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Key (and Possible Cure) to Cancer-Related Bone Pain Found

June 8, 2017
By targeting S1P1 pathway, researchers at Saint Louis University were able to show that the MS drug Gilenya mitigated bone pain and neuroinflammation in a mouse model.

A key molecular pathway that drives cancer-related bone pain has been identified by researchers at Saint Louis University (SLU). The researchers observed that increases in sphingosine 1-phosphate are a key component in the development of pain. And that targeting sphingosine 1-phosphate receptor subtype 1 (S1PR1) mitigates bone pain and neuroinflammation, reported the team in the journal Pain.1

“Pain is a huge problem—for the patient, the caregiver, the family, the doctors,” said Daniela Salvemini, PhD, professor of pharmacology and physiology at SLU, and lead author of a paper. Metastatic bone pain is the single most common form of cancer pain. Cancer-induced bone pain (CIBP) is reported by 30% to 50% of all cancer patients and by 75% to 90% of late-stage patients.2 CIBP is driven by a combination of tumor-associated skeletal, inflammatory, and neuropathic mechanisms.

Daniela Salvemini, PhD, professor of pharmacology and physiology at Saint Louis University Photo Credit: Ellen Hutti for Saint Louis University

Innovations in the treatment of bone cancer pain primarily have focused on addressing bone loss and vulnerability to painful skeletal-related events. However, no therapies currently target the neuropathic mechanisms of CIBP, according to press release from SLU. In addition, pain often continues even for patients whose cancer enters remission, increasing the need for effective therapies rather than relying only on palliative care. “Better understanding of cancer-induced bone pain is critical to the development of such strategies,” Dr. Salvemini said.

In an earlier study, Dr. Salvemini and colleagues showed that “the development of paclitaxel [Taxol]-induced neuropathic pain was associated with ceramide and S1P formation in the spinal dorsal horn that corresponded with the engagement of S1PR1-dependent neuroinflammatory processes.”3 The pathway included:

  • Activation of redox-sensitive transcription factors (NFκB) and MAPKs (ERK and p38)
  • Enhanced formation of pro-inflammatory and neuroexcitatory cytokines (TNF-α and IL-1β)

Treatment with intrathecal S1PR1 antagonist FTY720 reduced these neuroinflammatory processes but increased interleukin (IL)-10 and IL-4, potent anti-inflammatory/neuroprotective cytokines. Fingolimod/FTY720 (Gilenya), is FDA-approved as an oral therapy for relapsing multiple sclerosis.4

Dr. Salvemini’s current paper reports on an experiment her team conducted studying an animal model of breast cancer that has metastasized to the femur. The researchers observed in the spinal cord changes to key pathways suggesting that increases in sphingosine 1-phosphate are a key component of developing pain and that blocking this signal limits pain.”We demonstrate for the first time the bioactivity of spinal sphingolipid metabolites S1P and dihyro-S1P and the ensuing neuroinflammation are critical components of CIBP,” wrote the researchers.1

To test pain in the mice, the researchers measured pain behaviors prior to surgery (day 0, baseline, BL) and again on postsurgery day 10 for acute treatment studies, or on days 7, 10 and 14 for continuous treatment studies. Following the establishment of CIBP (day 11), animals were administered an intrathecal injection of vehicle, S1PR1 antagonist TASP0277308, or FTY720. Administration of TASP0277308 or FTY720, but not their vehicle, rapidly (≤ 30 min) reversed flinching and guarding behavior with an effect that peaked within 30 min and resolved by 3 h, wrote the team.1

The team confirmed that targeting S1PR1 mitigates bone pain and neuroinflammation, and identifies S1PR1 as a potential therapeutic target alone or as a secondary therapy to address cancer-induced bone pain.

"Thanks to an exceptional team that included the expertise of Dr. Todd Vanderah, known for his seminal work in pain, and Dr. Sarah Spiegel, known for her work in sphingolipid biology and the discovery of S1P, we were able to make this significant advance toward providing pain relief for those who are suffering," Dr. Salvemini said. 

Other researchers on the study include Shaness A. Grenald, Timothy M. Doyle, Hong Zhang, Lauren M. Slosky, Zhoumou Chen and Tally M. Largent-Milnes.

This study was funded by grants from the Leukemia and Lymphoma Society (6241-13) with additional support from the Saint Louis University Cancer Center and by NIH/NCI grant RO1CA142115 and NIH/NIGMS grant R01GM043880.

 

Last updated on: June 8, 2017
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