Three decades-old antibiotics could offer an alternative to opioid-based painkillers

Three decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, UT Southwestern researchers report. The finding, published online today in PNAS, could offer an alternative to opioid-based painkillers, addictive prescription medications that are responsible for an epidemic of abuse in the U.S.

Over 100 million Americans are affected by chronic pain, and a quarter of these experience pain on a daily basis, a burden that costs an estimated $600 billion in lost wages and medical expenses each year. For many of these patients – those with cancer, diabetes, or trauma, for example – their pain is neuropathic, meaning it's caused by damage to pain-sensing nerves.

To treat chronic pain, prescriptions for opioid painkillers have increased exponentially since the late 1990s, leading to a rise in abuse and overdoses. Despite the desperate need for safer pain medications, development of a new prescription drug typically takes over a decade and more than $2 billion according to a study by the Tufts Center for the Study of Drug Development, explains study leader Enas S. Kandil, M.D., associate professor of anesthesiology and pain management at UTSW.

Seeking an alternative to opioids, Kandil and her UT Southwestern colleagues – including Hesham A. Sadek, M.D., Ph.D., professor of internal medicine, molecular biology, and biophysics; Mark Henkemeyer, Ph.D., professor of neuroscience; Mahmoud S. Ahmed, Ph.D., instructor of internal medicine; and Ping Wang, Ph.D., a postdoctoral researcher – explored the potential of drugs already approved by the Food and Drug Administration (FDA).

The team focused on EphB1, a protein found on the surface of nerve cells, which Henkemeyer and his colleagues discovered during his postdoctoral training nearly three decades ago. Research has shown that this protein is key for producing neuropathic pain. Mice genetically altered to remove all EphB1 don't feel neuropathic pain, he explains. Even mice with half the usual amount of this protein are resistant to neuropathic pain, suggesting EphB1's promise as a target for pain-relieving drugs. Unfortunately, no known drugs inactivate EphB1.

Exploring this angle further, Ahmed used computer modeling to scan a library of FDA-approved drugs, testing if their molecular structures had the right shape and chemistry to bind to EphB1. Their search turned up three tetracyclines, members of a family of antibiotics used since the 1970s. These drugs – demeclocycline, chlortetracycline, and minocycline – have a long history of safe use and minimal side effects, Ahmed says.

To investigate whether these drugs could bind to and inactivate EphB1, the team combined the protein and these drugs in petri dishes and measured EphB1's activity. Sure enough, each of these drugs inhibited the protein at relatively low doses. Using X-ray crystallography, Wang imaged the structure of EphB1 with chlortetracycline, showing that the drug fits neatly into a pocket in the protein's catalytic domain, a key portion necessary for EphB1 to function.

In three different mouse models of neuropathic pain, injections of these three drugs in combination significantly blunted reactions to painful stimuli such as heat or pressure, with the triplet achieving a greater effect at lower doses than each drug individually. When the researchers examined the brains and spinal cords of these animals, they confirmed that EphB1 on the cells of these tissues had been inactivated, the probable cause for their pain resistance. A combination of these drugs might be able to blunt pain in humans too, the next stage for this research, says Kandil.

Unless we find alternatives to opioids for chronic pain, we will continue to see a spiral in the opioid epidemic. This study shows what can happen if you bring together scientists and physicians with different experience from different backgrounds. We're opening the window to something new."

Enas S. Kandil, M.D., Associate Professor, Anesthesiology and Pain Management, UT Southwestern

Source:

UT Southwestern Medical Center

Posted in: Medical Science News | Medical Research News | Pharmaceutical News

Tags: Anesthesiology, Animal Model, Antibiotic, Cancer, Cardiology, Chronic, Chronic Pain, Crystallography, Diabetes, Drugs, Education, heat, Medicine, Minocycline, Molecular Biology, Nerve, Neuropathic Pain, Neuroscience, Opioids, Pain, Pain Management, pH, Prescription Drug, Protein, Receptor, Research, Tetracycline, Trauma, X-Ray

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Combination therapy produces clinical benefit for early stage non-small cell lung cancer

The first randomized Phase II clinical trial to report on single and combined neoadjuvant immune checkpoint inhibitor therapy in stage I-III non-small cell lung cancer (NSCLC) found combination therapy produced a significant clinical benefit, as assessed by major pathologic response (MPR) rate, as well as enhanced tumor immune cell infiltration and immunological memory. Researchers from The University of Texas MD Anderson Cancer Center published the study results today in Nature Medicine.

The NEOSTAR trial tested combined neoadjuvant therapy of nivolumab plus ipilimumab, as well as neoadjuvant nivolumab monotherapy in patients with operable NSCLC. The trial met its prespecified primary endpoint efficacy threshold in the combination arm, with eight of 21 treated patients (38%) achieving major pathological response, defined as ≤10% viable tumor at surgery.

MPR has been shown to correlate with improved survival outcomes after neoadjuvant chemotherapy in NSCLC. The prespecified efficacy boundary for each treatment to be considered promising for further testing was six or more MPRs in 21 evaluable patients. With MPR in five of 23 treated patients (22%), monotherapy did not meet the efficacy boundary.

