Two New Breast Cancer Genes Emerge from Lynch Syndrome Gene Study

The findings suggest that genetic screening for breast cancer should be expanded to include MSH6 and PMS2

Researchers at Columbia University Irving Medical Center and NewYork-Presbyterian have identified two new breast cancer genes. Having one of the genes—MSH6 and PMS2—approximately doubles a woman’s risk of developing breast cancer by age 60.

The study, in collaboration with GeneDx, a genetic testing company, was published online today in Genetics in Medicine.

The two genes were previously known to cause Lynch syndrome, an inherited condition that raises the risk of colorectal, ovarian, stomach, and endometrial cancer. Lynch syndrome is the most common inherited cause of colorectal cancer, accounting for about 3 percent of newly diagnosed cases. One in 440 Americans has a gene variant that causes Lynch syndrome.

Researchers had suspected that Lynch syndrome genes may also cause breast cancer. Some studies had found a link, whereas others had not.

“People with Lynch syndrome aren’t thinking they may also be at risk for breast cancer,” said Wendy Chung, MD, PhD, the Kennedy Family professor of pediatrics (in medicine) at Columbia University Irving Medical Center, clinical geneticist at NewYork-Presbyterian/Columbia, and the study’s senior author. “Given the fact that genomic analysis is becoming more common in patients with a personal or family history of cancer, we have an opportunity to do more targeted breast cancer screening in women who carry any of the genes associated with risk for this disease.”

The researchers analyzed a database of more than 50,000 women who had undergone multi-gene hereditary cancer testing between 2013 and 2015. Of these, 423 women had a mutation in one of the four genes that cause Lynch syndrome: MLH1, MSH2, MSH6, and PMS2.

Additional analyses revealed that women with a mutation in two specific Lynch syndrome genes—MSH6 and PMS2—had a two-fold higher risk of breast cancer compared to women in the general population.

Based on the incidence of cancer in the study population, the researchers calculated that about 31 to 38 percent of women with cancer-causing MSH6 and PMS2 variants will develop breast cancer, compared to around 15 percent of women in the general population.

“The new study suggests MSH6 and PMS2 should be added to the list of genes to screen for when there is a history of breast cancer,” said Dr. Chung, who is also director of the clinical genetics program at NewYork-Presbyterian/Columbia. “Screening for these genes also would give these families potentially life-saving information to prevent colon cancer by encouraging individuals with the genes to increase the frequency of their colonoscopies.”

Currently, testing for Lynch syndrome genes is generally only done when someone has a personal or family history of colon or uterine cancer.

Dr. Chung added, “Given that Lynch syndrome is not rare in the general population, this finding has the potential to impact tens of thousands of people in the U.S. and could change standard practice related to one of the most common cancer predisposition syndromes.”

The study is titled, ‘MSH6 and PMS2 Germline Pathogenic Variants Implicated in Lynch Syndrome are Associated with Breast Cancer.’

Rare Melanoma Type Highly Responsive to Immunotherapy

Desmoplastic melanoma is a rare subtype of melanoma that is commonly found on sun-exposed areas, such as the head and neck, and usually seen in older patients. Treatment is difficult because these tumors are often resistant to chemotherapy and lack actionable mutations commonly found in other types of melanoma that are targeted by specific drugs. However, Moffitt Cancer Center researchers report in the Jan. 10 issue of Nature that patients with desmoplastic melanoma are more responsive to immune-activating antiPD-1/PD-L1 therapies than previously assumed.

Drugs that reactivate a patient’s own immune system to target cancer cells are rapidly changing the face of cancer therapy. Pembrolizumab and nivolumab have been approved to treat melanoma, and others are in development. These drugs block the interaction between the proteins PD-1 and PD-L1. During cancer development, PD-1 and PD-L1 inhibit the immune system and allow tumor cells to escape detection and continue to grow. By blocking their interaction, immune-activating drugs restimulate the immune system to detect and destroy cancer cells.

Scientists previously believed that the tissue architecture of desmoplastic melanomas would reduce the ability of immune cells to infiltrate the tumor area and limit the effectiveness of immune-activating drugs. However, based on anecdotal reports of favorable responses, a group of researchers including Moffitt’s Zeynep Eroglu, M.D., Jane Messina, M.D., and Dae Won Kim, M.D., hypothesized that patients with desmoplastic melanoma may be more responsive to antiPD-1/PD-L1 therapies than previously assumed, and explored this in the largest group of immunotherapy-treated desmoplastic melanoma patients studied to date.

To test their hypothesis, the researchers analyzed 60 patients with advanced/metastatic desmoplastic melanoma who were previously treated with a drug that targets either PD-1 or PD-L1. They discovered that 42 patients had a significant response to treatment.  Approximately half of these patients had a complete response in which their tumors entirely disappeared, and the remainder had a partial response, with significant reduction of their tumors.  Seventy-four percent of patients were still alive more than two years after beginning treatment. This 70 percent response rate is one of the highest reported for antiPD-1/PD-L1 therapies to date, and is even higher than response rates commonly observed in patients with other subtypes of melanoma, which are approximately 35 to 40 percent.

In a collaborative effort involving 10 United States and international cancer centers including Moffitt and University of California Los Angeles, researchers wanted to determine the biological reasons why patients with desmoplastic melanoma may benefit from drugs that target PD-1 or PD-L1. They first confirmed that desmoplastic melanomas have high levels of DNA mutations, as they are highly associated with ultraviolet light DNA damage caused by sun exposure. NF-1 mutations were found as the most common driving genetic event.  They also demonstrated that desmoplastic melanomas have the pre-existing immune cells and proteins necessary to mount an immune response against cancer cells. They compared tissue biopsies from patients with desmoplastic melanoma and non-desmoplastic melanoma. They discovered that desmoplastic melanomas have more cells with high levels of the PD-L1 protein within both the tumor and the invading edges of the tumor. Desmoplastic melanomas also have high levels of immune cells called CD8 T cells that are critical for immune-activating drugs to be effective.

“Our findings challenge the previous school of thought that immunotherapy would offer little benefit to patients with desmoplastic melanoma due to the dense tissue architecture of these tumors. These tumors in fact have the necessary biological ingredients to be very effective targets for anti-PD-1 drugs,” said Eroglu, assistant member of the Cutaneous Oncology Department at Moffitt. “Often, combinations of two immunotherapy drugs are used to treat patients with melanoma to try to improve tumor response rates and survival above current reported rates.  However, these combinations can lead to significantly higher rate of severe side-effects than treatment with anti-PD-1 therapy alone.  Our data suggest that single-agent anti-PD-1 therapy may well be sufficient for patients with desmoplastic melanoma, potentially sparing them the increased toxicities generally observed with combinations of immunotherapies.”

Beta Blockers May Boost Immunotherapy, Help Melanoma Patients Live Longer

A common, inexpensive drug that is used to prevent heart attacks and lower blood pressure may also help melanoma patients live longer.

Researchers at Penn State found that melanoma patients who received immunotherapy while taking a specific type of beta blocker lived longer than patients who received immunotherapy alone. In a follow-up experiment with mice, the researchers saw the same results.

Todd Schell, professor of microbiology and immunology at Penn State College of Medicine, said that because beta blockers are already widely available, the findings – published in the journal OncoImmunology – could indicate a simple way for physicians to better treat their patients.

