpin in amplifying processes important for development of CINP and will provide the scientific basis for the rationale to develop S1P/S1PR1 targeted therapies to minimize chemotherapy-induced neurotoxicities in a non-addictive manner while enhancing anti-cancer effects. As FTY720/fingolimod also shows promising anticancer potential and is U.S. Food and Drug Administration-approved, and second-generation S1PR1 modulators are already in clinical trials, it is anticipated that our study will provide the foundation for “fast-track” support for rapid clinical translation of o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010434
Entities
People
- Sarah Spiegel
Organizations
- United States Army
- Virginia Commonwealth University