Spaser can detect, kill circulating tumor cells to prevent cancer metastases, study finds

A nanolaser known as the spaser can serve as a super-bright, water-soluble, biocompatible probe capable of finding metastasized cancer cells in the blood stream and then killing these cells, according to a new research study.

The study found the spaser can be used as an optical probe and when released into the body (possibly through an injection or drinking a solution), it can find and go after circulating tumor cells (CTCs), stick to them and destroy these cells by breaking them apart to prevent cancer metastases. The spaser absorbs laser light, heats up, causes shock waves in the cell and destroys the cell membrane. The findings are published in the journal Nature Communications.

The spaser, which stands for surface plasmon amplification by stimulated emission of radiation, is a nanoparticle, about 20 nanometers in size or hundreds times smaller than human cells. It has folic acid attached to its surface, which allows selective molecular targeting of cancer cells. The folate receptor is commonly overexpressed on the surface of most human cancer cells and is weakly expressed in normal cells.

The discovery was made by researchers at Georgia State University, the University of Arkansas for Medical Sciences, the University of Arkansas at Little Rock and the Siberian Branch of the Russian Academy of Science.

“There is no other method to reliably detect and destroy CTCs,” said Dr. Mark Stockman, director of the Center for Nano-Optics and professor of physics at Georgia State. “This is the first. This biocompatible spaser can go after these cells and destroy them without killing or damaging healthy cells. Any other chemistry would damage and likely kill healthy cells. Our findings could play a pivotal role in providing a better, life-saving treatment option for cancer patients.”

Metastatic cancer occurs when cancer spreads to distant parts of the body, often to the bone, liver, lungs and brain, through a process called metastasis. Many types of cancers refer to this as stage IV cancer. Once cancer spreads, it can be difficult to control, and most metastatic cancer can’t be cured with current treatments, according to the National Institute of Health’s National Cancer Institute. One of the most dangerous ways metastasizing occurs is through the CTCs, which this study aims to detect and destroy using spasers.

The spasers used in this study measure just 22 nanometers, setting the record for the smallest nanolasers. A nanometer is one-billionth of a meter. Most results were obtained with a gold, spherical nanoparticle surrounded by a silica shell and covered with a uranine dye, which is widely used for tracing and biomedical diagnostics.

The researchers studied the spaser’s capabilities in vitro in human breast cancer cells with high folate receptor expression and endothelial cells with low folate receptor expression, as well as in mouse cells in vivo.

They found cells with spasers demonstrated high image contrasts with one or many individual “hot spots” at different laser energies above the spasing threshold. The presence of spasers was confirmed with several optical and electron microscopy techniques, which revealed an initial accumulation of individual spasers on the cell membrane followed by their entrance into the cell cytoplasm.

The study also found low toxicity of the spasers for human cells. At the same time, the spasers subjected to laser irradiation selectively killed the tumor cells without damaging the healthy ones.

Based on the study’s results, spaser-based therapeutic applications with high-contrast imaging is a promising field. The data suggest spasers have high potential as therapeutic and diagnostic agents that integrate optical diagnosis and photothermal-based cell killing, using just a few laser pulses to kill cancer cells.

Wistar scientists develop novel immunotherapy technology for prostate cancer

A study led by scientists at The Wistar Institute describes a novel immunotherapeutic strategy for the treatment of cancer based on the use of synthetic DNA to directly encode protective antibodies against a cancer specific protein. This is the first application of the new technology, called DNA-encoded monoclonal antibody (DMAb), for cancer immunotherapy. The study was published online in Cancer Immunology, Immunotherapy.

Prostate cancer is the second most common cancer in men worldwide. Traditional treatments are invasive and can impair the quality of life of patients, underscoring the need for alternative therapeutic strategies, including immunotherapy. One of the immunotherapeutic approaches that has been explored thus far relies on the use of monoclonal antibodies that specifically target a protein present on the surface of prostate cancer cells called prostate specific membrane antigen (PSMA) to elicit an anti-tumor immune response and control the cancer. Although promising, this strategy is limited by the production cost required to make these therapeutic antibodies. Additionally, multiple infusions are often required to achieve efficacy.

Wistar researchers devised a novel DNA-based approach in which an engineered DNA plasmid is constructed and used to deliver the instructions to make the desired anti-PSMA antibody so that the therapy can be generated in the patient’s body in a sustained manner. This research has important implications for the use of DNA-encoded monoclonal antibody technology as a platform for delivering the next generation of immunotherapies for cancer and many human diseases.

“This is an important demonstration of the possibilities opened up for immunotherapy by DMAb technology to direct in vivo production of antibodies of major relevance to human cancer,” said David B. Weiner, Ph.D., executive vice president of The Wistar Institute, director of The Wistar Institute Vaccine & Immunotherapy Center, W.W. Smith Charitable Trust Professor in Cancer Research, and senior author of the study. “There is a great need for such new approaches for prostate disease as well as many other cancers. As recent data suggest, PSMA is an important cancer antigen expressed on many human prostate, bladder, renal as well as ovarian cancers, so additional study of the possible benefits of this therapy are important.”

The new technology was tested in mice for the ability to generate antibodies in their blood stream that would target human PSMA as well as target PSMA-positive tumors. Results showed that antibodies were able to bind to the cancer cells and recruited specific immune cells called natural killer cells, resulting in shrinkage of the tumor, significantly improving survival.

“Our data provide proof of concept that DMAb engineered DNA plasmids can be successfully used to target important cancers,” said Kar Muthumani, M.Sc., Ph.D., assistant professor in the Translational Tumor Immunology Program at Wistar, member of the Vaccine & Immunotherapy Center and lead author of the study. “The unique features of our synthetic DNA-based system make it a promising novel approach for cancer therapy, alone or in combination with other treatments.”

Skewing the aim of targeted cancer therapies

Headlines, of late, have touted the successes of targeted gene-based cancer therapies, such as immunotherapies, but, unfortunately, also their failures.

Broad inadequacies in a widespread biological concept that affects cancer research could be significantly deflecting the aim of such targeted drugs, according to a new study. A team exploring genetic mechanisms in cancer at the Georgia Institute of Technology has found evidence that a prevailing concept about how cells produce protein molecules, particularly when applied to cancer, could be erroneous as much as two-thirds of the time.

Prior studies by other researchers have also critiqued this concept about the pathway leading from genetic code to proteins, but this new study, led by cancer researcher John McDonald, has employed rare analytical technology to explore it in unparalleled detail. The study also turned up novel evidence for regulating mechanisms that could account for the prevailing concept’s apparent shortcomings.

RNA concept incomplete

The concept stems from common knowledge about the assembly line inside cells that starts with code in DNA, is transcribed to messenger RNA, then translated into protein molecules, the cell’s building blocks.

That model seems to have left the impression that cellular protein production works analogously to an old-style factory production line: That the amount of a messenger RNA encoded by DNA on the front end translates directly into the amount of a corresponding protein produced on the back end. That idea is at the core of how gene-based cancer drug developers choose their targets.

To put that assumed congruence between RNA production and protein production to the test, the researchers examined — in ovarian cancer cells donated by a patient — 4,436 genes, their subsequently transcribed messenger RNA, and the resulting proteins. The assumption, that proverbial factory orders passed down the DNA-RNA line determine in a straightforward manner the amount of a protein being produced, proved incorrect 62 percent of the time.

RNA skews drug cues

“The messenger RNA-protein connection is important because proteins are usually the targets of gene-based cancer therapies,” McDonald said. “And drug developers typically measure messenger RNA levels thinking they will tell them what the protein levels are.” But the significant variations in ratios of messenger RNA to protein that the researchers found make the common method of targeting proteins via RNA seem much less than optimal.

McDonald, Mengnan Zhang and Ronghu Wu published their results on August 15, 2017 in the journal Scientific Reports. The work was funded by the Ovarian Cancer Institute, The Deborah Nash Endowment, Atlanta’s Northside Hospital and the National Science Foundation. The spectrophotometric technology needed to closely identify a high number of proteins is rare and costly but is available in Wu’s lab at Georgia Tech.

Whereas many studies look at normal tissue versus cancerous tissue, this new study focused on cancer progression, or metastasis, which is what usually makes cancer deadly. The researchers looked at primary tumor tissue and also metastatic tissue.