“The type of beta blocker we found to be effective against melanoma – pan beta blockers – was actually the least prescribed,” Schell said. “Most patients are either prescribed beta 1 selective blockers or are not taking beta blockers at all. This means there’s a large population of patients who may be eligible to take pan beta blockers while being treated with immunotherapy. And because beta blockers are already FDA approved, it’s something we know is safe and can be very quickly implemented in patient care.”

Patients with metastatic melanoma, or melanoma that has spread to other parts of the body, often have a poor prognosis, and while some forms of immunotherapy – treatments that boost the body’s immune system to fight disease – are promising, response rates are less than 35 percent.

Previous research has shown that physiological stress prevents the immune system from fighting tumors effectively, while lower stress boosts the benefits of anti-cancer treatments. The researchers were curious about whether lowering stress with beta blockers would improve outcomes in patients treated with immunotherapies.

“Beta blockers slow your heart rhythm, but they can also affect immune cells and improve immune function,” Schell said. “We wanted to see if there would be a correlation between the beta blockers patients were taking for another condition and their response to immunotherapy. For metastatic melanoma, there are currently three different types of immunotherapy approved for use, and we specifically looked at that population of people.”

In studies developed by Dr. Kathleen Kokolus, a postdoctoral fellow, the researchers analyzed data from 195 metastatic melanoma patients who were treated with immunotherapy between 2000 and 2015, 62 of which were also taking beta blockers. They compared survival between the patients taking beta one-selective blockers, pan beta blockers and no beta blockers.

While there was little difference in how long patients taking beta one-selective blockers or no beta blockers lived, the results indicate that patients taking pan beta blockers lived significantly longer than the others. Five years after immunotherapy, about 70 percent of patients receiving pan beta blockers were still alive, versus about 25 percent of those taking beta one-selective blockers or no beta blockers at all.

To help explain the results, the team performed a parallel experiment in mice with melanoma. They treated the mice with immunotherapy and with or without the pan beta blocker propranolol. The researchers found that the propranolol significantly delayed tumor growth and increased survival when combined with immunotherapy.

Dr. Joseph Drabick, professor of medicine, said the results suggest that reducing physiological stress with beta blockers can help improve the effectiveness of immunotherapy and survival for melanoma patients.

“These new immunotherapies are great, but they don’t work for everyone,” Drabick said. “So how can we make these treatments better? We saw that for patients taking pan beta blockers, there was a dramatic improvement in survival, and we were able to duplicate these findings in mice and see the exact same phenomenon.”

Drabick also said the study was a good example of the benefits of finding new uses for drugs that have been around awhile.

“The benefit of this is that beta blockers already have a long history of safety in people, and they’re cheap and generic,” Drabick said. “And now they have the potential to augment some of these newer immunotherapy drugs to help people with cancer.”

Schell said that in the future, they’ll be working on a clinical trial to further explore and understand the role of beta blockers in treating cancer.

New Cellular Approach Found to Control Progression of Chronic Kidney Disease

Study findings indicate a more effective way to slow organ damage in Alport syndrome

Researchers have demonstrated for the first time that extracellular vesicles – tiny protein-filled structures – isolated from amniotic fluid stem cells (AFSCs) can be used to effectively slow the progression of kidney damage in mice with a type of chronic kidney disease. The findings, by a research team at the Saban Research Institute of Children’s Hospital Los Angeles, provide new insights about the mechanisms of kidney disease and point to a new approach for improved treatments. Results of the study were recently published online in Scientific Reports.

Alport syndrome, a type of chronic kidney disease, is an inherited disease that causes damage to the kidneys by the progressive damage to the glomerulus – the area of the kidney responsible for filtering blood. In patients with Alport syndrome, vascular endothelial growth factor (VEGF) – is known to be elevated early on in the disease. Increased VEGF causes scar tissue and severe damage to the cells that line the surface of blood vessels in the glomeruli eventually leading to kidney failure.

“By the time children born with Alport syndrome reach adult life, they typically need dialysis to clear the waste from their blood and will require a kidney transplant,” said Laura Perin, PhD, co-director of the GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology and principal investigator of the study.

In earlier studies, Perin’s research team demonstrated that injection of AFSCs could delay the progression of renal fibrosis and glomerular sclerosis in particular in mice with Alport syndrome.  However, the mechanisms responsible for this therapeutic effect had not been determined.

In the current study, the research team hypothesized that AFSCs provide this protection to the kidney through release of extracellular vesicles–tiny membrane surrounded structures that contain receptors on their surface that can bind VEGF and reduce its biological activity on renal cells. The researchers isolated these vesicles and found that they could effectively target the glomerulus to control cellular homeostasis and maintain a stable level of functioning.

“We have demonstrated that these vesicles can be used to regulate VEGF activity and prevent the glomerular capillary damage,” said Sargis Sedrakyan, PhD, who is the first author on the paper.  “We can efficiently use the vesicles to help restore normal kidney function by curbing the progression of endothelial damage in the filtration unit of the kidney.”

While vesicles previously have been shown to be promising targets for developing treatments, this study represents the first time they have been applied to glomerular disease by preventing endothelial damage. The finding represents a potential glomerulus-targeted intervention for chronic kidney disease.

“The advantage of this approach is that we can really modify the amount and the types of extracellular vesicles that we inject and they seem to be homing to and acting directly in the area that requires treatment,” explained Perin.

The team’s next step will be to validate the stem cell-derived vesicle in different types of kidney disease with the final aim of finding a therapy that is effective for all patients who suffer from chronic kidney disease.

Tumor Mutational Burden and Response to Immune Checkpoint Therapy

Predicting how patients will respond to anti-cancer therapies can be vital in informing clinical decisions and improving treatment outcome.  Researchers at Rutgers Cancer Institute of New Jersey examined an association between mutational burden and response to immune checkpoint therapy in several cancer types and found that a mutational burden threshold exists in eight cancers that predict response to an immune checkpoint blockade.

The work’s co-corresponding authors Shridar Ganesan, MD, PhD, associate director for translational science and chief of molecular oncology at Rutgers Cancer Institute, the Omar Boraie Chair in Genomic Science, and  associate professor of medicine and pharmacology at Rutgers Robert Wood Johnson Medical School; and  Rutgers Cancer Institute research member Gyan Bhanot, PhD, professor of molecular molecular biology and biochemistry and professor of physics in the School of Arts and Sciences at Rutgers University, along with lead author Anshuman Panda, MPhil, a Rutgers Physics Department graduate student, share more about the work, published in the December 7 online edition of JCO Precision Oncology (DOI: 10.1200/PO.17.00146): 

Q:  Why is this topic important to explore?

A:  Immune checkpoint blockade therapies have recently been in the news as novel ways to target a variety of cancers. However, these therapies are very expensive and have significant side effects. Furthermore, not all patients respond to such therapy. It is therefore important to identify markers of response for these therapies in relation to the various cancer types to improve treatment efficacy.

Q:  Describe the research and your findings.

A:  We analyzed mutation and gene expression data for more than 9,000 tumor samples from 33 solid tumor types using data from The Cancer Genome Atlas (TCGA) to test whether a high mutational burden is associated with a signature of a blocked immune response. We found that such a mutational burden threshold, which we call the iCAM threshold, exists in eight solid tumors, namely melanoma, lung, colon, stomach adenocarcinoma, endometrial, bladder-urothelial and cervical cancer, and ER+HER2− breast cancer. The efficacy of this threshold in predicting response to anti-immune checkpoint blockade therapy was validated in published data for melanoma, colon and lung adenocarcinoma as well as in a large prospective cohort of 113 samples from Rutgers Cancer Institute and the Vanderbilt Ingram Cancer Center. We also showed that the iCAM threshold is identifiable with high accuracy using routine sequencing assays, such as the FoundationOne and StrandAdvantage assays. Finally, we find that iCAM+ and iCAM- tumors have very distinct mutational profiles, suggesting these are distinct diseases driven by different biological pathways.

