PainRelief.com: What are the main findings?
Response: We have three main findings from our recent study:
1) Using BH4 activation as a cellular biomarker for in vitro ‘pain’ compound screening in sensory neurons worked very well
2) Identified fluphenazine hydrochloride, a known anti-psychotic previously used to treat schizophrenia, as a new way to block Gch1 upregulation and reduce BH4 levels and neuropathic pain in rodents
3) Also uncovered an interesting link between EGFR/KRAS signaling and BH4 regulation in both injured neuropathic pain and in lung cancer
PainRelief.com: What should readers take away from your report?
Response: Chronic pain is an extremely heterogenous and complex disorder in its own right and new therapies and appropriate models are needed to find the next generation of effective and safe analgesics. Repurposing drugs using relevant phenotypic screening platforms is a viable approach to achieve this.
Moreover, the link between EGFR/KRAS signaling and BH4 regulation is very interesting. EGFR/KRAS is an established pathway intimately linked to a variety of cancers and huge efforts and various strategies are being made to block this pathway in cancer. We suggest that such strategies could also work with certain chronic pain conditions in which this pathway is also activated and also adds to the emerging cross talk between cancer and sensory neurons/chronic pain.
PainRelief.com: What recommendations do you have for future research as a result of this study?
Response: We are excited to move this research forward looking more closely at the connection between EGFR/KRAS activation and BH4 in chronic pain (and indeed cancer). We will look at many other animal models of neuropathic, inflammatory and cancer pain, and will also use iPSC-derived human nociceptors as additional platforms to investigate this link and also test drugs such as fluphenazine (and many others) in these models.
Shane J. F. Cronin, Shuan Rao, Miguel A. Tejada, Bruna Lenfers Turnes, Simon Licht-Mayer, Takao Omura, Christian Brenneis, Emily Jacobs, Lee Barrett, Alban Latremoliere, Nick Andrews, Keith M. Channon, Alexandra Latini, Anthony C. Arvanites, Lance S. Davidow, Michael Costigan, Lee L. Rubin, Josef M. Penninger, Clifford J. Woolf. Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer. Science Translational Medicine, 2022; 14 (660) DOI: 10.1126/scitranslmed.abj1531
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