Hiding drug targets

“The idea that any change in RNA level in cancerous development flows all the way up to the protein level could be leading to drug targeting errors,” said McDonald, who heads Georgia Tech’s Integrated Cancer Research Center. Drug developers often look for oddly high messenger RNA levels in a cancer then go after what they believe must be the resulting oddly high levels of a corresponding protein.

Taking messenger RNA as a protein level indicator could actually work some of the time. In the McDonald team’s latest experiment, in 38 percent of the cases, the rise of RNA levels in cancerous cells did indeed reflect a comparable rise of protein levels. But in the rest of cases, they did not.

“So, there are going to be many instances where if you’re predicting what to give therapeutically to a patient based on RNA, your prescription could easily be incorrect,” McDonald said. “Drug developers could be aiming at targets that aren’t there and also not shooting for targets that are there.”

RNA muted or magnified

The analogy of a factory producing building materials can help illustrate what goes wrong in a cancerous cell, and also help describe the study’s new insights into protein production. To complete the metaphor: The materials produced are used in the construction of the factory’s own building, that is, the cell’s own structures.

In cancer cells, a mutation makes protein production go awry usually not by deforming proteins but by overproducing them. “A lot of mutations in cancer are mutations in production levels. The proteins are being overexpressed,” said McDonald, who is also a professor in Georgia Tech’s School of Biological Sciences.

A bad factory order can lead to the production of too much of a good material and then force it into the structures of the cell, distorting it. The question is: Where in the production line do bad factory orders appear?

According to the new study, the answer is less straightforward than perhaps previously thought.

Micro RNA managing

The orders don’t all appear on the front end of the assembly line with DNA over-transcribing messenger RNA. Additionally, some mutations that do over-transcribe messenger RNA on the front end are tamped down or canceled by regulating mechanisms further down the line, and may never end up boosting protein levels on the back end.

Regulating mechanisms also appear to be making other messenger RNA, transcribed in normal amounts, unexpectedly crank out inordinate levels of proteins.

At the heart of those regulating systems, another RNA called micro RNA may be micromanaging how much, or little, of a protein is actually produced in the end.

“We have evidence that micro RNAs may be responsible for the non-correlation between the proteins and the RNA, and that’s completely novel,” McDonald said. “It’s an emerging area of research.”

Micro RNA, or miRNA, is an extremely short strand of RNA.

No one at fault

McDonald would like to see tissues from more cancer patients undergo similar testing. “Right now, with just one patient, the data is limited, but I also really think it shows that the phenomenon is real,” McDonald said.

“Many past studies have looked at one particular protein and a particular gene, or a particular handful. We looked at more than 4,000,” McDonald said. “What that brings up is that the phenomenon is probably not isolated but instead genome-wide.”

The study’s authors would also like to see rarely accessible, advanced protein detecting technology become more widely available to biomolecular researchers, especially in the field of cancer drug development. “Targeted gene therapy is a good idea, but you need the full knowledge of whether it’s affecting the protein level,” McDonald said.

He pointed out that no one is at fault for the possible incompleteness of commonly held concepts about protein production.

As science progresses, it naturally illuminates new details, and formerly useful ideas need updating. With the existence of new technologies, it may be time to flesh out this particular concept for the sake of cancer research progress.

Research opens possibility of reducing risk of gut bacterial infections with next-generation probiotic

A team of researchers is exploring the possibility that next-generation probiotics – live bacteria that are good for your health – would reduce the risk of infection with the bacterium Clostridium difficile. In laboratory-grown bacterial communities, the researchers determined that, when supplied with glycerol, the probiotic Lactobacillus reuteri produced reuterin, an antibacterial compound that selectively killed C. difficile. The study appears in Infection and Immunity.

C. difficile causes thousands of deaths and billions of dollars in healthcare expenses in the U.S. each year. Although most patients respond to antibiotic treatment, up to 35 percent will relapse and require extended antibiotic treatments,” said first and corresponding author Dr. Jennifer K. Spinler, instructor of pathology & immunology at Baylor College of Medicine, who oversees microbial genetics and genomics efforts at the Texas Children’s Microbiome Center at Texas Children’s Hospital.

C. difficile infections are the most common cause of diarrhea associated with the use of antibiotics. If these bacteria attempt to invade the human gut, the ‘good bacteria,’ which outnumber C. difficile, usually prevent them from growing. However, when a person takes antibiotics, for example to treat pneumonia, the antibiotic also can kill the good bacteria in the gut, opening an opportunity for C. difficile to thrive into a potentially life-threatening infection.

“When repeated antibiotic treatments fail to eliminate C. difficile infections, some patients are resorting to fecal microbiome transplant – the transfer of fecal matter from a healthy donor – which treats the disease but also could have negative side effects,” Spinler said. “We wanted to find an alternative treatment, a prophylactic strategy based on probiotics that could help prevent C. difficile from thriving in the first place.”

“Probiotics are commonly used to treat a range of human diseases, yet clinical studies are generally fraught by variable clinical outcomes and protective mechanisms are poorly understood in patients. This study provides important clues on why clinical efficacy may be seen in some patients treated with one probiotic bacterium but not with others,” said senior author Dr. Tor Savidge, associate professor of pathology & immunology and of pediatrics at Baylor and the Texas Children’s Microbiome Center.

Working in the Texas Children’s Microbiome Center, Spinler and her colleagues tested the possibility that probiotic L. reuteri, which is known to produce antibacterial compounds, could help prevent C. difficile from establishing a microbial community in lab cultures.

An unexpected result with major implications for a preventative strategy

Spinler and Savidge established a collaboration with co-author Dr. Robert A. Britton, professor of molecular virology and microbiology at Baylor and member of the Dan L Duncan Comprehensive Cancer Center.

The Britton lab uses mini-bioreactor arrays – multiple small culture chambers – that provide a platform in which researchers could recreate the invasion of an antibiotic-treated human intestinal community by C. difficile.

“Using the mini-bioreactors model we showed that L. reuteri reduced the burden of C. difficile infection in a complex gut community,” Britton said. “To achieve its beneficial effect, L. reuteri requires glycerol and converts it into the antimicrobial reuterin.”

The literature reports reuterin as a broad-spectrum antibiotic; it affects the growth of a wide variety of bacteria when they are tested individually in the lab. What was intriguing in this study is that reuterin didn’t have a broad-spectrum effect in the mini-bioreactor bacterial community setting.

“I expected reuterin to have an antibacterial effect on several different types of bacteria in the community, but it only affected C. difficile and not the good bacteria, which was exciting because it has major implications for a preventative strategy,” Spinler said.

“Although these results are too preliminary to be translated directly into human therapy, they provide a foundation upon which to further develop treatments based on co-administration of L. reuteri and glycerol to prevent C. difficile infection,” said co-author Dr. Jennifer Auchtung, director of the Cultivation Core at Baylor’s Alkek Center for Metagenomics and Microbiome Research and assistant professor of molecular virology and microbiology at Baylor.

In the future, this potential treatment could be administered prophylactically to patients before they take antibiotics known to disrupt normal gut microbes. The L. reuteri/glycerol formulation would help maintain the healthy gut microbial community and also help prevent the growth of C. difficile, which would result in decreased hospital stay and costs and reduced long-term health consequences of C. difficile recurrent infections.

Spider peptides battle superbugs and cancer

As antibiotic resistance rises and fears over superbugs grow, scientists are looking for new treatment options. One area of focus is antimicrobial peptides (AMPs), which could someday be an alternative to currently prescribed antibiotics, many of which are becoming increasingly useless against some bacteria. Now, a team reports in ACS Chemical Biology that they have improved the antimicrobial — and anticancer — properties of an AMP from a spider.

According to the U.S. Centers for Disease Control and Prevention, 2 million people become infected with antibiotic-resistant bacteria in the U.S. each year. Because no known antibiotics work against these bacteria, patients simply have to hope that their natural defenses eventually overcome the infection. But some patients experience severe symptoms, landing them in a hospital, and in extreme cases, they could die. Researchers are trying to find alternatives to traditional antibiotics, and one such possibility is a group of peptides called AMPs. These peptides are found in all plants and animals as a type of immune response and have been shown to be potent antibiotics in the laboratory. Gomesin, an AMP from the Brazilian spider Acanthoscurria gomesiana can function as an antibiotic, but it also has anticancer activity. When gomesin was synthesized as a circle instead of as a linear structure, these characteristics were enhanced. Sónia Troeira Henriques and colleagues wanted to further boost the peptide’s traits.