Q:  What are the implications for future treatments with checkpoint therapy drugs?

A: The iCAM threshold provides a simple, cost-effective way to identify patients likely to respond to immune checkpoint therapy in eight cancer types using routine sequencing assays currently used in clinical practice.

UCLA Researchers Create Skeletal Muscle From Stem Cells

Discovery is major step towards a stem cell replacement therapy for Duchenne Muscular Dystrophy

UCLA scientists have developed a new strategy to efficiently isolate, mature and transplant skeletal muscle cells created from human pluripotent stem cells, which can produce all cell types of the body. The findings are a major step towards developing a stem cell replacement therapy for muscle diseases including Duchenne Muscular Dystrophy, which affects approximately 1 in 5,000 boys in the U.S. and is the most common fatal childhood genetic disease.

The study was published in the journal Nature Cell Biology by senior author April Pyle, associate professor of microbiology, immunology and molecular genetics and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. Using the natural human development process as a guide, the researchers developed ways to mature muscle cells in the laboratory to create muscle fibers that restore dystrophin, the protein that is missing in the muscles of boys with Duchenne.

Without dystrophin, muscles degenerate and become progressively weaker. Duchenne symptoms usually begin in early childhood; patients gradually lose mobility and typically die from heart or respiratory failure around age 20. There is currently no way to reverse or cure the disease.

For years, scientists have been trying different methods that direct human pluripotent stem cells to generate skeletal muscle stem cells that can function appropriately in living muscle and regenerate dystrophin-producing muscle fibers. However, the study led by Pyle found that the current methods are inefficient; they produce immature cells that are not appropriate for modeling Duchenne in the laboratory or creating a cell replacement therapy for the disease.

“We have found that just because a skeletal muscle cell produced in the lab expresses muscle markers, doesn’t mean it is fully functional,” said Pyle. “For a stem cell therapy for Duchenne to move forward, we must have a better understanding of the cells we are generating from human pluripotent stem cells compared to the muscle stem cells found naturally in the human body and during the development process.”

By analyzing human development, the researchers found a fetal skeletal muscle cell that is extraordinarily regenerative. Upon further analysis of these fetal muscle cells two new cell surface markers called ERBB3 and NGFR were discovered; this enabled the reserchers to precisely isolate muscle cells from human tissue and separate them from various cell types created using human pluripotent stem cells.

Once they were able to isolate  skeletal muscle cells using the newly identified surface markers, the research team matured those cells in the lab to create dystrophin-producing muscle fibers. The muscle fibers they created were uniformily muscle cells, but the fibers were still smaller than those found in real human muscle.

“We were missing another key component,” said Michael Hicks, lead author of the study. The skeletal muscle cells were not maturing properly, he explained. “We needed bigger, stronger muscle that also had the ability to contract.”

Once again, the team looked to the natural stages of human development for answers. Hicks discovered that a specific cell signaling pathway called TGF Beta needs to be turned off to enable generation of skeletal muscle fibers that contain the proteins that help muscles contract. Finally, the team tested their new method in a mouse model of Duchenne.

“Our long term goal is to develop a personalized cell replacement therapy using a patient’s own cells to treat boys with Duchenne,” said Hicks. “So, for this study we followed the same steps, from start to finish, that we’d follow when creating these cells for a human patient.”

First, the Duchenne patient cells were reprogrammed to become pluripotent stem cells. The researchers then removed the genetic mutation that causes Duchenne using the gene editing technology CRISPR-Cas9. Using the ERBB3 and NGFR surface markers, the skeletal muscle cells were isolated and then injected into mice at the same time a TGF Beta inhibitor was administered.

“The results were exactly what we’d hoped for,” said Pyle. “This is the first study to demonstrate that functional muscle cells can be created in a laboratory and restore dystrophin in animal models of Duchenne using the human development process as a guide.”

Further research will focus on generating skeletal muscle stem cells that can respond to continuous injury and regenerate new muscle long-term using the team’s new isolation and maturation strategy.

Researchers repurpose immune-activating cytokine to fight breast cancer

The most lethal form of breast cancer could have a new treatment option, according to new research out of the Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine. In the Proceedings of the National Academy of Sciences, researchers showed triple-negative breast cancer cells are highly vulnerable to interferon-β–a potent antimicrobial that also activates the immune system. The new study shows interferon-β impairs breast cancer cells’ ability to migrate and form tumors. The study also suggests interferon-β treatment could improve outcomes for certain breast cancer patients.

“We demonstrate that interferon-β reverses some of the more aggressive features of triple-negative breast cancer, which are responsible for metastasis and therapy-failure,” said Mary Doherty, first author and pathology graduate student at Case Western Reserve School of Medicine. “Moreover, we found that evidence of interferon-β in triple-negative breast cancer tumors correlates with improved patient survival following chemotherapy.”

Doherty’s advisor, Mark Jackson, PhD, associate professor of pathology and associate director for training and education, Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine, is senior author on the study. The study team also included researchers from Cleveland Clinic Lerner Research Institute, University Hospitals Cleveland Medical Center, Stanford University School of Medicine, and other members of the Case Comprehensive Cancer Center.

Triple-negative breast cancer is one of the deadliest, most aggressive forms of breast cancer. It spreads rapidly and is resistant to many available chemotherapies. Even when therapies appear successful, tumors often recur. Said Doherty, “While chemotherapy kills the majority of tumor cells, it fails to eliminate a sub-set of cancer cells, called cancer stem cells. The survival of these cancer stem cells following therapy is believed to be responsible for therapy failure in patients.”

The new study showed interferon-β directly targets cancer stem cells. In laboratory dishes, regular treatments of interferon-β kept triple-negative breast cancer stem cells from migrating–the first step in metastasis. Even two days after stopping treatment, dishes with interferon-β added had approximately half the number of migrating stem cells as controls. Cells exposed to interferon-β also lacked markers characteristic of early tumors and failed to aggregate into tumor-like spheres.

The researchers validated their laboratory findings using a breast cancer tissue database. They found elevated interferon-β levels in breast tissue correlated with extended patient survival and lower cancer recurrence rates. Patients with higher interferon-β levels in their breast tissue were approximately 25 percent less likely to experience a recurrence than those with low levels. The authors concluded that interferon-β plays a “positive, critical role” in triple-negative breast cancer outcomes.

The researchers are now studying how interferon-β may modulate the immune system to carry out its anti-cancer effects. They also plan to conduct clinical trials evaluating interferon-β as a new therapeutic option for triple-negative breast cancer, either alone or in combination with traditional chemotherapy. Such a study could require novel methods to deliver interferon-β to breast cancer tumors. Said Doherty, “Our future studies will examine improved methods of interferon-β delivery to the tumor site incorporating nanoparticle technology.” Together, the studies could expand treatment options for patients suffering from drug-resistant breast cancers.

