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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Dr. Kwatra Awarded Funding for Glioblastoma Study

Madan M. Kwatra, PhDGenzada Pharmaceuticals has awarded Dr. Madan Kwatra a two-year, $763,200 grant, titled “Evaluation of novel anti-cancer agents, either alone or in combination, for activity against glioblastoma subtypes: a personalized medicine approach.”

Genzada specializes in pharmaceuticals derived from plants. Their lead compounds have shown activity in preclinical models of several cancers. These agents will be tested against glioblastoma because they have the ability to penetrate the blood brain barrier and represent a natural, alternative therapy against glioblastoma. The compounds will be tested against GBMs of multiple molecular subtypes allowing for a personalized and targeted approach to treating this deadly disease.

Dr. Kwatra is an associate professor in anesthesiology and the director of the Molecular Pharmacology Laboratory at Duke Anesthesiology, which focuses on understanding the role of G protein-coupled receptors in human diseases.

Chris KeithDr. Kwatra Awarded Funding for Glioblastoma Study
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FAER Awards Dr. Quinones Research Training Grant

Quintin Quinones, MD, PhDThe Foundation for Anesthesia Education and Research has awarded Duke Anesthesiology’s Quintin Quinones, MD, PhD, a two-year, $175,000 mentored research training grant, titled “Reversible Immunomodulation as a Strategy for Ischemia Tolerance in Hibernation.” His mentor for this grant is Dr. Mihai Podgoreanu, chief of the Cardiothoracic Anesthesia Division.

During surgery or critical illness, patients sometimes suffer organ dysfunction related to uncontrolled inflammation. There are currently no drugs that effectively treat this problem. To work towards new treatments, Dr. Quinones and a team of investigators have developed a surgical model to study a hibernating mammal known as the arctic ground squirrel (AGS). These animals show a remarkable, natural resistance to injury in a robust surgical model that closely mirrors what humans experience during major heart surgery. To understand how arctic ground squirrels are different, they’re comparing them to rats in the same surgical model; rats do not show any natural resistance and suffer organ dysfunction much in the way that humans do.

The focus of the study is a unique trait found in hibernators – the AGS can regulate its innate immune system to decrease inflammation following surgical injury. Dr. Quinones and his co-investigators will examine protein levels and the function of white blood cells in the AGS vs. the rat. They will also look at protein levels in human white blood cells. By understanding how the AGS is able to regulate its innate immune system, they hope to identify potential targets that will lead to treatments for human patients during surgery and critical illness.

There is a fundamental knowledge gap regarding the role of innate immunity in injury during ischemia and reperfusion in the perioperative period and during critical illness. Hibernating mammals enjoy natural resistance to ischemia/reperfusion injury as a result of adaptations that allow them to survive winter torpor-arousal cycles without injury. One such adaptation is natural reversible modulation of innate immunity that reduces responses to danger-associated molecular patterns and pathogen-associated molecular patterns. A comparative biology approach provides the opportunity to study animals that are naturally adapted to survive ischemia and reperfusion. Dr. Quinones hypothesizes that hibernator resistance to ischemia/reperfusion is secondary to reversible modulation of innate immunity.

Dr. Quinones is an assistant professor of anesthesiology in the department’s Cardiothoracic Anesthesia Division. His research on hibernation biology has been featured in several publications, including the journal, Anesthesiology (June 2016), as well as the 2016 edition and 2013 edition of Duke Anesthesiology’s annual BluePrint magazine.

Chris KeithFAER Awards Dr. Quinones Research Training Grant
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Duke Anesthesiology Marks Academic Evening’s Silver Anniversary

A special 25th anniversary edition of Academic Evening was held on May 16 at the Millennium Hotel in Durham. All training levels and divisions of Duke Anesthesiology were represented by the 102 poster abstracts, presented by the department’s junior-level investigators and faculty. The annual event supports research and discovery with the overall goal of advancing anesthesia, critical care and pain management.