The team made several variations of the cyclic gomesin peptide and found that some of these were 10 times better at killing most bacteria than the previously reported cyclic form. In other experiments, the new AMPs specifically killed melanoma and leukemia cells, but not breast, gastric, cervical or epithelial cancer cells. The researchers determined that the modified peptides killed bacteria and cancer cells in a similar way — by disrupting the cells’ membranes. The group also notes that the modified AMPs were non-toxic to healthy blood cells.

Prostate Cancer Cells Become ‘Shapeshifters’ to Spread to Distant Organs

Johns Hopkins Kimmel Cancer Center scientists report they have discovered a biochemical process that gives prostate cancer cells the almost unnatural ability to change their shape, squeeze into other organs and take root in other parts of the body. The scientists say their cell culture and mouse studies of the process, which involves a cancer-related protein called AIM1, suggest potential ways to intercept or reverse the ability of cancers to metastasize, or spread.

Results of the research are described in the July 26 issue of Nature Communications.

For the study, the Johns Hopkins scientists mined publically available research data on the genetics and chemistry of hundreds of primary and metastatic cancers included in five studies of men with prostate cancer. They found that a gene called AIM1 (aka “absent in melanoma 1”), which makes proteins also called AIM1, is deleted in approximately 20 – 30 percent of prostate cancers confined to the gland and about 40 percent of metastatic prostate cancers. In addition, the scientists found, on average, two- to fourfold less amounts of AIM1 expression in metastatic prostate cancers compared with normal prostate cells or those from men with prostate cancers confined to the prostate, suggesting that reduction of AIM1 proteins is somehow linked to tumor spread.

Aside from its link to the development of melanoma, a deadly skin cancer, scientists knew little about the function of AIM1.

“Our experiments show that loss of AIM1 proteins gives prostate cancer cells the ability to change shape, migrate and invade. These abilities could allow prostate cancer cells to spread to different tissues in an animal and presumably a person,” says Michael Haffner, M.D., Ph.D., a pathology resident and former postdoctoral fellow at the Johns Hopkins Kimmel Cancer Center who is involved in the research. “It’s not the whole story of what is going on in the spread of prostate cancer, but it appears to be a significant part of it in some cases.”

Looking more closely at the AIM1 gene and its protein levels in prostate cancer tissues, the Johns Hopkins scientists found that many times, even when the gene isn’t completely deleted and its protein production is reduced, its location in the prostate cancer cell is highly abnormal compared with normal prostate cells. This occurs even in primary prostate cancer cells, which have invaded the local structures to form invasive cancer within the prostate gland, say the scientists.

The research team used dyes to track the location of AIM1 proteins in human cells grown in the lab and followed where they appear in normal and cancerous prostate tissues. In normal prostate cells, AIM1 was located along the outside border of each cell and paired up with a protein called beta-actin that helps form the cell’s cytoskeleton, or scaffolding. However, in prostate cancer cells, the protein spread away from the outer border of the cells and no longer paired up with beta-actin.

The scientists found this pattern among a set of human prostate tissue samples including 81 normal prostates, 87 localized prostate cancers and 52 prostate cancers that had spread to the lymph nodes.

“It appears that when AIM1 protein levels drop, or when it’s abnormally spread throughout the cell instead of confined to the outer border, the prostate cancer cells’ scaffolding becomes more malleable and capable of invading other tissues,” says Vasan Yegnasubramanian, M.D., Ph.D., associate professor at the Kimmel Cancer Center and a member of the research team. With AIM1, the scaffold, Yegnasubramanian says, keeps normal cells in a rigid, orderly structure. Without AIM1, cells become more malleable, shapeshifting nomads that can migrate to other parts of the body, he says.

To track how these shapeshifting cancer cells move, the Johns Hopkins scientists, with Steven An, Ph.D., an expert in cellular mechanics and an associate professor at the Johns Hopkins Bloomberg School of Public Health, took a close-up look at AIM1-lacking prostate cancer cells, using sophisticated and quantitative single-cell analyses designed to probe the material and physical properties of the living cell and its cytoskeleton.

They found that cells lacking AIM1 remodeled their scaffolding more than twice as much as cells that had normal levels of AIM1, and that they exert three- to fourfold more force on their surroundings than cells with normal levels of the protein. Such cellular properties are reminiscent of cells with high potential to invade and migrate, An notes.

In addition, the scientists found that AIM1-lacking prostate cells were capable of migrating to unoccupied spaces on a culture dish or invading through connective tissue-like materials at rates fourfold higher than cells with normal levels of AIM1.

Next, the scientific team implanted human prostate cancer cells engineered without AIM1 in five mice and found that the cells spread to other tissues at levels 10 to 100 times more than cells with normal levels of AIM1 that were implanted in five similar mice. However, the AIM1-lacking cells were not able to establish full colonies and tumors at those other tissues, suggesting that AIM1 depletion is not the whole story in the spread and growth of metastatic prostate cancer.

“AIM1 may help prostate cancer cells disseminate throughout the body, but something else may be helping them form full-blown metastatic tumors when they get there,” says Yegnasubramanian.

The Johns Hopkins scientists plan to further study what happens to the AIM1 protein to cause its abnormal location in prostate cancers and identify other proteins and genes that work with AIM1 to cause metastasis. Such studies could help scientists find new drug targets aimed at preventing or reversing prostate metastasis.

First Long-Term Study on Medical Marijuana’s Impact on Opioid Use for Pain

The National Institutes of Health (NIH) has awarded researchers at Albert Einstein College of Medicine and Montefiore Health System a five-year, $3.8 million grant for the first long-term study to test whether medical marijuana reduces opioid use among adults with chronic pain, including those with HIV.

Millions of Americans experience chronic, severe pain as a result of their health conditions.  Many take prescribed opioids, including Oxycodone, to help relieve their symptoms. But given the dangers of opioid use and misuse, both doctors and patients are seeking safe and effective alternatives to manage pain.

“There is a lack of information about the impact of medical marijuana on opioid use in those with chronic pain,” says Chinazo Cunningham, M.D., M.S., associate chief of general internal medicine at Einstein and Montefiore and principal investigator on the grant. “We hope this study will fill in the gaps and provide doctors and patients with some much needed guidance.”

Compared to the general population, chronic pain and opioid use is even more common in people with HIV. Between 25 and 90 percent of adults with HIV suffer from chronic pain. Previous studies have reported that despite the high risk for misuse of opioid pain relievers, adults with HIV are likely to receive opioids to help manage their pain. In recent years, medical marijuana has gained recognition as a treatment option. Twenty-nine states, plus the District of Columbia, have legalized its use; in those states, chronic pain and/or HIV/AIDS are qualifying conditions for medical marijuana use.

Researchers have never studied—in any population—if the use of medical marijuana over time reduces the use of opioids. Additionally, there are no studies on how the specific chemical compounds of marijuana, tetrahydrocannabinol (THC) and cannabidiol (CBD), affect health outcomes, like pain, function, and quality of life. Most studies that have reported negative effects of long-term marijuana use have focused on illicit, rather than medical, marijuana.

“As state and federal governments grapple with the complex issues surrounding opioids and medical marijuana, we hope to provide evidence-based recommendations that will help shape responsible and effective healthcare practices and public policies,” notes Dr. Cunningham.

Dr. Cunningham will enroll 250 HIV-positive and HIV-negative adults with chronic pain who use opioids and who have received certification from their physicians to use medical marijuana, which is provided through approved dispensaries in New York State. Over 18 months, the study subjects will complete web-based questionnaires every two weeks, which will focus on pain levels and the medical and illicit use of marijuana and opioids. They’ll also provide urine and blood samples at in-person research visits every three months. In addition, in-depth interviews with a select group of these participants will explore their perceptions of how medical marijuana use affects the use of opioids.

Fat Rats Show Why Breast Cancer May Be More Aggressive in Patients with Obesity

Women with obesity are more likely to get breast cancer, and a number of studies have provided a reasonable explanation why: after menopause, fat tissue manufactures estrogen, and the estrogen then promotes tumor growth. But why, then, do women with obesity continue to have more aggressive tumors even after anti-estrogen treatment? Once the tumor’s source of estrogen is removed, obesity should have no effect on prognosis, but it does.