New vaccine technology shows promise as a tool to combat the opioid crisis

Researchers with the U.S. Military HIV Research Program at the Walter Reed Army Institute of Research (WRAIR) report that an experimental heroin vaccine induced antibodies that prevented the drug from crossing the blood-brain barrier in mice and rats. The vaccine was co-developed at the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health, which funded the preclinical research.

“By eliciting antibodies that bind with heroin in the blood, the vaccine aims to block the euphoria and addictive effects,” said Dr. Gary Matyas, Chief of Adjuvants and Formulations for the U.S. Military Research Program (MHRP), WRAIR. “We hope to give people a window so they can overcome their addiction.”

The study, published in the Journal of Medicinal Chemistry, showed that the vaccine produced antibodies against other commonly misused opioids, including hydrocodone, oxycodone, hydromorphone, oxymorphone and codeine. The vaccine appeared to dampen the impact of heroin at a high-dose, which might indicate a potential to prevent overdose.

In clinical settings, it is essential that the antibodies induced by a heroin or opioid vaccine do not cross-react with the therapies for opioid misuse, such as methadone, buprenorphine and naltrexone. Researchers found that the antibodies did not react with these compounds and, more importantly, the antibodies induced by the vaccine did not cross-react with naloxone, which is used as the overdose rescue treatment to reverse respiratory depression due to heroin and other opioid overdose.

Although the use of opioids for pain management in people suffering from addiction is of concern, researchers found that methadone, tramadol, fentanyl, sufentanil, nalbuphine and buprenorphine did not bind to the antibodies, indicating that they could be used if acute pain treatment is required for emergency use in vaccinated patients. Researchers also found that there was no binding to the non-narcotic pain relievers like aspirin, ibuprofen and acetaminophen, so these would likely remain effective.

The misuse of opioids, which include heroin and fentanyl, is a growing problem in the U.S. According to the CDC, 91 Americans die every day from an opioid overdose. Most pharmacological treatments for opioid misuse involve opioid management therapy (OMT), but treatment access is an issue. In addition, adherence varies greatly and relapse rates can be high. To end the opioid overdose crisis, many different types of treatments and medications will be needed to meet the needs of individuals addicted to these drugs.

“Although we are still in the early phase, this study suggests that vaccination can be used together with standard therapies to prevent the withdrawal and craving symptoms associated with opioid withdrawal,” said Matyas.

WRAIR researchers leveraged their expertise in vaccine development and novel adjuvants research to develop this experimental heroin vaccine with their partners at NIDA. The vaccine includes a potent adjuvant to stimulate the immune system called the Army Liposome Formulation (ALF), which was also developed by researchers at WRAIR. The vaccine was developed jointly with intramural scientists at the Drug Design and Synthesis Section (Dr. Kenner C. Rice, Chief), Molecular Targets and Medications Discovery Branch, NIDA.

Mitochondrial Protein in Cardiac Muscle Cells Linked to Heart Failure, Study Finds

Reducing a protein found in the mitochondria of cardiac muscle cells initiates cardiac dysfunction and heart failure, a finding that could provide insight for new treatments for cardiovascular diseases, a study led by Georgia State University has shown.

The researchers discovered that reducing an outer mitochondrial membrane protein, FUN14 domain containing 1 (FUNDC1), in cardiac muscle cells, also known as cardiomyocytes, activates and worsens cardiac dysfunction. Also, disrupting how FUNDC1 binds to a particular receptor inhibited the release of calcium from another cell structure, the endoplasmic reticulum (ER), into the mitochondria of these cells and resulted in mitochondrial dysfunction, cardiac dysfunction and heart failure. The findings are published in the journal Circulation.

Mitochondria play numerous roles in the body, including energy production, reactive oxygen species generation and signal transduction. Because the myocardium, the muscular wall of the heart, is a high-energy-demand tissue, mitochondria play a central role in maintaining optimal cardiac performance. Growing evidence suggests deregulated mitochondrial activity plays a causative role in cardiovascular diseases.

In the body, mitochondria and ER are interconnected and form their own endomembrane networks. The points where mitochondria and ER make physical contact and communicate are known as mitochondria-associated ER membranes (MAMs). MAMs play a major role in regulating the transfer of calcium between ER and mitochondria. Dysfunctional MAMs are involved in several neuronal disorders, including Alzheimer’s disease and Parkinson’s disease. Until now, the role of MAMs in cardiac pathologies has not been well understood.

“Our study found the formation of MAMs mediated by the mitochondrial membrane protein FUNDC1 was significantly suppressed in patients with heart failure, which provides evidence that FUNDC1 and MAMs actively participate in the development of heart failure,” said Dr. Ming-Hui Zou, director of the Center for Molecular and Translational Medicine at Georgia State and a Georgia Research Alliance Eminent Scholar in Molecular Medicine. “This work has important clinical implications and provides support that restoring proper function of MAMs may be a novel target for treating heart failure.”

The researchers used mouse neonatal cardiomyocytes, mice with a genetic deletion of the FUNDC1 gene, control mice with no genetic deficiencies and the cardiac tissues of patients with heart failure.

The cardiac functions of the mice were monitored using echocardiography at 10 weeks of age. Mice with the genetic deletion of FUNDC1 had markedly reduced ventricular filling velocities, prolonged left ventricular isovolumic relaxation time, diastolic dysfunction, decreased cardiac output (which indicates impaired systolic functions) and interstitial fibrosis of the myocardium, among other issues. The mitochondria in the hearts of mice with FUNDC1 gene deletion were larger and more elongated, a 2.5-fold increase of size compared to mitochondria in the control mice.

To determine if FUNDC1 reduction occurred in human hearts and contributed to heart failure in patients, the researchers examined four heart specimens from heart failure patients and four heart specimens from control donors. They found the levels of FUNDC1 were significantly reduced in patients with heart failure compared to control donors. Also, the contact between ER and mitochondria in failed hearts was significantly reduced. In addition, the mitochondria in heart failure hearts were more elongated compared to those in control donors.

Phase III Immunotherapy Trial for Migraine Shows Positive Results

An antibody therapy against a key inflammatory molecule involved in migraines reduces the number of headaches that chronic migraine patients experience per month in a phase III trial.

A new study of fremanezumab, an immunotherapy that counteracts one of the molecules released during migraine, was found successful in reducing the number of days that chronic migraine sufferers experienced headaches. The results of the phase III clinical trial were published November 29, 2017 in the New England Journal of Medicine.

The World Health Organization estimates that between 127 and 300 million people around the world experience chronic migraine, defined as 15 or more headaches per month for at least three months. The disease can be debilitating and although a number of interventions exist, many only work for a certain time before they fail to prevent or relieve pain.

“This therapeutic approach offers new hope for people whose migraines cannot be treated with existing medicine,” says Stephen D. Silberstein, M.D., principal investigator of the HALO CM trial, Professor of Neurology and Director of the Jefferson Headache Center at the Vickie & Jack Farber Institute for Neuroscience at Thomas Jefferson University Hospital. “Our worldwide effort to evaluate this novel therapeutic approach has shown positive results and was safe in patients.”

Fremanezumab, a monoclonal antibody developed by Teva Pharmaceuticals, is a biological agent that binds to and blocks the action of a migraine-associated protein called calcitonin gene-related peptide (CGRP). Mounting evidence of its importance in migraines has made CGRP a focal point of research and drug development. The peptide is released at high levels during migraine in response to inflammation, and triggers a cascade effect that stimulates more CGRP release. This results in increasing sensitivity of the brain to pain. By blocking this peptide, doctors hope to break the cycle of increasing inflammation and increased pain sensitivity that contributes to migraine headaches.

