Abstract
Pain is a major symptom of bone metastases from advanced cancer and represents a clinical challenge to treat effectively. Basic neurobiology in preclinical animal models implicates enhanced sensory processing in the central nervous system, acting through N-methyl-D-aspartate (NMDA) glutamate receptors, as an important mechanism underpinning persistent pain. The non-receptor tyrosine kinase Src is thought to act as a hub for regulating NMDA receptor activity and the orally available Src inhibitor saracatinib has shown promise as a potential analgesic in recent animal studies. Here we tested the efficacy of saracatinib as a novel analgesic in an exploratory phase II randomized controlled trial on cancer patients with painful bone metastases. Twelve patients completed the study, with 6 receiving saracatinib 125 mg/day for 28 days and 6 receiving placebo. Pharmacokinetic measurements confirmed appropriate plasma levels of drug in the saracatinib-treated group and Src inhibition was achieved clinically by a significant reduction in the bone resorption biomarker serum cross-linked C-terminal telopeptide of type I collagen. Differences between the saracatinib and placebo groups self-reported pain scores, measured using the short form of the Brief Pain Inventory, were not clinically significant after 4 weeks of treatment. There was also no change in consumption of maintenance analgesia in the saracatinib-treated group and no improvement in Quality-of-Life scores. The data were insufficient to demonstrate saracatinib has efficacy as analgesic, although it may have a role as an anti-bone resorptive agent.
Highlights
Pain from bone metastases is a common feature of advanced cancer, occurring in approximately 70% of patients with late-stage disease [1,2]
The consensus of preclinical laboratory studies is that synaptic plasticity in spinal cord neurons, increased glutamatergic excitatory neurotransmission, is thought to be a major mechanism underlying central sensitization that contributes to pain hypersensitivity [5,7,8,9]
This form of synaptic plasticity involves activation of G-protein coupled membrane receptors and intracellular signaling pathways that are thought to converge on the protein tyrosine kinase Src [10,11]; activation of spinal N-methyl-D-aspartate (NMDA) glutamate receptors follows, with phosphorylation of the GLUN1 and GluN2B subunits
Summary
Pain from bone metastases is a common feature of advanced cancer, occurring in approximately 70% of patients with late-stage disease [1,2]. The consensus of preclinical laboratory studies is that synaptic plasticity in spinal cord neurons, increased glutamatergic excitatory neurotransmission, is thought to be a major mechanism underlying central sensitization that contributes to pain hypersensitivity [5,7,8,9]. This form of synaptic plasticity involves activation of G-protein coupled membrane receptors and intracellular signaling pathways that are thought to converge on the protein tyrosine kinase Src [10,11]; activation of spinal N-methyl-D-aspartate (NMDA) glutamate receptors follows, with phosphorylation of the GLUN1 and GluN2B subunits. In the current study we have tested whether saracatinib has analgesic efficacy in cancer patients with bone pain due to metastatic disease
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