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Breast cancer: Molecular pathophysiology of paclitaxel-induced pain
Pain in breast-cancer patients, a critical quality of life issue, can be caused by treatment with taxanes, such as paclitaxel. This treatment, unfortunately, leads to a painful sensory neuropathy in a significant percentage of patients. By using rats chronically treated with paclitaxel, we have discovered that the calcium-permeable TRP channel, TRPM3, was selectively expressed in the spinal cord dorsal horn in control rats, the first synaptic relay for nociceptive afferents, and significantly up-regulated in chronically paclitaxel-treated rats. TRPM3 was expressed in glutamatergic spinal cord dorsal horn neurons, thus incriminating TRPM3, upregulated by paclitaxel, as pro-nociceptive. Based on these preliminary results, we will address the following aims. (1) To elaborate that paclitaxel leads to TRPM3 up-regulation in the spinal cord dorsal horn. (2) To subject the paclitaxel-treated rats to intrathecal administration of antisense oligonucleotides specific for TRPM3, in order to determine whether this treatment will ameliorate the pain-related behavior and down-regulate TRPM3 in the spinal cord dorsal horn. Aim (1) would link up-regulation of TRPM3 expression to chronic paclitaxel treatment, Aim (2) would establish a causality of this link. Our preliminary data suggest that TRPM3 functions as a pro-nociceptive, calcium-conducting effector-mechanism in paclitaxel-induced pain. We propose experiments that will verify this exciting lead, addressing the question whether anti-TRPM3 therapy ameliorates paclitaxel-induced pain. If successful, this would establish TRPM3 as a novel molecular target for therapy of paclitaxel-induced pain, so that rational anti-neuropathic, anti-TRPM3 treatment modalities could be devised.
Breast cancer patients suffer from pain, which critically impacts their quality of life. One of the contributing factors to this pain is the administration of taxane-like drugs (e.g. paclitaxel=taxol), the main pillars of chemotherapy against breast cancer. Paclitaxel damages nerves in an unknown way and thus contributes to pain. The experiments in this proposal will shed light on the origins of this pain. We will focus on one area in the spinal cord, the area which functions as the first switch-relay station of incoming pain impulses from the peripheral nerve-fibers damaged by paclitaxel. We will first examine whether a novel protein functioning as a valve for calcium ions, a calcium ion channel, facilitates the transmission of pain impulses in the switch-relay part of the spinal cord of paclitaxel-treated rats. Compelling preliminary data have been gathered. The novel calcium ion channel is found in the spinal cord relay switch, its abundance is significantly increased in rats chronically treated with paclitaxel, and it is found in excitatory nerve cells. These findings suggest that the novel calcium ion channel functions as a pain-enhancer. In the proposed experiments, these data will be extended, so that we will be able to critically link calcium influx through the novel channel to treatment with paclitaxel. Finally, rats will be subjected to a treatment that inhibits the novel calcium channel, to test whether this treatment will ameliorate the clinical course, thus addressing the question whether the novel calcium ion channel is causally linked to paclitaxel-induced neuropathic pain. In summary, we have identified a potentially new molecular target in the form of a novel calcium ion channel, for future pain therapies in paclitaxel-induced nerve damage, a dreaded clinical complication that commonly occurs in treatment of breast cancer with taxanes. Our proposed approach of inhibiting the novel ion channel could, if successful, lead to a new treatment of taxane-induced or ?enhanced pain in breast cancer.