Researchers from 132 sites across nine countries enrolled 1130 patients and randomly assigned them to one of three groups: one that received quarterly treatments, a group that received one treatment per month, and one that received placebo injections. The trial lasted for 16 weeks, with a 12-week treatment window.

The results of the trial show that treatment with fremanezumab reduced the number of days patients experience headache by an average of 4.3 days with quarterly treatment and 4.6 days with monthly treatment. “We saw some patients with 100 percent reduction in migraine, others with 75 percent reduction,” says Dr. Silberstein. The level of response varied between patients.

The researchers also looked at how well the therapy worked relative to each patient’s headache burden. They calculated the percent of patients who had more than a 50 percent reduction in the number of days they experienced either a severe or moderate headache per month. Using this measure, the researchers saw that 37.6 percent of patients on the monthly regimen, and 40.8 percent on the quarterly regimen had at least a 50 percent reduction in the number of moderate headaches per month, compared to 18.1 percent in the placebo group.

The therapy had a favorable safety profile with the most common adverse event reported as irritation at injection site, which was reported in the placebo group as well.

“If approved, this treatment would provide physicians with an important new tool to help prevent migraine, reduce a patient’s migraine load, and potentially help patients return to normal” says Dr. Silberstein.

Discovery of key molecules involved in severe malaria

Malaria*1 is one of three major infectious diseases*2 affecting approximately 300 million people every year, accounting for about 500,000 deaths, but effective vaccine development has not been successful. Among malaria parasites infecting humans, Plasmodium falciparum (P. falciparum)*3 causes especially severe disease. In addition, acquired immunity to malaria is inefficient, even after repeated exposures to P. falciparum, but the immune regulatory mechanisms used by P. falciparum remain largely unclear. Therefore, malaria parasites appear to have a mechanism to escape our immune system.

A research group led by Fumiji Saito, Kouyuki Hirayasu, Hisashi Arase at Osaka University found that proteins called RIFIN expressed on erythrocytes infected with P. falciparum help the parasite to suppress the host immune response, causing severe malaria (Fig. 1). These findings are expected to contribute to the development of effective vaccines and therapeutic drugs against malaria.

Malaria parasites infect mainly erythrocytes in the host and proliferate within infected erythrocytes. The team found that proteins called RIFIN*4 expressed on P falciparum-infected erythrocytes bind to a host inhibitory receptor LILRB1*5. Furthermore, RIFIN suppresses the immune response to malaria, resulting in severe complications of malaria.

This research disclosed for the first time in the world that P. falciparum has a new mechanism to suppress the host immune response by using an inhibitory receptor, contributing to the pathogenesis of severe malaria. The results of this research are expected to greatly contribute to the development of therapeutic drug and vaccine against malaria.

*1 Malaria
Infectious diseases caused by malaria parasites

*2 Three major infectious diseases
Malaria, tuberculosis, and HIV/AIDS

*3 Plasmodium falciparum
Malaria parasites infecting humans, and causing the most severe complications of malaria

*4 RIFIN
RIFIN proteins are encoded by the rif (repetitive interspersed family) genes of P. falciparum. There are about 150 rif genes per parasite genome. However, their functions have been still unclear.

*5 LILRB1
One of the immune inhibitory receptors that suppress the activation of immune cells and prevent autoimmune responses by recognizing self-molecules like major histocompatibility complex (MHC) class I. Human cytomegalovirus is also known to have a viral MHC class I-like molecule (UL18) that suppresses the immune response via LILRB1 for immune escape.

2-Drug Combination May Boost Immunotherapy Responses in Lung Cancer Patients

Johns Hopkins Kimmel Cancer Center researchers and colleagues have identified a novel drug combination therapy that could prime nonsmall cell lung cancers to respond better to immunotherapy. These so-called epigenetic therapy drugs, used together, achieved robust anti-tumor responses in human cancer cell lines and mice.

During the study, published Nov. 30, 2017, in the journal Cell, a team of researchers led by graduate student Michael Topper; research associate Michelle Vaz, Ph.D.; and senior author Stephen B. Baylin, M.D., combined a demethylating drug called 5-azacytidine that chemically reignites some cancer suppressor genes’ ability to operate, with one of three histone deacetylase inhibitor drugs (HDACis). The HDACis work against proteins called histone deacetylases that are involved in processes, such as cell copying and division, and can contribute to cancer development. The combination therapy triggered a chemical cascade that increased the attraction of immune cells to fight tumors and diminished the work of the cancer gene MYC. Based on these findings, investigators have launched a clinical trial of the combination therapy in patients with advanced, nonsmall cell lung cancer.

The development of therapeutic approaches for patients with lung cancer has been a critical medical need, says Baylin, the Virginia and Daniel K. Ludwig Professor of Cancer Research at the Kimmel Cancer Center. While immune checkpoint therapy has been “a tremendous step forward, less than half of patients with lung cancer have benefited to date,” he says.

“In our study, the two-drug epigenetic therapy combination worked exceedingly well, even before putting in the immune checkpoint inhibitors,” Baylin says. “In animal models of lung cancer, the two agents either prevented cancer from emerging or blunted the effects of more aggressive cancers. In both scenarios, a large component of the results involved an increase in immune recognition of the tumors.”

In a series of experiments, researchers studied the combination of 5-azacytidine with the HDACis entinostat, mocetinostat or givinostat in human cancer cell lines and in mouse models of nonsmall cell lung cancers. The treatments were found to alter the tumor microenvironment. In cancer cell lines, 5-azacytidine worked against the cancer gene MYC, causing down regulation of the entire MYC signaling program. Adding the HDACis further depleted MYC, and together the drugs subsequently caused actions that prevented cancer cell proliferation, simultaneously attracted more immune system T cells to the area of the tumor and activated these cells for tumor recognition.

In mouse models, the strongest response was observed when using 5-azacytidine plus givinostat. In one mouse model with a mutant form of nonsmall cell lung cancer, this drug combination given for three months yielded prevention of benign, precursor tumors from becoming cancers and caused 60 percent reduction of overall area of benign tumor appearance in the lungs. By contrast, a group of mice with the same form of lung cancer that were given a mock treatment universally developed large, cancerous lesions in the lungs.

In a second model of mice with established, aggressive, nonsmall cell lung cancer, treatment with an alternating schedule of 5-azacytidine with givinostat and of 5-azacytidine with mocetinostat not only reduced the growth of established, rapidly growing primary tumors but also dramatically reduced metastatic occurrence.

Baylin and colleagues at Memorial Sloan Kettering Cancer Center in New York and Fox Chase Cancer Center in Philadelphia have started a phase I/Ib clinical trial to evaluate if giving mocetinostat with a 5-azacytidinelike drug called guadecitabine can boost immune checkpoint therapy responses in patients with advanced, nonsmall cell lung cancers. The trial is part of the Van Andel Research Institute–Stand Up To Cancer Epigenetics Dream Team and is funded by Merck through the Stand Up To Cancer  (SU2C) Catalyst program, an initiative led by SU2C to bring innovative cancer treatments to patients quickly. Matthew Hellmann, M.D., an author on the paper, will lead this trial at Memorial Sloan Kettering, and Jarushka Naidoo, M.B.B.Ch., assistant professor of oncology, will lead at Johns Hopkins. For more information, click here.