While combination immunotherapy has been approved for a subset of patients with metastatic NSCLC, this is the first randomized study to report on the role of combination checkpoint inhibitors for operable, early stage disease.

More than 50% of patients with localized non-small cell lung cancer will relapse if treated with surgery alone. Adding chemotherapy produces only a modest improvement in overall survival, and it comes with toxicity. The results from our study with neoadjuvant combination immunotherapy are particularly encouraging in that we found that this dual treatment can induce higher pathologic responses and trigger immunological memory. This may translate into a reduced risk for tumor relapse in more patients with early stage non-small cell lung cancer."

Tina Cascone, MD., Ph.D., Assistant Professor, Thoracic/Head & Neck Medical Oncology and Study Lead Author

Study design and secondary endpoints

The Phase II single-institution study enrolled 44 patients with surgically resectable stage IA to IIIA NSCLC between June 2017 and November 2018. The median age of trial participants was 66 years old, and 64% were male. Participants were 84% white, 9% Black and 5% Asian. Most participants had a history of smoking: 23% identified as current smokers and 59% as former smokers.

Patients were randomized to one of two treatment arms with immune checkpoint inhibitors prior to surgery: 23 received three doses of nivolumab alone and 21 received three doses of nivolumab plus one dose of ipilimumab. Each arm was compared against historical controls of neoadjuvant chemotherapy. Overall, 41 patients completed the planned three doses of therapies, 37 patients had surgery on trial and two patients underwent surgery off trial after additional therapies.

Among the 37 patients who had surgical resection on the study, the combination arm showed higher MPR rates (50% versus 24%) and fewer viable tumor cells at resection than monotherapy (a median of 9% versus 50%). Combination therapy also showed better pathological complete response rates than monotherapy (38% versus 10%). After a median follow-up of 22 months, median overall survival and lung cancer-related recurrence-free survival were not reached.

Toxicities were manageable overall, with no new safety concerns compared to known adverse event profiles of either drug. The median time to surgery was 31 days after the last dose of nivolumab. Some patients experienced nodal immune flare (NIF), or the appearance of nodal disease progression on radiographic imaging, which invasive node biopsy revealed to be immune cell infiltration rather than malignant disease.

Exploratory analyses reveal immune impact, potential biomarkers

In an exploratory analysis of resected tissues, investigators found — and reported for the first time — higher levels of immune cell infiltration in tumors treated with combination therapy, including an abundance of CD3+ and CD3+CD8+ T lymphocytes, tissue-resident memory and effector memory T cells. Tumors that responded better to treatment had higher PD-L1 expression at baseline, but responses were also observed in those without PD-L1 expression in tumor cells.

The researchers analyzed the gut microbiome, as well, and found that pathologic response to combination therapy was associated with the presence of certain fecal microbes that also have been correlated with immunotherapy response in melanoma and other cancers. Immune checkpoint inhibitor therapy did not significantly affect the diversity or composition of the microbiome in this study.

"Our exploratory results suggest the gut microbiome may play a role in responses to neoadjuvant immune checkpoint inhibitors in lung cancer," Cascone said. "The immune microenvironment findings also give us an opportunity to look at immune cell populations and potential biomarkers that can be evaluated in the future to identify those patients who are most likely to benefit from these agents in new prospective trials."

The NEOSTAR trial has been amended to a modular platform design, which provides the opportunity to add treatment arms to rapidly test and advance promising new neoadjuvant therapeutic combinations. Results from a third arm testing neoadjuvant nivolumab plus chemotherapy are expected later this year. A fourth arm testing the combination of dual immunotherapy plus chemotherapy is ongoing.

"The NEOSTAR trial results set the stage for evaluating the role of dual immunotherapy added to neoadjuvant chemotherapy, which we are currently exploring, and expediting the investigation of novel agents in the perioperative setting," Cascone said. "This is a population with potentially curable disease. We should do whatever it takes to minimize the risk of relapse and increase the cure rates for these patients."

The NEOSTAR trial was supported by the Lung Cancer Moon Shot®, part of MD Anderson's Moon Shots Program®, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients' lives. Boris Sepesi, M.D., associate professor of Thoracic and Cardiovascular Surgery, served as co-principal investigator of the study. A full list of co-authors and author disclosures can be found in the paper.

Source:

University of Texas M. D. Anderson Cancer Center

Journal reference:

Cascone, T., et al. (2021) Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nature Medicine. doi.org/10.1038/s41591-020-01224-2.

Posted in: Drug Trial News | Medical Condition News

Tags: Biopsy, Cancer, Cardiovascular Surgery, CD3, Cell, Chemotherapy, Clinical Trial, Efficacy, Imaging, Immunotherapy, Laboratory, Lung Cancer, Malignant, Medicine, Melanoma, Microbiome, Neck, Non-Small Cell Lung Cancer, Oncology, PD-L1, Perioperative, pH, Research, Small Cell Lung Cancer, Smoking, Surgery, Translation, Tumor

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