Cancer-Pain Discovery at Duke Makes Headlines

Ru-Rong Ji, PhDOnce hailed as a breakthrough in cancer treatment, immunotherapies are now raising concerns as doctors note new side effects like severe allergic reactions, acute-onset diabetes and heart damage.

These drugs, which work by unleashing the immune system to fight cancer, are only effective in about a fifth of cases, prompting many patients to wonder if they are worth the risk.

But a new study from Duke University researchers, featured in Duke TODAY and The San Diego Union-Tribune, suggests there may be a quick and easy way to predict which cancer patients are likely to benefit from immunotherapy treatments.

The researchers showed that a molecule called PD-L1, which is blocked by the popular immunotherapy drug, nivolumab, acts not only on immune cells but also on the nerve cells that signal pain. That insight could lead to a simple test that measures subtle differences in pain sensitivity to gauge whether or not the body is responding to treatment.

The findings, published May 22 in the journal, Nature Neuroscience, underscore the surreptitious nature of cancer, which uses a variety of tricks to evade detection by the body’s natural defense mechanisms.

“Cancer cells are smart. We already knew that they produced PD-L1 to suppress the immune system,” said senior study author Ru-Rong Ji, Ph.D., professor of anesthesiology and neurobiology at Duke University School of Medicine. “But there’s another defense system at play as well, and that is pain. We showed that this well-known molecule can mask pain, so that cancers can grow without setting off any alarms before metastasis.”

In its early stages, when cancer cells are just starting to grow and multiply in a given tissue or organ, the disease is not usually painful. But as the cancer becomes more aggressive and spreads throughout the body, these cells secrete thousands of pain-inducing chemicals, which either trigger pain-sensing nerve fibers or, in the case of molecules like nerve growth factor, generate entirely new ones. The pain can become so unbearable that some cancer patients die from opioid overdoses.

Ji has been studying pain for over twenty years. Recently, his group noticed that mouse models of melanoma didn’t show the typical signs of pain that he observed in mice with other kinds of cancer, which would flinch or lick their hind paws whenever they were in discomfort.

Ji also knew that melanoma cells could produce a molecule called PD-L1, which latched onto a receptor called PD-1 on the surface of white blood cells, effectively putting the brakes on the immune response. Ji wondered whether there was a connection. So his team treated mice with nivolumab, a drug that prevents PD-L1 from binding to PD-1. Then they poked the animals’ hind paws with a calibrated filament and measured how much force it took for them to withdraw their hind paws. They found that the mice responded to much lower forces than before treatment, indicating they had become more sensitive to pain. In addition, they also found that nivolumab caused spontaneous pain in mice with melanoma, which made them tend to their affected hindpaws like never before.

Next, the researchers performed the opposite experiment. They injected PD-L1 — the pain-masking factor in this equation — into the hind paws or spinal cord of mouse models of three different kinds of pain — inflammatory, neuropathic and bone cancer pain. In every case, the injections of PD-L1 had an analgesic effect, deadening the mice’s sensitivity to pain.

“The effect was surprisingly fast,” said Ji. “We saw a reduction of pain in under half an hour.”

To figure out the mechanism behind this quick response, Ji’s team examined the sensory neurons of the dorsal root ganglion (DRG), a collection of nerves and neurons near the top of the spinal cord. They isolated these cells from mouse DRGs as well as human DRGs from donors and cultured them in a dish, with or without PD-L1, and then recorded their electrical activity. The researchers found that PD-L1 impaired the ability of sodium channels to fire neurons (action potentials) in response to pain.

Ji believes the finding could potentially lead to new treatments for pain, as well as new ways to predict the efficacy of already existing treatments based on PD-1 and PD-L1. “The response to cancer drugs can take a long time, weeks to months,” he said. “The response to pain happens in minutes to hours.”

Sensory neurons from human dorsal root ganglia, a collection of nerves and neurons near the top of the spinal cord, show red for PD-1, a binding site for immunotherapies against cancer. The blue stain shows cell nuclei. Photo credit: Ru-Rong Ji Lab, Duke Anesthesiology

Sensory neurons from human dorsal root ganglia, a collection of nerves and neurons near the top of the spinal cord, show red for PD-1, a binding site for immunotherapies against cancer. The blue stain shows cell nuclei. Photo credit: Ru-Rong Ji Lab, Duke Anesthesiology

In the future, Ji would like to explore whether the mechanism uncovered in this study also applies to other immunotherapy treatments. He is also interested in working with clinicians to measure changes in patients’ pain sensitivity after treatment, a first step toward developing a diagnostic test.