Researchers show stress suppresses response to cancer treatments

New research shows that chronic stress suppresses the immune system’s response to cancer, reducing the effectiveness of immunotherapy treatments.

University of Queensland scientists say they are investigating dual therapies for patients to reduce stress signalling and improve their response to treatments.

UQ Diamantina Institute researcher Dr Stephen Mattarollo said lymphoma progressed more rapidly in mouse models when stress pathways were induced to reflect chronic psychological stress.

“When we used immunotherapies on these mice they were not able to respond as effectively as those which had not been stressed,” Dr Mattarollo said.

“This is because the stress led to poor function against the cancer by T-cells, which are very important in the immune system’s control and surveillance of tumours and are a major target in many immunotherapy treatments.”

Dr Mattarollo said increased anxiety was natural with a cancer diagnosis, and it should be managed to ensure the best possible outcome for patients.

“Absolutely there is now pre-clinical evidence to suggest that treatments and lifestyle interventions to manage or reduce stress levels will improve the chances of these patients responding to therapies,” he said.

“This applies particularly to immunotherapies, but many conventional therapies such as chemotherapy also rely on components of the immune system for their effectiveness.

“It is quite possible that by increasing the immune function in patients they will also respond better to some other therapies.”

PhD candidate Michael Nissen said as immunotherapies became more widely available, it was important to build on the knowledge of factors which influence their effectiveness.

“The more we know, the better chance we have of designing them effectively and efficiently to work in cancer patients,” Mr Nissen said.

Dr Mattarollo said the lab was hoping to combine immunotherapy treatments with commonly used blood pressure drugs that block the effects of stress hormones.

“We hope this will reduce the stress-induced neural signalling and improve immune function,” Dr Mattarollo said.

“We are about to test this combination in animal models.”

Dr Mattarollo said psychoneuroimmunology – or the interaction between the mind, the nervous system and the immune system – is a rapidly growing discipline and is becoming an increasing focus of the lab’s cancer research.

The research is published in Cancer Immunology Research.

Dr Mattarollo’s lab is located at the Translational Research Institute.

New strategy for multiple myeloma immunotherapy

In recent decades monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies for both solid tumors and blood cancers. Monoclonal antibodies (mAb), as the name implies, are antibodies that are made by clonal cells derived from a single parent cells and therefore share the identical amino acid sequences.

One of the leading technologies to emerge in mAb-based treatment is CAR-T, where CAR stands for “chimeric antigen receptor”, and T represents T cells, a type of white blood cells that have pivotal roles in immune defenses. CARs are produced by combining together the gene for an antibody that recognizes a tumor antigen with the gene for a receptor that resides on the surface of the T cells; insert this new gene into a T cell and it will be precisely targeted at the tumor.

Theoretically, new antigens – molecules capable of inducing an immune response to produce an antibody – that arise from cancer-specific mutations of cell-surface proteins are excellent targets. However, mAb therapy targeting such antigens is impractical because of these proteins’ vast diversity within and between individual tumors, which renders identifying new cancer-specific target antigens difficult.

However, such challenges have driven researchers centered at Japan’s Osaka University to think outside of the box; cancer-specific antigen formed by the modification of proteins during or after synthesis, such as glycosylation (attachment of sugar moieties to protein) or conformational changes, might have been missed in previous analyses. The team believed new antigen epitopes, which is the part of an antigen recognized by the immune cells, could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens they recognize.

“We applied this strategy to identify novel therapeutic targets for multiple myeloma (MM), a cancer that forms in a type of white blood cell called a plasma cell,” explains Naoki Hosen, lead author of the study, which was recently published in Nature Medicine. “Despite advances in MM treatment, relapse remains common. As such, there is an ongoing need for new therapeutic approaches, including mAb-based therapies.”

The team screened more than 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β7, a cell-surface receptors that facilitate cell-extracellular matrix adhesion. MMG49 reacted to MM cells, but not other bone marrow cell types in MM patient samples. This prompted the researchers to design a CAR that incorporates a fragment derived from MMG49. The resulting MMG49 CAR T was found to have anti-MM effects without damaging normal blood cells.

“Our results also demonstrate that the active conformer of integrin β7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM,” study coauthor Yukiko Matsunaga says. “Therefore it’s highly plausible that there are other cancer immunotherapeutic targets that have yet to be identified in many cell-surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific.”

Promising new treatment for rare pregnancy cancer leads to remission in patients

Three out of four patients with the cancerous forms of gestational trophoblastic disease (GTD) went into remission after receiving the immunotherapy drug pembrolizumab in a clinical trial carried out by researchers at Imperial College London.

The trial, which took place at Charing Cross Hospital, part of Imperial College Healthcare NHS Trust, is the first to show that pembrolizumab can be used to successfully treat women with GTD.

The team hopes that this small early stage study, published in The Lancet, could provide another treatment option for women who have drug-resistant GTD and lead to a 100 per cent cure rate.

Professor Michael Seckl, lead author of the study, said:

“We have been able to show for the first time that immunotherapy may be used to cure patients of cancerous GTD. The current treatments to tackle GTD cure most cases of the disease. However, there are a small number of women whose cancers are resistant to conventional therapies and as a result have a fatal outcome. Immunotherapy may be a life-saving treatment and can be used as an alternative to the much more toxic high dose chemotherapy that is currently used. These are landmark findings that have implications on how we treat the disease in the UK and around the world.”

GTD is the term used to describe abnormal cells or tumors that start in the womb from cells that normally give rise to the placenta. They are extremely rare but can happen during or after pregnancy.

The most common type of GTD is so-called molar pregnancy where a foetus doesn’t form properly in the womb and a baby doesn’t develop, instead a lot of abnormal placental-like tissue forms. A molar pregnancy can usually be treated with a simple procedure to remove the growth of abnormal placental cells from the womb but some of this material is usually left behind. This can become cancerous and spread to other parts of the body, requiring lifesaving chemotherapy. In around one in 50,000 pregnancies cancerous GTD known as choriocarcinoma develops after other types of pregnancy including normal pregnancies and this also requires life-saving chemotherapy.

Globally, 18,000 women are diagnosed annually with cancerous forms of GTD, most of whom are cured with chemotherapy or surgery. However, up to five per cent of these women’s outcomes are fatal due to factors such as chemotherapy resistance and rare forms of the cancer such as placental site trophoblastic tumours (PSTT) that develop four or more years after the causative pregnancy has ended.

Immunotherapy is a type of treatment that helps a person’s immune system fight diseases such as a cancer. The immune system fights off invading infections but can miss cancer cells. Pembrolizumab works by stimulating the body’s immune system to target and kill cancer cells. The drug is also used to treat some cases of lung cancer and melanoma.

The researchers wanted to test whether pembrolizumab could be used to treat four patients aged between 37-47 years with multi-drug resistant cancerous GTD.

The patients were given pembrolizumab intravenously every three weeks over a period of about six months between 2015-2017.

The trial also took place at the Department of Women’s and Children’s Health in Stockholm.

The researchers then carried out a blood test to measure the amount of the pregnancy hormone hCG in their system, which is an indicator of whether abnormal placental cells are left in the womb or elsewhere in the body.

They found that most patients’ hCG levels started to fall by three doses and once their hCG was normal five consolidation doses of pembrolizumab were given before stopping treatment. This contrasts with melanoma and lung cancer where this drug is given to patients continuously for two or more years. The patients remain without signs of cancer recurrence for between five months to over two years on follow-up.

