Overview: Repurposing drugs used in lung cancer treatment may offer hope of symptom relief for patients suffering from chronic pain.
Pain is an important alarm system that alerts us to tissue damage and prompts us to withdraw from harmful situations. Pain is expected to decrease as the injuries heal, but many patients experience persistent pain long after recovery.
Now, a new study published in Science Translational Medicine points to possible new treatments for chronic pain with a surprising link to lung cancer.
The work was led by an international team of researchers from IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Harvard Medical School and Boston Children’s Hospital.
Their research findings, conducted in laboratory mouse models, open up multiple therapeutic avenues that could allow the world to improve the management of chronic pain and eclipse the opioid epidemic.
Acute pain is an important danger signal. Chronic pain, on the other hand, is based on sustained injury and can be experienced even in the absence of a stimulus, injury, or disease. Despite the hundreds of millions of people affected, chronic pain is one of the least well-managed areas of healthcare.
To improve how persistent pain is treated and in the face of the raging opioid crisis, it is paramount to develop new drugs based on a fundamental understanding of the underlying mechanisms.
“We had previously shown that sensory neurons produce a specific metabolite, BH4, which then causes chronic pain, such as neuropathic pain or inflammatory pain,” said project leader and co-corresponding author Shane Cronin, a staff scientist in the Penninger lab at IMBA and a former postdoc in Woolf lab at Harvard Medical School and FM Kirby Neurobiology Center, Boston Children’s Hospital.
“The concentrations of BH4 correlated very well with pain intensity. So of course we thought this was a great way to target.”
To identify drugs that lower BH4 levels in pain neurons, the researchers performed a “phenotypic screen” of 1,000 target-annotated, FDA-approved drugs. This approach enabled the scientists to begin their search for drugs currently used for various indications, and to identify undescribed, off-target analgesic properties.
One of the first findings of this hypothesis-driven search was that the team was able to link the previously observed analgesic effects of several drugs, including clonidine and capsaicin, to the BH4 pathway.
“However, our phenotypic screen also allowed us to ‘reuse’ a surprising drug,” Cronin says. The drug ‘fluphenazine’, an antipsychotic, has been used to treat schizophrenia. “We found that fluphenazine blocks the BH4 pathway in damaged nerves. We also demonstrated its effects in chronic pain after nerve injury in vivo.”
The researchers also found that the effective analgesic dose of fluphenazine in their experiments in the mouse model is comparable to the low doses indicated safely for schizophrenia in humans.
In addition, the screen revealed a new and unexpected molecular link between the BH4 pathway and EGFR/KRAS signaling, a pathway involved in multiple cancers. Blocking EGFR/KRAS signaling reduced pain sensitivity by decreasing levels of BH4.
The genes of EGFR and KRAS are the two most mutated genes in lung cancer, prompting the researchers to look at BH4 in lung cancer.
Surprisingly, by removing a key enzyme, GCH1, in the BH4 pathway, the mouse models of KRAS-driven lung cancer developed fewer tumors and survived much longer. Therefore, the researchers discovered a common signaling pathway for chronic pain and lung cancer via EGFR/KRAS and BH4, opening up new treatment options for both conditions.
“Chronic pain is currently subject to often ineffective palliative treatments. In addition, effective pain relievers such as opioids, if used improperly, can lead to serious addiction. It is therefore critical to find and develop new and repurposed drugs to treat chronic pain,” said co-corresponding author Clifford Woolf, a professor of neurology and neurobiology at Harvard Medical School and director of the FM Kirby Neurobiology Center at the University of California. Boston Children’s Hospital.
An intriguing aspect of the study is the mechanistic link between pain and lung cancer.
“The same triggers that stimulate tumor growth also appear to be involved in determining the pathway to chronic pain, often experienced by cancer patients. We also know that sensory nerves can cause cancer, which could explain the vicious circuitry of cancer and pain,” adds co-corresponding author Josef Penninger, IMBA group leader and founder, who is also currently the director of the Life Sciences Institute at the University of British Columbia (UBC), Vancouver, Canada.
“Understanding this cross-talk is therefore not only critical for cancer treatments, but may also help improve the quality of life of cancer patients towards less pain.”
About this research news on pain and neuropharmacology
Author: Daniel F. Azaria
Contact: Daniel F. Azar – IMBA
Image: The image is attributed to Cronin/IMBA
Original research: Closed access.
“Phenotypic drug screening reveals GCH1/BH4 metabolic pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer” by Cronin, SJ F et al. Science Translational Medicine
Phenotypic drug screening reveals the GCH1/BH4 metabolic pathway as a key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer
Elevated tetrahydrobiopterin (BH4) generated in damaged sensory neurons contributes to increased pain sensitivity and its persistence. GTP-cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, along with mouse genetic modeling, have shown that decreased GCH1 leads to both decreased BH4 and pain.
However, little is known about the regulation of Gch1 expression in nerve damage and whether this can be modulated as an analgesic therapeutic intervention.
We performed a phenotypic screening using approximately 1000 bioactive compounds, many of which are FDA-approved drugs, for their effect on regulating Gch1 expression in rodent injured dorsal root ganglion neurons. From this approach, we have discovered relevant pathways that regulate: Gch1 expression in sensory neurons.
We report that EGFR/KRAS signaling triggers have increased Gch1 expression and contributes to neuropathic pain; conversely, inhibition of EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular association between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to induce lung cancer, identifying a potentially drugable pathway.
Our screen shows that pharmacological modulation of GCH1 expression and BH4 can be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and rodent cancer.