The study was a collaboration between Duke University and two Chinese universities, Fudan University and Nantong University. Professor Yu-Qiu Zhang from Fudan University, the co-senior author of the paper, is a well-known expert in cancer pain. The lead author, Dr. Gang Chen, was an Assistant Professor at Duke  and is now a Professor at Nantong.

The research was supported by the National Institutes of Health (NS87988, DE17794, and DE22743), the National Science Fund of China (31420103903), and the National Research Foundation of Korea (2013R1A6A3A04065858)

CITATION:  “PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1,” Gang Chen, Yong Ho Kim, Hui Li, Hao Luo, Da-Lu Liu, Zhi-Jun Zhang, Mark Lay, Wonseok Chang, Yu-Qiu Zhang, and Ru-Rong Ji. Nature Neuroscience, May 22, 2017. DOI: doi:10.1038/nn.4571

Source: Duke University Office of News and Communications (Durham, N.C. – Tuesday, May 23, 2017)

Chris KeithCancer-Pain Discovery at Duke Makes Headlines
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Duke University Awards Dr. Maixner Distinguished Professorship

William Maixner, DDS, PhDWe are pleased to announce that Duke Anesthesiology’s William Maixner, DDS, PhD, has received one of the highest honors in academia with his appointment as the Joannes H. Karis, MD, Professor of Anesthesiology, designated by the Duke University School of Medicine. This endowed professorship recognizes Dr. Maixner’s extraordinary achievements in advancing medical science, significantly shaping the field of pain research and education, profoundly impacting patient care and exemplifying superior mentorship.

Endowed professorships established within Duke Anesthesiology are awarded to the department’s most distinguished physician-scientists who have exhibited both outstanding accomplishments and strong potential for future pursuits. These highly coveted, permanently named memorials, promote scientific discovery and the advancement of anesthesia care.

Dr. Maixner is an internationally-renowned pain researcher who has dedicated his career to unraveling the mysteries of chronic pain and is committed to translating basic discoveries into novel diagnostics and treatments that will impact research, education and patient care, worldwide. He is the director of Duke Anesthesiology’s Center for Translational Pain Medicine (CTPM), established in January of 2016 to further expand the department’s clinical and research program in pain medicine. Bringing together leading basic scientists, clinicians and clinical researchers who have a common core mission of developing novel therapies to improve patient care, this center is rapidly becoming internationally-recognized as the best-in-class translational pain medicine program. Dr. Maixner was also a driving force in the development of Duke Innovative Pain Therapies, a first-of-its-kind multispecialty pain practice in Raleigh that opened its doors to patients in September of 2016. He plays a key role as a knowledge leader in the field of pain; Dr. Maixner was recently named president elect of the American Pain Society and currently serves on our nation’s Health and Human Services Interagency Pain Research Coordinating Committee and the National Institute of Health’s Pain Consortium, which shapes the direction of our nation’s future national strategies in pain research, education and patient care. Additionally, Dr. Maixner was appointed as a member in the Foundation for Anesthesia Education and Research (FAER) Academy of Research Mentors in Anesthesiology. His mentorship skills are evidenced by the success of the more than 20 students, trainees and mid-career scientists whom he has mentored throughout the past 30 years.

“It’s a wonderful honor to be recognized by Duke University and the Karis family,” says Dr. Maixner. “Dr. Karis was a pioneer in the area of translational research where he developed and implemented new ways of treating patients in the operating room. I hope to be able to follow in his footsteps by developing new ways of treating patients with pain conditions, an area that he was beginning to pursue late in his career. This endowed professorship will truly enable myself and my colleagues to push the frontiers forward as Dr. Karis did in his own career.”

In 2012, Duke Anesthesiology proudly announced the Joannes H. Karis Professorship, made possible through the generous donations of the Karis family, including Dr. Karis’ wife, Martha, and their children, Drs. Martha Karis Fikrig and John Karis, in effort to preserve his legacy.