The researchers also found that pembrolizumab was well tolerated in GTD patients. This is in comparison to chemotherapy which can cause nausea, vomiting and hair loss.

The team suggests that this could have cost saving implications for the NHS as six months of the drug costs about £30,000 per patient compared to two rounds of high dose chemotherapy which costs £70,000.

Melody Ransome took part in the clinical trial after being diagnosed with choriocarcinoma, which had spread from her uterus to her liver, kidney, pancreas, lungs and brain. Melody was given the immunotherapy drug over five months in 2015. After her second infusion, Melody’s hCG levels dropped by 50 per cent and she was in remission two months later. Melody continues to be in remission two and half years after receiving the immunotherapy.

“Before the trial I was being treated by high dosage of chemotherapy which made me feel awful. I experienced hair loss, fatigue and it was difficult to carry out normal tasks like looking after my two children. On top of that, the chemotherapy wasn’t working.

This all changed for me once I was given the immunotherapy drug. Each week I felt better and better. I had no side effects and I started to feel more normal. When I was told that I was in remission I was shocked that the treatment had worked in such a short amount of time. It’s been life changing and I’ve been able to enjoy spending quality time with my family again. I used to be able to swim 40 lengths before my illness and since having the immunotherapy I am close to it. It’s been an incredible journey.”

Following the findings, NHS England has agreed provisional funding to treat some cases of GTD with pembrolizumab for two years at Charing Cross and Sheffield Hospitals where these cases are managed in the UK.

The researchers will carry out a further study to assess the effects of pembrolizumab on fertility to see whether it can be offered to women at an earlier stage of treatment.

Palliative Care and Cancer Treatment

A cancer diagnosis is frightening and often impacts patients on both a physical and an emotional level. It can actually lead to symptoms such as pain, nausea, anxiety and depression. These symptoms, as well as those that are caused by the cancer and/or the cancer treatment, can be eased through the incorporation of palliative medicine into the patient’s care plan.

Palliative medicine, which is commonly referred to as palliative care, provides an extra layer of support to patients and their families throughout the cancer journey. This support can include both medical and holistic approaches to care depending on the patient’s wishes and personal circumstances.

“As a palliative care physician, I strive to get to know each patient individually by encouraging them to talk about their cancer journey and learning what is important to them. Many patients find this to be very helpful and therapeutic. By getting to know patients and finding ways to help them to manage their symptoms, I can help them live in a way in which their cancer diagnosis is not on their minds 24/7,” explains Ayelet Spitzer, D.O., Supportive Care Specialist, Valley-Mount Sinai Comprehensive Cancer Care.

Some examples of palliative care services are:

  • Symptom management
  • Support for complex decision managing
  • Goal setting
  • Advance care planning
  • Social and caregiver assessment and support
  • Spiritual care
  • Care coordination/transition management
  • Self-management techniques

“Please keep in mind that palliative care should not be confused with hospice care, which is palliative care provided during the end of life. All cancer patients can benefit from palliative care services, regardless of where they are on their cancer journey. In fact, most palliative care services are offered while patients are receiving cancer treatment. Palliative care is not about dying—it is about living life to the fullest,” adds Dr. Spitzer.

Integrative Medicine Approaches for Pain Treatment – Can They Be an Alternative to Opioids?

Anesthesiologists Are Eager to Share Their Expertise on Strategies to Combat the Opioid Crisis

Can acupuncture and yoga help to fight the opioid epidemic? These and other integrative medicine approaches have shown at least preliminary evidence of effectiveness in pain management, according to an article in the December issue of Anesthesia & Analgesia—a special thematic issue addressing the opioid crisis.

“In the current opioid crisis era, many integrative medical therapies can be used as complements to mainstream medicine to address pain and reduce opioid abuse and addiction-related disease,” write Yuan-Chi Lin, MD, MPH, and colleagues of Harvard Medical School. In the special issue, they and other anesthesia and pain medicine physicians share evidence on this and other potentially effective strategies to reducing reliance on opioids to treat chronic and postoperative pain.

Complementary Medicine as Alternatives to Opioids – What’s the Evidence?

Dr. Lin and coauthors reviewed and analyzed current evidence on integrative medicine therapies—also called complementary and alternative medicine—for the treatment of pain. “Integrative medicine for pain can play a major role in reducing the frequency and amount of opioid usage,” the researchers write.

The analysis included a total of 32 studies evaluating seven different types of integrative medicine therapies for pain. Acupuncture was the treatment showing the strongest evidence for effectiveness in reducing pain. Overall there was “strong positive evidence” showing a beneficial effect of acupuncture for the treatment of chronic pain. There were also studies showing that acupuncture reduced the dose of opioids needed to control pain after surgery, with reduction in opioid-related side effects.

Most of the other therapies studied showed “positive preliminary evidence” of effectiveness in pain treatment. These included yoga, relaxation techniques (such as mindfulness meditation), tai chi, massage therapy, and spinal manipulation. Few of these studies addressed the effects on use of prescription medications in general or opioids in particular. There was conflicting evidence on the pain-reducing effectiveness of the supplements glucosamine and chondroitin for knee pain.

The authors acknowledge some important limitations of the current evidence on integrative therapies for pain. The studies in the review varied in terms of the methods used and the types of pain studied, in addition to the special challenges of studying the effectiveness of alternative therapies (such as controlling for the placebo effect). While emphasizing the need for additional studies, Dr. Lin and coauthors conclude: “The consensus and results of this review suggest that complementary health approaches can help to improve pain and reduce opioid use.”

The special issue also includes current evidence reviews on topics of special interest, including other types of medications that may provide alternatives to opioids for treatment of chronic pain; new types of pain medications under development, including opioid and non-opioid drugs; strategies to help reduce the risk of chronic opioid use after surgery; and opioid-sparing strategies to reduce the need for opioids after surgery.

Anesthesiology and pain medicine specialists play a critical role in developing effective strategies for responding to the opioid crisis. according to an introductory article by Guest Editors Honorio T. Benzon, MD, of Northwestern University Feinberg School of Medicine, Chicago, and T. Anthony Anderson, MD, PhD, of Stanford University School of Medicine “We wanted to show to the medical community that we, anesthesiologists, can play an active role in identifying and solving the issues,” the Guest Editors write.

“We are the leaders in opioid prescription…and should take the lead in solving the problem.”

Pairing Cancer Genomics with Cognitive Computing Highlights Potential Therapeutic Options

A University of North Carolina Lineberger Comprehensive Cancer Center-led study has demonstrated the ability of cognitive computing to scour large volumes of data from scientific studies and databases to identify potentially relevant clinical trials or therapeutic options for cancer patients based on the genetics of their tumors.

The researchers said their findings, published in the journal The Oncologist, suggest that cognitive computing applications could help physicians to stay abreast of an ever-expanding body of scientific literature as well as highlight potential therapeutic options, specifically as it relates to cancer genetics.

“Our findings, while preliminary, demonstrate that cognitive computing might have a role in identifying more therapeutic options for cancer patients,” said UNC Lineberger’s William Kim, MD, the study’s corresponding author and an associate professor of medicine and genetics in the UNC School of Medicine. “I can tell you that as a practicing oncologist, it’s very reassuring for patients to know that we’re able to explore all possible options for them in a very systematic manner.”