A University of Colorado Cancer Center study published in the journal Hormones & Cancer offers a possible explanation: In an animal model of obesity and breast cancer (affectionately referred to as the “fat rat”), tumor cells in obese animals, but not lean animals, had especially sensitive androgen receptors, allowing these cells to magnify growth signals from the hormone testosterone. Similar to the way in which many breast cancers drive their growth with estrogen receptors, these tumors in obese rats drove their growth with androgen receptors.

“Our original goal was to make a model of obesity and breast cancer that would reflect the condition in women.  At first, we were disappointed to discover that rats don’t make much estrogen in fat tissue like humans do. But we then realized that this aspect of the model gave us an excellent opportunity to study cancer progression after anti-estrogen treatment. Because fat cells in these rats don’t make estrogen, they are like human breast cancer patients treated to remove estrogen.  This allowed us to ask what is responsible for obesity-associated tumor progression in conditions of low estrogen availability,” says Elizabeth Wellberg, PhD, the paper’s first author, who works with Steven Anderson, PhD and Paul MacLean, PhD. Dr. Anderson is the vice chair for research at CU Cancer Center and James C. Todd Professor of Experimental Pathology in the CU School of Medicine. Dr. MacLean is a professor in the Division of Endocrinology, Metabolism, & Diabetes, also in the CU SOM.  Together, these investigators and their team have identified an important role for obesity in changing how breast tumors respond to hormones.

About 40 percent of American women have obesity; about 75 percent of breast cancers are estrogen-receptor positive, most of which will go on to be treated with anti-estrogen therapies. This combination means that thousands of women every year could benefit from treatments aimed at the aspects of obesity that promote breast cancer in low- or non-estrogen environments.

Androgen receptors and their hormone partner, testosterone, have long been known as drivers of prostate cancer and work at CU Cancer Center and elsewhere is implicating androgen as a driver in many breast cancers. When Wellberg and colleagues treated their obese rats with the anti-androgen drug enzalutamide, existing tumors shrank and new tumors failed to form. But this brought up another question: If overactive androgen receptors create poor prognosis in obese breast cancer patients, what is creating these overactive androgen receptors? It wasn’t that they were simply responding to more testosterone – it was that these receptors had been somehow tuned to be more sensitive to existing levels of testosterone.

“When you talk about what’s different between lean and obese individuals there are a lot of things – resistance to insulin, high sugar, and an elevated inflammatory response, what we call chronic low-grade inflammation, to name a few. In a lot of ways, you can walk through these differences looking for what may be causing this androgen receptor sensitivity,” says Anderson.

The group had previously shown that a component of inflammation, namely levels of a cytokine known as interleukin 6 (IL-6), is higher in the circulation of obese compared to lean rats. In the current paper, the group shows that administering IL-6 to breast cancer cells amplifies the activity of androgen receptors. In all, the storyline of this paper suggests the following:

  • Obesity leads to inflammation
  • Inflammation is associated with higher levels of IL-6
  • IL-6 sensitizes androgen receptors
  • Sensitized androgen receptors amplify growth signals that drive breast cancer even in an environment of low estrogen availability.

The current paper and others in this line of study lay the groundwork for considering obesity as a variable in the clinic.

“Down the line, we can imagine a day in which the BMI or metabolic state of breast cancer patients would be considered when choosing a treatment. These patients may benefit significantly from a more personalized therapeutic strategy, based on what obesity is doing to the tumor environment,” Wellberg says.

Immune cells may be key to better allergy, infection therapies

By learning how a recently discovered immune cell works in the body, researchers hope to one day harness the cells to better treat allergies and infections, according to new Cornell University research.

Type 1 regulatory (Tr1) cells are a type of regulatory immune cell that help suppress immune responses, including inflammation and tissue damage, but very few details were known about their development and function.

A new study with mice and humans, published in the journal Nature Communications, describes how an enzyme called ITK plays a crucial role in the development of Tr1 cells during an immune response. The enzyme offers an entry point for researchers to manipulate the development of Tr1 cells to enhance them to treat allergies, for instance, or block their development to treat viral and bacterial infections.

“The more we understand about how these cells develop, the signals and pathways they use, the more likely we’ll be able to devise approaches to manipulate them,” said Avery August, professor of microbiology and immunology in Cornell’s College of Veterinary Medicine and the paper’s senior author. Weishan Huang, assistant research professor of microbiology and immunology, is lead author.

Doctors employ antigen immunotherapy to treat allergies by administering a regimen that exposes a patient to increasing doses of an allergen over a period of months. Since allergies are caused by an overactive immune response to an allergen, the treatment works because Tr1 cells help suppress the immune system and lower inflammation. In the future, clinicians may want to enhance the pathway to produce more Tr1 cells, August said.

But when treating viral infections such as the flu, bacterial infections and tumors, clinicians may want to selectively block the pathway to lower the number of Tr1 cells. In experiments with mice, August and colleagues found that Tr1 cells increase when a mouse is infected with viruses or bacteria or when fighting tumors. By tempering the development of Tr1 cells, and carefully reducing their activity to suppress the immune response, patients may recover faster from certain diseases.

“This is a balance because these cells are there for a purpose, and we think their purpose is to make sure the immune system doesn’t destroy and cause pathology in an immune response,” August said.

The danger with flu, for example, is that at a certain point other types of immune system T cells, whose purpose is to kill infected cells, start to destroy tissue. In such cases, an overactive immune response can lead to death.

“We’d have to do experiments to find out whether we can tune the function of Tr1 cells,” August said, “so we balance the beneficial aspects of the immune response with the damaging aspects of the immune response.”

In the study, August, Huang and their colleagues bred genetically altered mice so they carried a gene that makes Tr1 cells glow green when they develop, which allows for easy tracking. They then bred another type of mouse that had fluorescent Tr1 cells and also allowed the researchers to specifically block the enzymatic activity of ITK. Using the same protocol, they created a third type of mouse that lacked ITK.

In both the mice where ITK was inhibited and the mice that lacked ITK, Tr1 cells failed to develop. Using blood cells from anonymous human volunteers, they got the same results.

In a second experiment, the researchers identified a second critical enzyme in the pathway that leads to the development of Tr1 cells. This other enzyme, called IRF4, is a transcription factor that regulates the expression of a number of genes and proved key for controlling whether Tr1 cells developed. The team also confirmed that the same pathway exists in people.

Scientists create stem cell therapy for lung fibrosis conditions

A team of scientists from the UNC School of Medicine and North Carolina State University (NCSU) has developed promising research towards a possible stem cell treatment for several lung conditions, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cystic fibrosis — often-fatal conditions that affect tens of millions of Americans.

In the journal Respiratory Research, the scientists demonstrated that they could harvest lung stem cells from people using a relatively non-invasive, doctor’s-office technique. They were then able to multiply the harvested lung cells in the lab to yield enough cells sufficient for human therapy.

In a second study, published in the journal Stem Cells Translational Medicine, the team showed that in rodents they could use the same type of lung cell to successfully treat a model of IPF – a chronic, irreversible, and ultimately fatal disease characterized by a progressive decline in lung function.

The researchers have been in discussions with the FDA and are preparing an application for an initial clinical trial in patients with IPF.

“This is the first time anyone has generated potentially therapeutic lung stem cells from minimally invasive biopsy specimens,” said co-senior author of both papers Jason Lobo, MD, an assistant professor of medicine at UNC and medical director of lung transplant and interstitial lung disease.

Co-senior author Ke Cheng, PhD, an associate professor in NCSU’s Department of Molecular Biomedical Sciences and the UNC/NCSU Joint Department of Biomedical Engineering, said, “We think the properties of these cells make them potentially therapeutic for a wide range of lung fibrosis diseases.”

These diseases of the lung involve the buildup of fibrous, scar-like tissue, typically due to chronic lung inflammation. As this fibrous tissue replaces working lung tissue, the lungs become less able to transfer oxygen to the blood. Patients ultimately are at risk of early death from respiratory failure. In the case of IPF, which has been linked to smoking, most patients live for fewer than five years after diagnosis.

