On the therapeutic potential of cancer drugs for spinal cord injury

Abstract: Spinal cord injury progresses in two stages. After the damage-causing physical event, comes an extended period when additional loss of cells and nerve fibers will occur and inflammatory and scar forming processes will come to prevail. The secondary events, however, also present a window of opportunity during which pharmacological intervention may decrease the extent of permanent neurological impairment. A few drugs have been tested clinically for such effects, but none is currently in use for spinal cord injured patients. Hence there is a need for additional therapeutic candidates. This thesis addresses the lack of clinical candidates by investigating the possibility to reposition drugs in clinical use for other indications, by testing them in the acute stage of spinal cord injury. We evaluated the therapeutic potential of the three cancer drugs erlotinib, rapamycin, and imatinib. These drugs all inhibit receptor tyrosine kinase signaling and their respective molecular targets are likely to be involved in promoting the degenerative secondary events following the initial trauma. Hence these drugs offer a potentially fast translational process to serve as a first line treatment, protecting vulnerable tissue and allowing improved functional recovery. In vitro, we characterized astrocytic cultures from adult rats and found that both growth conditions and choice of rat substrain will change astrocyte parameters and we further identified which of the tested substrains produce an astrocytic culture most similar to a human astrocytic culture (Paper I). We then characterized the spontaneous functional recovery of different rat substrains subjected to a mild contusion injury and found differences in recovery of hindlimb locomotion function, bladder function and sensory function with regard to mechanical stimuli (Paper III). The results should aid in optimizing the experimental and translational value of these in vitro and in vivo model systems. To determine the therapeutic potential of erlotinib, rapamycin and imatinib, we administered the drugs per os with a 30 minute delay during the acute stage of a contusion injury in rats and monitored functional recovery. We found erlotinib treatment to accelerate bladder and locomotor recovery (Paper IV). We also characterized the spatiotemporal activation of the target of rapamycin, mTORC1, after the spinal cord injury. We found a biphasic activation of glial cells, primarily macrophages and microglia, revealing possible windows of opportunity for targeting mTORC1 with rapamycin in spinal cord injury (Paper V). However, acute treatment with rapamycin did not alter recovery of bladder function or locomotion (Paper IV). We found that imatinib enhanced recovery of locomotion and bladder function by effectively reducing negative secondary events and rescuing spinal tissue, including axons (Paper II). To determine the possible clinical potential of imatinib we further delayed the initial administration of the drug, assessed motor and sensory recovery and searched for potential biomarkers in serum (Paper VI). We found imatinib to improve hind limb locomotion when administered with a 4 hour delay and to improve bladder recovery even with a 24 hour delay. The 4 hour delay treatment had modest positive effects on recovery of mechanical and thermal sensory functions and we identified alterations of two cytokines/chemokines as candidate biomarkers. In conclusion, further studies of erlotinib and rapamycin are needed in order to determine their therapeutic potential in spinal cord injury. Imatinib, however, stands out as a candidate drug for clinical trials in acute spinal cord injury