Mr. and Mrs. KarisJoannes H. Karis, MD, is one of Duke Anesthesiology’s most distinguished emeritus faculty. He is known as a remarkable leader, scientist, pioneer, and philanthropist who was instrumental in the growth and development of both the cardiac and pediatric divisions at the Duke University School of Medicine. In 1975, Dr. Karis’ mentor, Dr. Merel H. Harmel, the “founding father of Duke Anesthesiology,” recruited him to Duke where he spent the final 18 years of his career doing cardiac anesthesia. Through his groundbreaking research, Dr. Karis helped to uncover the dangers of ultraviolet radiation in the operating room and identify the physiologic mechanisms of neuromuscular blockade agents. He served as the director of one of the world’s first surgical intensive care units and was a key player in refining early physiological monitoring and anesthesia delivery systems that have evolved to become essential components of the modern operating room.

In a “Career Reflections” article written by Dr. Karis in 2012, he said, “My wife and I hope that our sponsorship of an endowed chair within the Duke University Department of Anesthesiology will help to build on the phenomenal level of research, teamwork, patient care, and physician education with which I am honored and proud to be affiliated.”

Dr. Maixner is the fifth faculty member of Duke Anesthesiology to be named a distinguished professor. The department believes that investing in the promotion of its faculty’s professional growth and the enhancement of learning for students is vital to the future of medicine. Creating endowed professorships provides distinguished faculty with the means to discover unprecedented breakthroughs, adding to the thriving academic environment at Duke, and to attract world-class faculty for generations to come.

Please join us in congratulating Dr. Maixner on being named the Joannes H. Karis, MD, Professor of Anesthesiology as we wish him continued success in his career.

Chris KeithDuke University Awards Dr. Maixner Distinguished Professorship
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Dr. Jordt Cited in National Media About Venezuela Protests

Sven-Eric Jordt, PhDAfter two weeks of protests in Venezuela, Duke Anesthesiology’s Sven-Eric Jordt, PhD, is featured in an article published by TIME and ABC News about the use of tear gas by security forces.

As the article states, protestors demanding new elections faced-off with Bolivarian National Police who were blocking roadways in the Venezuelan capital of Caracas. According to the Associated Press, a dozen people were injured in the protest on Monday, April 11, where demonstrators were seen covering their faces to protect themselves against the plumes of tear gas. Opposition members also distributed a picture of an expired tear gas canister that they said was found detonated at a previous demonstration.

Dr. Jordt is an expert on tear gas and other similar noxious, reactive gases and vapors. He studies the damage these gases may have on human airways and whether lung function is reduced in those exposed to them. In the article, he says, “Expired tear gas chemicals and solvents inside a cartridge could potentially react with each other or oxygen in the area and degrade, forming highly toxic gases. A degraded pyrotechnic charge propelling the cartridge could also lead to uncontrolled explosions.”

Dr. Jordt is an associate professor in anesthesiology and the director of the Chemical Sensing, Pain and Inflammation Research Laboratory which focuses on the mechanisms that enable humans and animals to sense touch, pain and irritation. He and his lab members strive to gain a greater understanding about how the compounds in tear gas have a chemical corrosive effect on the epithelial lining, causing burns and modifying cells. You can learn more about his research which was featured in the 2015 edition of Duke Anesthesiology’s annual magazine, BluePrint, in an article titled, “Tear Gas: A Novel Perspective in Pain Research.”

Article Source: Fabiola Sanchez / AP (April 11, 2017). This article was also published by the Daily News and the Independent.

Chris KeithDr. Jordt Cited in National Media About Venezuela Protests
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Dr. Maixner Named President of American Pain Society

William Maixner, DDS, PhDOn March 6, the board of directors elected Duke Anesthesiology’s William Maixner, DDS, PhD, president of the American Pain Society (APS). It’s a multidisciplinary community that brings together a diverse group of scientists, clinicians and other professionals to increase the knowledge of pain and transform public policy and clinical practice to reduce pain-related suffering.