A key element to the evening was guest judge Dr. Aman Mahajan, the executive chairman of the Department of Anesthesiology & Perioperative Medicine at the UCLA David Geffen School of Medicine, and the Ronald L. Katz Professor of Anesthesiology and Bioengineering. Dr. Mahajan’s expertise is in cardiothoracic anesthesiology, cardiac electrophysiology and echocardiography. As director of the UCLA Perioperative Services at UCLA, he coordinates a multidisciplinary team of physicians involved in the care of patients undergoing surgical and interventional procedures. Dr. Mahajan’s research focuses on autonomic neural modulation of cardiac electrophysiology and assessment of cardiac mechanical function in heart failure.

After 23 years of service to Academic Evening, Dr. David Warner served as program director for the final time. Dr. Jeffrey Gadsden co-directed for the first time and will assume the event’s future leadership. “It was a pleasure and honor to work alongside Dr. Warner. He essentially built this event into what it is today,” says Dr. Gadsden.

“Academic Evening allows us to celebrate our academic successes and often serves to foster new and exciting research ideas and collaborations between departmental subspecialties,” says senior resident, Dr. Kendall Smith, winner of the Bill White Resident Research Award. “To receive this award among the many excellent resident entries this year was both a surprise and a great honor.”

At the night’s conclusion, Drs. Gadsden and Warner thanked all of the participants and everyone who helped make this event possible, especially those who served as abstract judges, moderators, mentors, and support staff. “Just when you think you couldn’t be more proud of the department you work in, you receive more than 100 abstracts of original research. It’s humbling,” says Dr. Gadsden.

Congratulations to each of the award winners and teams, listed below.

2017 Academic Evening Winners

1st Place
Martin Sigurdsson, MD

Runner-Up
Shu Yu, MD

Runner-Up
Chao Xiong, MD

1st Place
Rebecca Scholl, MD

Runner-Up
Hassan Amhaz, MD

Runner-Up
Claudia Villalpando, MD

1st Place
Kendall Smith, MD

Runner-Up
Jon Andrews, MD

Runner-Up
Rebecca Anderson, MD

1st Place
Benjamin Andrew, BS, RD

Runner-Up
Andrea Ansari, BS

1st Place
Michael Young, MD

1st Place
Benjamin Dunne, MD

Runner-Up 
James Kim, MD

1st Place
Suraj Yalamuri, MD
Michael Plakke, MD

Runner-Up
Tera Cushman, MD

Runner-Up
Jennifer Lee, MD

View the 25th Annual Academic Evening Photo Gallery

View the Academic Evening 25th Anniversary Video

Chris KeithDuke Anesthesiology Marks Academic Evening’s Silver Anniversary
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Simulation Specialist Receives Patient Safety Grant

Jeffrey M. Taekman, MDDurham Casualty has awarded Duke Anesthesiology’s Dr. Jeffrey Taekman $108,668 in funding for a patient safety project titled, “Simulation-Based Crisis Resource Management as a Risk Reduction Strategy for the Health System.”

Throughout medicine, safe and effective delivery of health care has relied on proper team coordination and communication. The Joint Commission cites failures of teamwork and communication as a root cause of more than 50 percent of sentinel events. These events can have both economic and patient safety implications. In perioperative medicine, communication breakdowns represent the second leading cause of preventable intraoperative error, resulting in patient harm, second only to technical error. Analysis of closed claims by the American Society of Anesthesiologists (ASA) and the American College of Surgeons (ACS) implicate poor communication as a major preventable cause of adverse events.

In order to combat communication errors, Dr. Taekman proposes to implement an interprofessional simulation-centric crisis resource management (CRM) learning experience within Duke University Hospital. The expected outcome of this project includes decreased malpractice liability exposure and improved patient outcomes.

The proposed program, with interprofessional simulation at its core, will be carried out in collaboration with the Department of OB/Gyn and the faculty and staff of the Duke Birthing Center. Dr. Taekman’s collaborators include Ankeet Udani, Zaneta Strouch, Chad Grotegut, Andrea Fiumefreddo, Joe Chapman, Trish Fletcher, and Jennifer Justice.  Dr. Taekman’s vision is to build a similar program for each of the high risk surgical/perioperative services.

Dr. Taekman is the assistant dean for educational technology and the director of the Duke Human Simulation and Patient Safety Center, a joint project of Duke Anesthesiology, the School of Medicine and the School of Nursing.

Chris KeithSimulation Specialist Receives Patient Safety Grant
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