Investigational cancer therapy shows promise for spinal regeneration
University of Birmingham scientists have shown that a drug currently in clinical development for cancers is a potential novel therapy to promote nerve regeneration and recovery of function after spinal trauma.
Research published in Clinical and Translational Medicine by scientists from the University of Birmingham(UK) has demonstrated the ability of an investigational cancer drug, AZD1390, to stimulate regeneration of damaged nerves after spinal cord injury.
AZD1390 was initially developed by AstraZeneca (Cambridge, UK) to increase the radiosensitivity and, therefore, treatability of cancer cells by inhibiting ataxia-telangiectasia mutated (ATM) signaling and the subsequent repair of DNA double-strand breaks (DSBs). DSBs, which occur in several common cancers and also after spinal cord injury, activate the DNA damage response system (DDR). Many of the downstream events of DDR are mediated by the ATM signaling pathway.
It was hypothesized by the corresponding authors, Zubair Ahmed and Richard Tuxworth, that persistent activation of the DDR may prevent recovery from spinal cord injury. Therefore, blocking the activation of this system using AZD1390 could promote nerve repair and restore function.
In initial investigations, the researchers found that AZD1390 inhibited the ATM signaling pathway and stimulated neurite growth in vitro, using an adult mouse neuron culture system that mimicked the environment of a spinal cord injury.
Following this, the researchers tested AZD1390 in vivo. In both mouse and rat models, they showed that oral delivery caused significant inhibition of ATM signaling and promoted axon regeneration in the dorsal column beyond the site of injury. The electrophysiological function was returned to these regenerated nerves and they were able to carry electrical signals across the site of the injury.
Zubair Ahmed, from the Institute of Inflammation and Ageing at the University of Birmingham, commented: “This is an exciting time in spinal cord injury research with several different investigational drugs being identified as potential therapies for spinal cord injury. We are particularly excited about AZD1390 which can be taken orally and reaches the site of injury in sufficient quantities to promote nerve regeneration and restore lost function. Our findings show a remarkable recovery of sensory and motor functions, and AZD1390-treated animals being indistinguishable from uninjured animals within 4 weeks of injury.”
Dr Tuxworth, from the University of Birmingham’s Institute of Cancer and Genomic Sciences, added: “This early study shows that AZD1390 could be used as a therapy in life-changing conditions. In addition, repurposing this existing investigational drug potentially means we can reach the clinic significantly faster than developing a new drug from scratch.”
University of Birmingham Enterprise has filed a patent application covering the inhibition of the ATM-mediated DDR pathway by compounds such as AZD1390 that may represent a potential therapeutic strategy to promote nerve repair.
Source: Research shows investigational drug fosters nerve repair after injury