The two FDA-approved drug treatments for IPF reduce symptoms but do not stop the underlying disease process. The only effective treatment is a lung transplant, which carries a high mortality risk and involves the long-term use of immunosuppressive drugs.

Scientists have been studying the alternative possibility of using stem cells to treat IPF and other lung fibrosis diseases. Stem cells are immature cells that can proliferate and turn into adult cells in order to, for example, repair injuries. Some types of stem cells have anti-inflammatory and anti-fibrosis properties that make them particularly attractive as potential treatments for fibrosis diseases.

Cheng and Lobo have focused on a set of stem cells and support cells that reside in the lungs and can be reliably cultured from biopsied lung tissue. The cells are called lung spheroid cells for the distinctive sphere-like structures they form in culture. As the scientists reported in an initial paper in 2015, lung spheroid cells showed powerful regenerative properties when applied to a mouse model of lung fibrosis. In their therapeutic activity, these cells also outperformed other non-lung-derived stem cells known as mesenchymal stem cells, which are also under investigation to treat fibrosis.

In the first of the two new studies, Lobo and his team showed that they could obtain lung spheroid cells from human lung disease patients with a relatively non-invasive procedure called a transbronchial biopsy.

“We snip tiny, seed-sized samples of airway tissue using a bronchoscope,” Lobo said. “This method involves far less risk to the patient than does a standard, chest-penetrating surgical biopsy of lung tissue.”

Cheng and his colleagues cultured lung spheroid cells from these tiny tissue samples until they were numerous enough – in the tens of millions – to be delivered therapeutically. When they infused the cells intravenously into mice, they found that most of the cells gathered in the animals’ lungs.

“These cells are from the lung, and so in a sense they’re happiest, so to speak, living and working in the lung,” Cheng said.

In the second study, the researchers first induced a lung fibrosis condition in rats. The condition closely resembled human IPF. Then the researchers injected the new cultured spheroid cells into one group of rats. Upon studying this group of animals and another group treated with a placebo, the researchers saw healthier overall lung cells and significantly less lung inflammation and fibrosis in the rats treated with lung spheroid cells.

“Also, the treatment was safe and effective whether the lung spheroid cells were derived from the recipients’ own lungs or from the lungs of an unrelated strain of rats,” Lobo said. “In other words, even if the donated stem cells were ‘foreign,’ they did not provoke a harmful immune reaction in the recipient animals, as transplanted tissue normally does.”

Lobo and Chen expect that when used therapeutically in humans, lung spheroid cells initially would be derived from the patient to minimize any immune-rejection risk. Ultimately, however, to obtain enough cells for widespread clinical use, doctors might harvest them from healthy volunteers, as well as from whole lungs obtained from organ donation networks. The stem cells could later be used in patients as-is or matched immunologically to recipients in much the same way transplanted organs are typically matched.

“Our vision is that we will eventually set up a universal cell donor bank,” Cheng said.

Cheng, Lobo, and their teams are now planning an initial study of therapeutic lung spheroid cells in a small group of IPF patients and expect to apply later this year for FDA approval of the study. In the long run, the scientists hope their lung stem cell therapy will also help patients with other lung fibrosis conditions of which there are dozens, including COPD, cystic fibrosis, and fibro-cavernous pulmonary tuberculosis.

Study identifies molecules that could help to prevent the development of brain tumors

Researchers from the University of Portsmouth’s Brain Tumour Research Centre of Excellence have identified molecules which are responsible for metastatic lung cancer cells binding to blood vessels in the brain.

In order for a cancer cell to enter the brain, it must first bind to the cells which line the structure separating the blood from the brain which is called the blood-brain barrier (BBB). Such information about the factors associated with this process may provide a way of preventing the cancer cells binding to the BBB and crossing over into the brain.

Twenty to 40 percent of patients with non-small cell lung cancer (NSCLC) develop brain metastasis.

The study, funded by the charity Brain Tumour Research and conducted by researchers at their UK Centre of Excellence at the University of Portsmouth, examined the factors present on the surface of NSCLC cells. These cells have different factors on their surfaces which determines how “sticky” the cells are and whether they are responsible for mediating the cancer cells binding to the blood vessel walls.

One of these factors is a molecule called CD15s. While it is present on a number of different types of cells in the body, it is expressed at higher levels on metastatic tumour cells, including those which have spread from the lung. It is only present at low levels in lung cancer cells which are not metastatic and remain within the lung.

The scientists examined what CD15s binds to on the blood vessel wall and identified another factor called CD62E. The researchers then used a specific tool to block the CD15s on the surface of the tumour cells, and this prevented the NSCLC cells from attaching to the blood vessels. They also used a model which simulated the cancer cells flowing through the blood vessels, and got the same result. So, blocking the adhesive properties of CD15s may provide a tool to prevent the establishment of secondary cancers.

Professor Geoff Pilkington, study co-author and Head of the Brain Tumour Research Centre, said: “Although this work is still at an early stage, we have demonstrated key elements that are associated with tumour cell binding to blood vessels and this may provide a target for future drug development to prevent the development of secondary tumours in the brain. Increasing our understanding of the adhesive properties of tumours may also help to develop new treatments to halt the development and spread of primary brain tumours.”

The adhesive properties of cancer cells play a key role in the formation and development of a tumour. While cells in a low-grade tumour bind very tightly together, the cells become less adhesive as the tumour becomes malignant. This is very important for the tumour cells which then spread into the surrounding nervous tissue.

Understanding more about the factors which mediate cell adhesion is key for the potential identification of new therapies.

Dr Kieran Breen, Director of Research at Brain Tumour Research, said: “Brain tumours kill more children and adults under the age of 40 than any other cancer, yet just 1 per cent of the national spend on cancer research has been allocated to this devastating disease. We are funding vital research in the UK to address this situation and are encouraged by Professor Pilkington’s findings.”

In addition to primary tumours which start in the brain, the secondary or ‘metastatic’ tumours which originate elsewhere and which migrate to the brain have been the focus of this new study. Secondary brain tumours are most likely to originate in the breast, lung or skin (melanoma). When they enter the brain, they generally form multiple tumours and can be extremely difficult to treat. Usually, treatment would require whole-brain radiation which is extremely toxic and the average survival time is just 3-6 months from diagnosis, with fewer than 20 per cent of patients surviving more than one year. If the people whose tumours are more likely to spread to the brain could be identified, researchers may be able to prevent this from happening.

A new HER2 mutation, a clinical trial and a promising diagnostic tool for metastatic breast cancer

There is a group of metastatic breast cancers that has the HER2 gene amplified – the cells have many copies of it – which leads to enhanced activity of the product enzyme, a tyrosine kinase. HER2 has been established as a therapeutic target in breast cancer, and breast cancers in which the HER2 gene is not amplified do not, in general, respond to HER2-directed therapeutic approaches.

A few years ago, when the research teams of Dr. Matthew Ellis and others carried out a molecular characterization of breast cancer tumors, they found a new mutation in HER2 that was different from gene amplification but also resulted in tyrosine kinase being constantly activated.

“In this particular activation mechanism, the cells develop a subtle mutation within the functional part of the HER2 gene that activates the enzyme,” said Ellis, professor and director of the Lester and Sue Smith Breast Center, part of the National Cancer Institute-designated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. “The mutation locks the enzyme into an ‘on’ position.”

Ellis and his colleagues developed a preclinical model to study this new HER2 mutation and discovered that the enhanced enzymatic activity could trigger tumor formation. Furthermore, these tumor cells were sensitive to an experimental drug, neratinib. With this information in hand, the researchers took the next step.

“We launched a phase II clinical trial of neratinib in patients with metastatic breast cancer carrying a HER2 mutation,” Ellis said. “Finding patients that are positive for a HER2 mutation required a national collaboration because we had to screen hundreds of patients to identify the 2 to 3 percent that have a tumor driven by a HER2 mutation. The results of the clinical trial were encouraging in that about 30 percent of the 16 patients treated with neratinib had a meaningful clinical response showing significant disease stabilization or regression. Neratinib was well tolerated by most patients.”

“This is the first time we had a reasonable number of patients treated for HER2 mutations in whom we could estimate the response rate.”

