The National Institutes of Health’s National Institute of Dental and Craniofacial Research has awarded Duke Anesthesiology’s Christopher Donnelly, DDS, PhD, a five-year, $3,311,196 R01 grant for his project titled, “Neuro-Immune Modulation of Pain in Health and Disease.”
Nociceptors are specialized sensory neurons that detect noxious stimuli. These neurons serve a vital protective role in protecting organisms at homeostasis, but pathologies leading to hyperactivation of nociceptors leads to debilitating pain. Donnelly’s project will explore how the innate immune sensor, STING, regulates pain in steady-state conditions and in head and neck cancer. This project will substantiate and refine the use of STING pathway agonists as a therapeutic treatment for cancer pain through bidirectional neuro-immune signaling. Completion of this project will accelerate the translation of STING agonists as cancer pain therapy.
The majority of patients with advanced stage cancers experience moderate to severe pain, and more than half of all cancer patients report insufficient pain relief by the currently available therapeutics. Head and neck squamous cell carcinomas (HNSCC) involving the oral cavity and/or oropharynx are regarded as a particularly painful cancer type which produces coincident functional impairments that lead to difficulties in feeding, swallowing and communication. These functional impairments substantially reduce quality of life for cancer patients and are associated with increased morbidity and mortality. Thus, there is a critical need for novel therapeutics that are capable of providing safe and effective pain relief. Moreover, any newly emerging pain therapeutic must be compatible with existing and emerging standard of care cancer treatments, such as cancer immunotherapy, which has emerged as the gold-standard treatment for many cancer subtypes over the last decade.
Donnelly and his collaborators recently discovered that pain-sensing peripheral sensory neurons (nociceptors) express the innate immune regulator, STING. Activation of STING can produce analgesia in preclinical models, both in normal conditions and in pathological pain states. This is noteworthy, as small molecule STING agonists have shown remarkable efficacy in promoting antitumor immunity and are currently being explored as cancer therapeutics in clinical trials. This project aims to identify the cellular and molecular mechanisms by which STING regulates nociception, both in steady-state conditions and in HNSCC pain models.
“There is a strong rationale to identify the cell types and the subcellular signaling mechanisms which underlie the protective analgesic and antitumor properties of STING agonists. Understanding the mechanism will allow us to develop more efficacious therapeutics for cancer pain, accelerate our timeline for clinical translation, and ultimately increase the likelihood that we are able to bypass the ‘valley of death’ separating preclinical studies from meaningful clinical advances,” says Donnelly, assistant professor in anesthesiology and faculty of Duke Anesthesiology’s Center for Translational Pain Medicine.
Beyond the translational applications of this work, Donnelly also advocates for the importance of understanding the fundamental properties of STING signaling in the nervous system. “Most of our understanding about STING signaling comes from experiments in immune cells, but sensory neurons have many unique features. With this project, we’re also exploring how STING signaling differs between sensory neurons and immune cells, and how these unique properties may differentially impact pain and inflammation. In the context of cancer, we’ve shown that STING signaling in sensory neurons and immune cells is highly protective, but there may also be contexts in which STING signaling can be detrimental. Developing a more a comprehensive understanding is critical to determine potential therapeutic applications. Overall, we’re confident that this project will yield new conceptual advances in our understanding of STING signaling in the nervous system and accelerate our push to develop STING-based ‘neuro-immunotherapies’ which provide relief for patients suffering from severe cancer pain,” says Donnelly.
Co-investigators and collaborators of this project include Dr. Andrea Nackley (Duke Anesthesiology), Dr. Rory Goodwin (Duke Neurosurgery), Dr. Zhicheng Ji (Duke Biostatistics and Bioinformatics), and Dr. Yu Lei (University of Michigan). Donnelly and Lei were also recently awarded a grant from the National Institutes of Health for a project titled “Identifying Non-Opioid Strategies to Manage Oral Cancer Pain,” which will develop strategies to overcome opioid-associated immune suppression and opioid-refractory cancer pain in HNSCC.