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http://hdl.handle.net/11375/23396
Title: | Development of Novel Targets for Cancer-Induced Bone Pain |
Authors: | Fazzari, Jennifer |
Advisor: | Singh, Gurmit |
Department: | Medical Sciences (Division of Physiology/Pharmacology) |
Publication Date: | 22-Jun-2018 |
Abstract: | A high proportion of advanced-stage breast cancer patients will experience bone metastases resulting in skeletal-related comorbidities including cancer-induced bone pain (CIBP). CIBP affects the quality of life of these patients and current treatments are associated with dose-limiting side-effects that negatively impact patient care. Novel mechanisms must therefore be explored to identify targeted therapies to address this unmet clinical problem. Targeting cancer-specific mechanisms is one strategy to treat this unique pain state peripherally. Glutamate is a key neurotransmitter and signaling molecule in the central nervous system and peripheral tissues including the bone. Particularly aggressive cancers that metastasize to the bone secrete high levels of glutamate via the glutamate/cystine antiporter (system xc-) which can disrupt normal bone turnover and induce CIBP. Therefore, identification of small molecule inhibitors of glutamate release from metastatic breast cancer cells is a novel approach to targeting CIBP. Using high-throughput screening, library compounds were tested for their ability to reduce glutamate release from MDA-MB-231 cells known to secrete high levels of glutamate through system xc- and induce CIBP in vivo. One compound, capsazepine (CPZ), was confirmed to inhibit the functional unit of system xc− (xCT) and successfully delay the onset of, and reverse nociceptive behaviours in a validated animal model. Another lead compound was found to show potent antagonism against glutaminase (GLS), the enzyme catalyzing the intracellular conversion of glutamine to glutamate. This offered another strategy to target glutamate-induced nociception upstream of xCT activity. The effects of GLS inhibition on CIBP behaviours was tested with the specific GLS antagonist, CB-839 but did not significantly modulate nociception, highlighting a redundancy in glutamine metabolism that confers metabolic flexibility in different cancer cell lines. These studies identify novel molecules to target CIBP and reveal that their antinociceptive effects are dependent on the glutamatergic target and metabolic status of the cancer subtype. |
URI: | http://hdl.handle.net/11375/23396 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Fazzari_Jennifer_1807_PhD.pdf | 5.21 MB | Adobe PDF | View/Open |
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