The number of patients who could potentially benefit from this new treatment approach is estimated to be in the thousands. The researchers estimate that as many as 200,000 patients are likely to be living with metastatic breast cancer today in the United States. Based on the estimate that the new mutation is present in 2 to 3 percent of cases, the researchers calculated that approximately 4,000 to 6,000 patients with metastatic breast cancer carry a HER2 mutation and are therefore potential candidates for neratinib treatment.

Circulating tumor DNA analysis, a promising diagnostic tool

To identify the patients in this study who carried the new HER2 mutation, the researchers required tissue from the tumor, a biopsy, from which they could extract and sequence the genetic material to determine the presence of the HER2 mutation. This task turned out to be a major challenge because for 20 to 30 percent of the patients the researchers did not have sufficient material to make the diagnosis.

“To assist in our ability to identify patients with HER2 mutation-positive tumors, we conducted circulating tumor DNA analysis,” Ellis said. “The tumor’s DNA is released into the human bloodstream, and we were able to determine the presence of the mutation in blood samples from the patients. Importantly the circulating tumor DNA results were highly concordant with the tumor sequencing results, and they were much easier to determine. Notably, the blood test was sensitive enough that we could use it as a tool to determine eligibility for the clinical trial.”

In addition to bringing to the table a novel treatment for metastatic breast cancer carrying a HER2 mutation, the researchers have tested the value of the circulating tumor DNA as a disease-monitoring marker.

“A circulating tumor DNA-based blood test also could therefore be potentially used to monitor tumor progression and to determine whether patients are responding or not to treatment after just one month of therapy,” Ellis said.

Ellis also is a McNair Scholar at Baylor.

Read all the details of this study, the full list of contributors and their financial support in Clinical Cancer Research.

New insights into diagnosing and treating invasive fungal infections will help save lives

Thousands of patients suffering from invasive fungal infections in intensive-care units or after organ transplantation will benefit from the latest insights into diagnostic and therapeutic interventions, published today in the prestigious journal The Lancet Infectious Diseases.

Fungal infections invading the bloodstream, lungs or other organs can cause prolonged illness and in extreme cases can lead to permanent disability or even death.

A new review paper has outlined the gold standard for identifying at-risk patients who are critically ill, or in receipt of organ transplants, for preventing, diagnosing and treating invasive fungal infections, potentially saving countless lives across both the developed and developing world.

Senior author, Professor Tania Sorrell from the Westmead Institute for Medical Research and the Marie Bashir Institute for Infectious Diseases and Biosecurity, said that invasive fungal infections can have serious consequences for patients and their families.

“These new insights into diagnosing and treating invasive fungal infections are significant because early and correct treatment clearly leads to better outcomes for the patient.

“These infections are uncommon but potentially life-threatening. Blood infections such as candidaemia and lung infections such as aspergillosis have high mortality rates of up to 85% in critically ill and immune-compromised patients,” Professor Sorrell said.

Professor Sorrell added that invasive fungal infections, overall, are a major problem in both developed and developing nations, killing more than 1.5 million people annually. The cost to the global healthcare system runs into billions of dollars each year.

“This is an important problem in Australia, but an even more serious issue in developing countries where mortality is unacceptably high despite the best available therapies and care.

“The research that has informed the recommendations in this paper will play an important role in educating doctors in both developed and developing countries about these diseases and outlining available diagnostic and therapeutic options in different medical contexts.

“It will allow clinicians to tailor their approach to managing these infections in different countries or when working with specific at-risk populations.

“This is vital, because rapid and accurate diagnosis, together with the right treatment, will significantly increase the chances of recovery for a patient.

“A significant proportion of these infections are preventable. We are also working to improve capability to identify patients at high risk of contracting these infections.

The Westmead team is now expanding their research in prevention, new diagnostic strategies, and therapeutic approaches towards infectious diseases of significant public health importance

A new HER2 mutation, a clinical trial and a promising diagnostic tool for metastatic breast cancer

There is a group of metastatic breast cancers that has the HER2 gene amplified – the cells have many copies of it – which leads to enhanced activity of the product enzyme, a tyrosine kinase. HER2 has been established as a therapeutic target in breast cancer, and breast cancers in which the HER2 gene is not amplified do not, in general, respond to HER2-directed therapeutic approaches.

A few years ago, when the research teams of Dr. Matthew Ellis and others carried out a molecular characterization of breast cancer tumors, they found a new mutation in HER2 that was different from gene amplification but also resulted in tyrosine kinase being constantly activated.

“In this particular activation mechanism, the cells develop a subtle mutation within the functional part of the HER2 gene that activates the enzyme,” said Ellis, professor and director of the Lester and Sue Smith Breast Center, part of the National Cancer Institute-designated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. “The mutation locks the enzyme into an ‘on’ position.”

Ellis and his colleagues developed a preclinical model to study this new HER2 mutation and discovered that the enhanced enzymatic activity could trigger tumor formation. Furthermore, these tumor cells were sensitive to an experimental drug, neratinib. With this information in hand, the researchers took the next step.

“We launched a phase II clinical trial of neratinib in patients with metastatic breast cancer carrying a HER2 mutation,” Ellis said. “Finding patients that are positive for a HER2 mutation required a national collaboration because we had to screen hundreds of patients to identify the 2 to 3 percent that have a tumor driven by a HER2 mutation. The results of the clinical trial were encouraging in that about 30 percent of the 16 patients treated with neratinib had a meaningful clinical response showing significant disease stabilization or regression. Neratinib was well tolerated by most patients.”

“This is the first time we had a reasonable number of patients treated for HER2 mutations in whom we could estimate the response rate.”

The number of patients who could potentially benefit from this new treatment approach is estimated to be in the thousands. The researchers estimate that as many as 200,000 patients are likely to be living with metastatic breast cancer today in the United States. Based on the estimate that the new mutation is present in 2 to 3 percent of cases, the researchers calculated that approximately 4,000 to 6,000 patients with metastatic breast cancer carry a HER2 mutation and are therefore potential candidates for neratinib treatment.

Circulating tumor DNA analysis, a promising diagnostic tool

To identify the patients in this study who carried the new HER2 mutation, the researchers required tissue from the tumor, a biopsy, from which they could extract and sequence the genetic material to determine the presence of the HER2 mutation. This task turned out to be a major challenge because for 20 to 30 percent of the patients the researchers did not have sufficient material to make the diagnosis.

“To assist in our ability to identify patients with HER2 mutation-positive tumors, we conducted circulating tumor DNA analysis,” Ellis said. “The tumor’s DNA is released into the human bloodstream, and we were able to determine the presence of the mutation in blood samples from the patients. Importantly the circulating tumor DNA results were highly concordant with the tumor sequencing results, and they were much easier to determine. Notably, the blood test was sensitive enough that we could use it as a tool to determine eligibility for the clinical trial.”

In addition to bringing to the table a novel treatment for metastatic breast cancer carrying a HER2 mutation, the researchers have tested the value of the circulating tumor DNA as a disease-monitoring marker.

“A circulating tumor DNA-based blood test also could therefore be potentially used to monitor tumor progression and to determine whether patients are responding or not to treatment after just one month of therapy,” Ellis said.

Ellis also is a McNair Scholar at Baylor.

Towards a safe and scalable cell therapy for type 1 diabetes by simplifying beta cell differentiation

More than 36 million people globally are affected by type 1 diabetes (T1D), a lifelong disorder where insulin producing cells are attacked and destroyed by the immune system resulting in deficient insulin production that requires daily blood glucose monitoring and administration of insulin. While successful outcomes from islet transplantations have been reported, very few patients can benefit from this therapeutic option due to limited access to cadaveric donor islets. Human pluripotent stem cell (hPSCs) could offer an unlimited and invariable source of insulin-producing beta cells for treatments of a larger population of T1D patients.

With the vision of providing a cell therapy for type 1 diabetes patients, scientists at the University of Copenhagen have identified a unique cell surface protein present on human pancreatic precursor cells providing for the first time a molecular handle to purify the cells whose fate is to become cells of the pancreas – including insulin producing cells. The work, outlined in a landmark study entitled ‘Efficient generation of glucose-responsive beta cells from isolated GP2+ human pancreatic progenitors’ has just been published in Cell Reports and is available here.