Dr. Maixner, professor in anesthesiology and director of the Center for Translational Pain Medicine (CTPM), is a world-renowned pain researcher who has dedicated his career to unraveling the mysteries of chronic pain. His research focuses on biological, environmental, and genetic factors involved in pain transmission and modulation.

In his new role, Dr. Maixner will help the APS achieve its goal of advancing the care of people in pain by ensuring access to treatment, removing regulatory barriers, increasing funding for pain research and educating practitioners and policy makers in all settings about advances and economics of effective treatment.

“This is a wonderful opportunity to help further shape the society’s activities in the area of pain research and pain management,” says Dr. Maixner. “This is one of the most established pain-oriented societies, and it’s such an honor to be recognized by my peers and to be part of the opportunity to further the mission of the APS which falls in line with the same mission statement that we have at the CTPM at local, state and federal levels for pain patients.”

Dr. Maixner was a key leader in establishing Duke Anesthesiology’s Center for Translational Pain Medicine in January of 2016, which brings together basic scientists, clinicians and clinical researchers who have a common core mission of transforming the way painful conditions are diagnosed and treated. He also helped develop Duke Innovative Pain Therapies, a first-of-its-kind multispecialty pain practice in Raleigh that opened in September of 2016. Learn more about these initiatives in the 2016 edition of the department’s BluePrint magazine.

Chris KeithDr. Maixner Named President of American Pain Society
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Postdoctoral Fellow Receives APS Award

Xin Zhang, PhDThe American Pain Society (APS) has awarded Duke Anesthesiology’s Xin Zhang, MD, PhD, the Young Investigator Travel Award for its 36th Annual Scientific Meeting!

Funding from this award will allow Dr. Zhang the opportunity to travel to Pittsburgh and present his poster abstract, titled “Sustained Activation of β2- and β3ARs Leads to Phosphorylation of Neuronal MAPKs and Activation of Glial Cells in Spinal Cord and DRG.” Co-authors of this project include director of The Nackley Lab, Dr. Andrea Nackley, and undergraduate researchers in the lab, Harrison Ballard and Julia Kozlowski. The APS  acknowledges the National Center for Complementary and Integrative Health (NCCIH) for support of the Young Investigator Travel Award program.

As noted in the abstract, functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines) activity. Consistent with clinical syndromes, The Nackley Lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites that persists for three weeks following OR486 cessation.

Results of this study suggest that treatments targeted towards βAR and MAPK signaling pathways may prove useful in the management of functional pain syndromes.

Dr. Zhang is a postdoctoral fellow with The Nackley Lab, part of Duke Anesthesiology’s Center for Translational Pain Medicine which is dedicated to unraveling the causes of painful conditions to better improve patient care.

Chris KeithPostdoctoral Fellow Receives APS Award
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Undergraduate Researcher Awarded Fellowship

Katie KanterDuke’s Summer Neuroscience Program (formerly known as NPR) has awarded Katie Kanter, a researcher with Duke Anesthesiology’s The Nackley Lab, a fellowship for her project, titled “Effects of MOR-1K Genetic Variation on Cellular Activity.”

Opioid-induced hyperalgesia manifests as increased pain sensitivity due to acute or chronic opioid administration. A truncated variant in the mu opioid receptor, MOR-1K, has been linked to pain in human genetic studies, and shown to produce cellular excitation, resulting in hyperalgesia rather than analgesia. The Nackley Lab has identified a candidate single nucleotide polymorphism (SNP) within the enhancer box regulatory motif on MOR-1K exon 13 in CXB7/ByJ mice, that is predicted to contribute to the increased pain sensitivity observed in this variant compared to 129S6 mice.

The proposed work will continue a previously unpublished study by The Nackley Lab to elucidate alterations to MOR-1K receptor function related to this SNP using a cAMP assay, and ultimately examine changes to transcriptional regulation via a luciferase assay.

The Nackley Lab is part of Duke Anesthesiology’s Center for Translational Pain Medicine. The main objectives of this lab’s research include: 1) To determine the factors that put some people, but not others, at risk for maladaptive chronic pain conditions, 2) to elucidate the mechanism(s) whereby genetic, biological, and environmental factors drive chronic pain, and 3) to improve pharmacologic management of pain.

Chris KeithUndergraduate Researcher Awarded Fellowship
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