The study’s first authors were Nirali Patel, MD, formerly of UNC Lineberger, and Vanessa Michelini of IBM Watson Health, Boca Raton, Florida. IBM Corp. provided in-kind access to the Watson technology for the study, as well as technical expertise.

The researchers used IBM Watson for Genomics to assess whether cognitive computing was more effective than a panel of cancer experts in identifying therapeutic options for tumors with specific genetic abnormalities. They compared Watson’s ability to identify possible therapeutic options tied to potentially clinically significant genetic mutations with the findings of UNC Lineberger’s molecular tumor board.

In a retrospective analysis of 1,018 cancer cases, the molecular tumor board identified actionable genetic alterations in 703 cases, which Watson also confirmed. In addition, Watson for Genomics identified additional potential therapeutic options in 323 patients, or one third of the cases reviewed that the molecular tumor board hadn’t identified. Of these, 96 were not previously identified as having an actionable mutation.

“To be clear, the additional 323 cases of Watson-identified actionable alterations consisted of only eight genes that had not been considered actionable by the molecular tumor board,” Kim said. In most of those cases, Watson identified a new clinical trial. One of those trials had opened within a week of Watson’s analysis.

The study drew on data from UNCseq, a UNC Lineberger clinical trial that used next-generation sequencing to analyze the genomics of a participant’s tumor with the goal of matching tumor abnormalities with a targeted therapeutic. Next-generation sequencing is “fundamental” to the promise of precision medicine, the researchers reported, but sequencing can uncover many different alterations in hundreds of genes, and the “majority of such events have no known relevance to the treatment of patients with cancers.”

“The major finding is that cognitive computing augmented the molecular tumor board process for the interpretation and collection of information regarding a patient’s genomic profile,” Kim said. “The study was not designed to analyze whether or not this helps patients in regard to outcome as defined by prolonged survival or treatment response.”

The program did identify new possible options for some patients. The findings were not relevant to most patients because the majority of the patients did not have active cancer, or had died by the time of the retrospective analysis. But for 47 patients with active disease, and needing additional options, the findings were reported to their treating physicians.

“To my knowledge, this is the first published examination of the utility of cognitive computing in precision cancer care,” Kim said. “I’m optimistic that as we get more sequencing data, well-annotated treatment information, as well as therapy response, tools like Watson for Genomics will begin to show their true promise. But, of course, we still need to formally answer these questions.”

Finding a Key to Unlock Blocked Differentiation in Microrna-Deficient Embryonic Stem Cells

This aids goal to use stem cells in therapy, where an important hurdle is efficient differentiation.

The more than 200 different types of human cells have the same DNA but express different ensembles of genes. Each cell type was derived from embryonic stem cells, which are called pluripotent stem cells because they can differentiate to all those different cell fates.

One very active area of biology is cells that mimic these fountainhead embryonic stem cells, cells that are called induced pluripotent stem cells, or iPSCs. With genetic and biochemical tricks, researchers can reverse a differentiated cell — such as a skin fibroblast — into a pluripotent state.

Such iPSCs have the potential to create tissue for regenerative medicine, such as repair heart attacks, create models of human disease or make cells that enable drug screening. But future progress with iPSCs needs a much greater understanding of the basic biology of pluripotency and differentiation.

“For the goal of using stem cells in therapy, the most important step is differentiation from iPSCs,” said Rui Zhao, Ph.D., an assistant professor of biochemistry and molecular genetics at the University of Alabama at Birmingham. “We need to be able to differentiate the iPSCs into a disease-relevant cell type at high efficiency and high purity.”

In a study published in Stem Cell Reports, Zhao and colleagues have partly solved a long-unanswered basic question about stem cells — why are pluripotent stem cells that have mutations to block the production of microRNAs unable to differentiate?

Zhao and colleagues, including co-corresponding author Kitai Kim, Ph.D., of the Sloan Kettering Institute, have found a key that allows those microRNA-deficient pluripotent stem cells to differentiate into neural cells, including subtypes with markers for dopaminergic, glutamatergic and GABAergic neurons

“For many years, we did not know why these cells did not differentiate,” Zhao said. The answer for neural cell differentiation in the microRNA-deficient cells turned out to be simple — a single microRNA or a single protein.

In the Stem Cell Reports study, Zhao and colleagues show that a microRNA-302 mimic — delivered by a specially constructed lentivirus — was sufficient to enable neural differentiation of mouse embryonic stem cells that lacked Dgcr8, a vital gene for the processing of the more than 2,000 microRNAs in cells.

When they examined gene expression profiles in the differentiated cells, they saw changes in many gene sets regulated by p53, also known as tumor suppressor p53. This tumor suppressor has been called “the guardian of the genome” because of its many roles in preventing DNA damage and cancer.

Zhao, Kim and colleagues showed that microRNA-302 acted to reduce p53 expression in the microRNA-deficient embryonic stem cells by binding to the 3′ untranslated region of p53 mRNA.

They further showed that direct inhibition of p53 with the simian virus large T antigen or short hairpin RNA, or even deleting the p53 gene itself, allowed embryonic stem cells or iPSCs to proceed to neural differentiation without the need for microRNA-302. Thus, the differentiation barrier that prevents the neuronal lineage specification from microRNA-deficient stem cells is expression of p53.

The keys to unlock the paths cells to other cell lineage specifications from microRNA-deficient embryonic stem are still unknown, Zhao says.

Deadly Lung Cancers Are Driven by Multiple Genetic Changes

Blood-Based Cancer Tests Reveal Complex Genomic Landscape of Non-Small Cell Lung Cancers

A new UC San Francisco–led study challenges the dogma in oncology that most cancers are caused by one dominant “driver” mutation that can be treated in isolation with a single targeted drug. Instead, the new research finds one of the world’s most deadly forms of lung cancer is driven by changes in multiple different genes, which appear to work together to drive cancer progression and to allow tumors to evade targeted therapy.

These findings — published online on November 6, 2017 in Nature Genetics — strongly suggest that new first-line combination therapies are needed that can treat the full array of mutations contributing to a patient’s cancer and prevent drug resistance from arising.

“Currently we treat patients as if different oncogene mutations are mutually exclusive. If you have an EGFR mutation we treat you with one class of drugs, and if you have a KRAS mutation we pick a different class of drugs. Now we see such mutations regularly coexist, and so we need to adapt our approach to treatment,” said Trever Bivona, MD, PhD, a UCSF Medical Center oncologist, associate professor in hematology and oncology, and member of the Helen Diller Family Comprehensive Cancer Center at UCSF.

Lung cancer is by far the leading cause of cancer death worldwide. Efforts to identify the genetic mutations that drive the disease have led to targeted treatments that improve life expectancy for many patients, but these drugs produce temporary remission at best — sooner or later, cancers inevitably develop drug resistance and return, deadlier than ever.

The new UCSF-led study — which analyzed tumor DNA from more than 2,000 patients in collaboration with Redwood City–based Guardant Health — is the first to extensively profile the genetic landscape of advanced-stage non–small cell (NSC) lung cancer, the most common form of the disease.

“The field has been so focused on treating the ‘driver’ mutation controlling a tumor’s growth that many assumed that drug-resistance had to evolve from new mutations in that same oncogene. Now we see that there are many different genetic routes a tumor can take to develop resistance to treatment,” said Bivona, who is also co-director of a new UCSF-Stanford Cancer Drug Resistance and Sensitivity Center funded by the National Cancer Institute. “This could also explain why many tumors are already drug-resistant when treatment is first applied.”