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Old cancer drugs hint at new ways to combat chronic pain

Summary: Medications used to treat lung cancer can offer hope of symptom relief for patients with chronic pain.

source: IMBA

Pain is an important alarm system that alerts us to tissue damage and urges us to withdraw from harmful situations. The pain is expected to subside as the injuries heal, but many patients experience persistent pain long after recovery.

Now, a new study has been published in Translational Medicine Sciences Indicates potential new treatments for chronic pain with a surprising association with lung cancer.

The work was led by an international team of researchers at IMBA – the Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Harvard Medical School and Boston Children’s Hospital.

Their findings from the research, conducted in laboratory mouse models, open up multiple treatment opportunities that could allow the world to better manage chronic pain and eclipse the opioid epidemic.

Acute pain is an important danger signal. By contrast, chronic pain is dependent on ongoing injury and can even be felt in the absence of a trigger, injury, or disease. Despite hundreds of millions of people affected, chronic pain is among the least well-managed areas of health care.

To improve how we manage ongoing pain and consider the raging opioid crisis, it is critical to develop new drugs based on a basic understanding of the underlying mechanisms.

“We’ve previously shown that sensory neurons produce a specific metabolite, BH4, which then leads to chronic pain, such as neuropathic pain or inflammatory pain,” says project leader and co-author Shane Cronin, a team scientist in IMBA’s Penninger Laboratory and a former researcher. Postdoc in Wolf’s Lab at Harvard Medical School and the FM Kirby Center for Neurobiology, Boston Children’s Hospital.

“BH4 concentrations correlate well with pain intensity. So we naturally thought this was a great route to target.”

To identify drugs that reduce BH4 levels in pain neurons, researchers performed a “typical screen” of 1,000 FDA-approved targeted annotated drugs. This approach allowed the scientists to begin their research with currently used drugs for different indications, and to determine the properties of non-prescribed and non-targeted analgesics.

Among the first results of this hypothesis-based research, the team was able to link previously observed analgesic effects of several drugs, including clonidine and capsaicin, to the BH4 pathway.

“However, our phenotype screen also allowed us to ‘repurpose’ a surprising drug,” Cronin says. Fluphenazine, an antipsychotic, has been used to treat schizophrenia. “We found that fluphenazine blocks the BH4 pathway in injured 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 rat model trials is comparable to the minimum doses safely indicated 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 implicated in many cancers. Blocking EGFR/KRAS signaling reduced pain sensitivity by lowering BH4 levels.

The EGFR and KRAS genes are the two genes most frequently mutated in lung cancer, leading researchers to look at BH4 in lung cancer.

Surprisingly, by deleting an important enzyme, GCH1, in the BH4 pathway, mouse models of KRAS-driven lung cancer developed fewer tumors and survived longer. Hence, the researchers revealed a common signaling pathway for chronic pain and lung cancer through EGFR/KRAS and BH4, thus opening new avenues of treatment for both conditions.

This shows sensory neurons
Mouse sensory neurons are shown in purple. BH4, the molecule that drives chronic pain, is shown in green. Hence, neurons in ‘Pain’ are shown in green/white. Credit: Cronin/IMBA

Chronic pain is currently undergoing often ineffective treatments. Moreover, effective painkillers such as opiates, if used inappropriately, can lead to severe addiction. It is therefore imperative to find and develop new and reused drugs to treat chronic pain,” says co-author Clifford Wolf, MD, professor of neurology and neuroscience at Harvard Medical School and director of the FM Kirby Neurobiology Center at Boston Children’s Hospital.

One interesting aspect of the study is the mechanistic link between pain and lung cancer.

The same tumor-stimulating factors also appear to be involved in paving the way to chronic pain, which cancer patients often experience. We also know that sensory nerves can lead to cancer, which could explain the vicious cycle of cancer and pain,” adds co-author Joseph Benninger, IMBA Group Leader and Founding Director, who is also currently director of the Life Sciences Institute at the University of British Columbia (UBC) Vancouver, Canada.

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This indicates a brain and a question mark

“So understanding these reciprocal conversations is not only critical for cancer treatments, but may also help improve the quality of life for cancer patients in order to reduce pain.”

About this news of pain and neurological drugs

author: Daniel F. Azar
source: IMBA
Contact: Daniel F. Azar – IMBA
picture: Photo credited to Cronin / IMBA

original search: Access closed.
A modular drug screen reveals the GCH1/BH4 metabolic pathway as a major regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer.By Cronin and SJ F et al. Translational Medicine Sciences


Summary

A modular drug screen reveals the GCH1/BH4 metabolic pathway as a major regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer.

Increased tetrahydrobiopterin (BH4) generated in affected sensory neurons contributes to increased and persistent pain sensitivity. GTP cyclohydrolase 1 (GCH1) is a rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, combined with mouse genetic modeling, have shown that decreased GCH1 results in decreased BH4 and pain.

However, not much is known about the organization Gch1 Expression when a nerve is injured and whether this can be modified as an analgesic intervention.

We performed a modular screen using approximately 1,000 biocomplexes, many of which are FDA-approved targeted annotated drugs, for their effects on regulation. Gch1 Expression in rodent-infected dorsal root ganglion neurons. From this approach, we explored relevant pathways that regulate Gch1 Expression in sensory neurons.

We reported that EGFR/KRAS signaling triggers increased Gch1 Expression and contributes to neuropathic pain. On the contrary, EGFR inhibition inhibited GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also demonstrate that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potential pathway for therapeutics.

Our screen shows that pharmacological modulation of GCH1 and BH4 expression can be used to develop pharmacological therapies for pain relief and to identify a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents.

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