A biomarker to clearly separate cell populations is a holy grail of cell therapy research for the reasons of safety and end product consistency. By using this cell surface marker, the researchers have engineered a streamlined and simplified differentiation process to generate insulin-producing cells for future treatment of type 1 diabetes patients. The process enables cost-efficient manufacturing and exploits at its core an intermediate cell bank of purified pancreatic precursor cells.

The discovery of the new marker has also enabled the researchers to streamline and refine the process of producing hPSC-derived insulin cells.

“By starting with a purified population of pancreatic precursor cells instead of immature stem cells we eliminate the risk of having unwanted tumorigenic cells in the final cell preparation and thus generate a safer cell product for therapeutic purposes”, explains Assistant Professor Jacqueline Ameri, first author on the paper.

Professor Henrik Semb, Managing Director of the Danish stem cell centre (DanStem) explains:

“Although significant progress has been made towards making insulin producing beta cells in vitro (in the lab), we are still exploring how to mass-produce mature beta cells to meet the future clinical needs. Our current study contributes with valuable knowledge on how to address key technical challenges such as safety, purity and cost-effective manufacturing, aspects that if not confronted early on, could hinder stem cell therapy from becoming a clinically and commercially viable treatment in diabetes.”

Indeed, Semb’s group is among the first to directly address not only the therapeutic concept but to incorporate very early the manufacturing considerations in their process to ensure that future commercialization will be possible.

To translate the current findings into a potential treatment of type 1 diabetes, Ameri and Semb aim to commercialize their recent patent pending innovations by establishing the spin out company PanCryos. PanCryos has assembled a team with experts in stem cell biology, islet transplantations, business and regulatory guidance and is currently funded by a KU POC grant and a pre-seed funding from Novo Seeds.

“In parallel with other groups in this field, we have been working on a cell therapy for type 1 diabetes for many years. What is unique about our approach is the simplification of our protocol which acknowledges that eventually the process will need to be scaled up for manufacturing. PanCryos is being established to ensure the development of the first scalable allogenic cell therapy for type 1 diabetes so we can offer the route to an affordable therapy by providing a product that will not be too expensive to produce, as has occurred too often in the developing cell therapy field”, explains Jacqueline Ameri, co-founder and CEO for PanCryos.

Cell mechanism discovery could lead to ‘fundamental’ change in leukaemia treatment

Researchers have identified a new cell mechanism that could lead to a fundamental change in the diagnosis and treatment of leukaemia.

A team in the University of Kent’s pharmacy school conducted a study that discovered that leukaemia cells release a protein, known as galctin-9, that prevents a patient’s own immune system from killing cancerous blood cells.

Acute Myeloid Leukaemia (AML) — a type of blood cancer that affects over 250,000 people every year worldwide — progresses rapidly because its cells are capable of avoiding the patient’s immune surveillance. It does this by inactivating the body’s immune cells, cytotoxic T lymphocytes and natural killer (NK) cells.

Existing treatment strategies consist of aggressive chemotherapy and stem cell transplantation, which often do not result in effective remission of the disease. This is because of a lack of understanding of the molecular mechanisms that allow malignant cells to escape attack by the body’s immune cells.

Now the researchers at the Medway School of Pharmacy, led by Dr Vadim Sumbayev, Dr Bernhard Gibbs and Professor Yuri Ushkaryov, have found that leukaemia cells — but not healthy blood cells — express a receptor called latrophilin 1 (LPHN1). Stimulation of this receptor causes these cancer cells to release galectin-9, which then prevents the patient’s immune system from fighting the cancer cells.

The discovery of this cell mechanism paves the way for new ‘biomarkers’ for AML diagnosis, as well as potential targets for AML immune therapy, say the researchers.

‘Targeting this pathway will crucially enhance patients own immune defences, helping them to eliminate leukaemia cells’, said Dr Sumbayev. He added that the discovery has the potential to also be beneficial in the treatment of other cancers.

Study uncovers potential ‘silver bullet’ for preventing and treating colon cancer

In preclinical experiments, researchers at VCU Massey Cancer Center have uncovered a new way in which colon cancer develops, as well as a potential “silver bullet” for preventing and treating it. The findings may extend to ovarian, breast, lung, prostate and potentially other cancers that depend on the same mechanism for growth.

Led by Massey’s Deputy Director Steven Grossman, M.D., Ph.D., a team of scientists targeted the gene CtBP with a drug known as HIPP (2-hydroxy-imino phenylpyruvic acid) and were able to reduce the development of pre-cancerous polyps by half and return a normal lifespan to mice born with a predisposition to intestinal polyps. In humans, this condition is known as familial adenomatous polyposis, a devastating inherited disease that causes pre-cancerous polyps to grow in the intestine at a young age, often leading to the removal of portions of the colon to prevent cancer.

“This work opens up a whole new avenue for anti-cancer therapeutic development, as it shows that CtBP drives the actions of what are known as cancer stem cells, which are keys to cancer metastasis and resistance to chemotherapy,” says Grossman, who is also the Dianne Nunnally Hoppes Endowed Chair in Cancer Research and co-leader of the Developmental Therapeutics research program at Massey as well as professor and chair of the Division of Hematology, Oncology and Palliative Care in the Department of Internal Medicine at the VCU School of Medicine.

In contrast to other cancer-promoting genes, CtBP is not mutated in colon cancer; instead, it is overexpressed to the point where the cancer depends on it for growth. CtBP works to reprogram cells by repressing the expression of genes that typically prevent cancer through a form of cell suicide known as apoptosis while simultaneously promoting the expression of other genes that lead to cancer growth and metastasis.

The researchers found that CtBP can cause normal human cells to become cancerous when inserted into the cell’s DNA. In mouse models of familial adenomatous, treatment with HIPP significantly reduced intestinal polyps and increased survival while mice bred without the CtBP gene lived twice as long as those with it.

“In our experiments, HIPP acted almost as a chemical ‘silver bullet’ to prevent polyp formation, thereby reducing the risk of colon cancer,” says Grossman. “Also, we believe that anti-CtBP therapies such as HIPP may be able to complement current therapies to counter drug resistance and decrease metastasis, ultimately increasing our ability to control and cure colon cancer.”

This study is the latest in a line of research investigating CtBP by Grossman and his colleagues that began in 2010. Moving forward, they plan to continue testing derivatives of HIPP for the treatment of colon cancer and also see if their findings extend to breast, lung, ovarian and prostate cancers.

Demand for Diagnostic for Early Detection of Brain Injury After Surprising Study On NFL Players Brains And CTE

Chronic Traumatic Encephalopathy (CTE) is a slowly developing neurodegenerative condition typical of athletes involved in contact sports. This was evidenced in a recent study in which nearly every former NFL player whose brain was investigated had suffered from CTE.  The findings released this week were part of a study conducted by two leading medical institutions devoted to CTE research — the VA Boston Healthcare System and Boston University School of Medicine — and the results concluded that of 111 NFL players’ brains that were donated to science after the players’ deaths, 110 (99%) were found to have CTE. The disease currently can only be diagnosed post-mortem.

The study, published in the Journal of the American Medical Association, researchers looked at the brains of 202 deceased people who had played football at various levels, from high school to the NFL. (The brains had been donated to a brain bank at Boston University for further study.) The researchers analyzed the brains for signs of CTE and spoke to family members about the players’ histories.

Dr. Jesse Mez, an assistant professor of neurology at Boston University School of Medicine, one of the co-authors of the study, said that “the goal of doctors and scientists is to eventually be able to diagnose CTE among the living”. Dr. Mez said that the goal of doctors and scientists is to eventually diagnose CTE among the living, so that research and development of treatment methods can be expedited. “One of the important points is to develop bio-markers and figure out ways of differentiating this disease (CTE) from other neurodegenerative diseases, most certainly Alzheimer’s.” he adds.

Today, the analysis is made post-mortem (after death) from individuals who engaged to donate their brain for research. Medicortex Finland Oy, a biotechnology company in Finland, is developing a diagnostic tool for rapid sideline detection of brain injury.

This is exactly what Medicortex Finland Oy is aiming at. Medicortex is working towards the identification of a Traumatic Brain Injury (TBI) biomarker in body fluids and incorporating it into a quick and reliable diagnostic kit that can be easily used by sideline paramedics, first responders and healthcare professionals, and also by people with no medical profession. A rapid TBI test will furthermore help prioritize evacuation order in mass casualties and reframe from administration of contraindicated medications.

Recently Medicortex completed analyzing the results from the first clinical trial. The trial consisted of patients that were hospitalized due to a head injury. The clinical results confirmed the presence of a unique biomarker that will be further developed into a new diagnostic tool. Medicortex’s test utilizes easily accessible, non-invasive samples of body fluids. It is easy to understand the result of the test which enables straightforward confirmation or ruling-out of TBI without a need of a medical professional. Suspected athletes can be tested for TBI after a prominent hit to the head at sport arenas. The test can be performed by the coach of the team or by a First Aid group in charge.

Dr. Adrian Harel, Chief Executive Officer of Medicortex Finland, says that “Brain injury is a devastating condition leading to mortality if not diagnosed. We have the opportunity to develop the first portable non-invasive kit for head injury and concussion to help the patients and families that so desperately need it is remarkable.”

Medicortex Finland Oy (http://www.medicortex.fi) is an early clinical stage company dedicated to improving the diagnostics and treatment of Traumatic Brain Injury (TBI). Medicortex is currently developing biomarker diagnostics for rapid detection of TBI. The second goal will be to develop an innovative drug to halt the progression of brain injury. Medicortex was founded by and it is headed by a neurobiologist and entrepreneur Adrian Harel (PhD, MBA). The company operates in Turku, Finland.

HemAcure and Sernova, A Big Deal

Richard (Rick) Mills
Ahead of the Herd

As a general rule, the most successful man in life is the man who has the best information

When most of us suffer a cut cells in the blood, called platelets, go to where the cut is, plug the hole and stop the bleeding. While the platelets are plugging the hole they release chemicals that attract more of the ‘sticky’ platelets and twelve (numbered using Roman numerals I through XII) proteins in the blood known as clotting factors are activated. These proteins mix with the platelets to form fibers which make the clot stronger and stop the bleeding.

Having too little of factors VIII (8) or IX (9) is what causes hemophilia. A person with hemophilia will lack only one factor, either factor VIII or factor IX, but not both. There are two major kinds of hemophilia: hemophilia A, which is a factor VIII deficiency; and hemophilia B, which is a factor IX deficiency.

Hemophilia is a genetic disorder which means it’s the result of a change in genes that was either inherited (passed on from parent to child) or occurred during development in the womb. Although it is mostly passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a change in a gene. All races and ethnic groups are equally affected by hemophilia A. The disease almost always affects males but can also affect females.

Many people believe that hemophiliacs bleed a lot from minor cuts but external wounds are usually not that serious. Much more serious is internal hemorrhaging that can take place in joints (especially knees, ankles and elbows) and into tissues and muscles. Bleeding can also occur in vital organs putting a hemophiliac’s life in danger.

Although effective treatment of the symptoms is available, there is no cure for hemophilia A at present and therapy has to be individualized to specific patients. Patients have to get lifelong infusions with recombinant factor VIII (rFVIII) several times a week to compensate for the missing clotting factor.

The global total hemophilia market was valued at US$ 9.3 billion in 2015. Approximately 20,000 people in the United States, 10,000 in Europe and approximately 2,500 in Canada have a moderate or severe form of hemophilia A. Annual costs for the treatment of the disease for each patient may range from US$60,000 to US$260,000 for a total cost of between $2-5B per year just in North America and Europe.

Grand View Research

The Horizon 2020 program

Horizon 2020 is the largest European Union (EU) research and innovation program ever undertaken with nearly €80 billion of funding available over the seven years between 2014 to 2020. Horizon 2020 promises breakthroughs, discoveries and world firsts by taking great ideas from the lab to the market, for example in the field of personalized medicine providing novel therapies such as gene or cell therapy.

HemAcure project, a novel personalized medicine curative therapy

An international research consortium, under the name HemAcure unites scientific academic institutions from Germany, Italy, the UK and Sernova Corp from Canada.

The following institutions are involved in HemAcure:

  • ARTTIC, a Munich-based enterprise that specializes in the management of EU-funded collaborative research projects, is in charge of project management.
  • The Department of Tissue Engineering and Regenerative Medicine of the Wuerzburg University Hospital is responsible for isolating the cells.
  • The Università del Piemonte Orientale (Italy) is developing, optimizing and performing the gene correction of the patient cells for expression of the Factor VIII therapy.
  • Scientists from Loughborough University (UK) are focussing on the manufacturing process and safety testing.
  • Sernova a Canadian public company, is responsible for conducting the preclinical safety and efficacy studies with the Factor VIII producing cells in its proprietary Cell Pouch™ using a model of hemophilia developed by consortium partner Universita del Piemonte Orientale (Italy) in preparation for clinical trials.
  • The quality management (GMP processes) is being monitored by IMS – Integrierte Management Systeme in Heppenheim, Germany. The company acts as a point of contact for international projects in the pharmaceutical and medical engineering sector.

The overall objective of the HemAcure project is to develop and refine the tools and technologies for a novel, curative ex vivo (outside the body) prepared cell based therapy to treat hemophilia A that should ultimately lead to improved quality of life for patients. The EU’s Horizon 2020 programme has stage funded the HemAcure project with €5.5 million (Cdn$8.06M, US$6.3). The most recent tranche of funding has just been approved based on the encouraging results to date.

The consortium’s idea: A personalized medicine solution using the patients’ own cells (remember each patient has to have individualized therapy) which are genetically modified outside the body to produce the missing clotting factor using precursor cells of endothelial cells flowing in the bloodstream. After modification these cells are transplanted back into the patient’s body in Sernova Corp’s Cell Pouch™.

After Sernova’s Cell Pouch™ is implanted in the body and forms its unique vascularized tissue chambers, the genetically modified cells are then transplanted into the vascularized chambers and are expected to continuously produce the clotting factor and release it into the bloodstream for a long period of time. This should mitigate the disease’s impact noticeably, increase the patients’ quality of life and reduce the overall cost of therapy.

Sernova

Sernova Corp. (TSX-V: SVA) (OTCQB: SEOVF) (FSE: PSH), is a Canadian publically traded, clinical stage, regenerative medicine company developing an implantable, scalable device, the Cell Pouch System™ and therapeutic cells for the treatment of diseases such as diabetes, and hemophilia.

Sernova’s Cell Pouch™ forms a natural vascularized environment for long-term survival and function of the therapeutic cells which release into the bloodstream required but missing proteins or hormones.

Sernova’s Cell Pouch™ technology would be beneficial if it provided a simple reduction in the number of therapeutic injections a patient must take; however, there is the possibility that it could even essentially ‘cure’ the disease through natural release and regulation of the therapeutic proteins or hormones.

“Sernova has developed its proprietary highly innovative Cell Pouch technologies for the placement and long-term survival and function of immune protected therapeutic cells. It has proven to be safe and efficacious in multiple small and large animal preclinical models and has demonstrated safety alone and with therapeutic cells in a clinical trial in humans for another therapeutic indication (diabetes – editor). We believe the Cell Pouch platform is the first such patented technology proven to become incorporated with blood vessel enriched tissue-forming tissue chambers without fibrosis for the placement and long-term survival and function of immune protected therapeutic cells.” Sernova News Release, Marketwire – July 24, 2017

Sernova is today a relatively unknown pure regenerative medicine play that has partnered their Cell Pouch™ with a network of academic cell therapy research and development partners. Below is a HemAcure consortium approved news release issued by Sernova Corp. on Monday July 24, 2017.

It’s your authors opinion ‘relatively unknown’ is a term that will shortly no longer apply to Sernova Corp.

Sernova-HemAcure Consortium Announce Significant Progress in Development of ‘First in World’ Regenerative Medicine Therapy for Treatment of Hemophilia A Patients

Breakthrough scientific progress is made in development of a disruptive personalized regenerative medicine therapy within Sernova’s Cell Pouch(TM) for treatment of Hemophilia A validated by European Commission’s confirmation of next stage of funding of the €5.6Million EU Horizon 2020 Grant Award to the HemAcure Consortium

LONDON, ONTARIO – (Marketwire – July 24, 2017) – Sernova Corp. (TSX-V: SVA) (OTCQB: SEOVF) (FSE: PSH), a clinical stage regenerative medicine company, announced today significant scientific progress achieved in the development of a ‘first in world’ personalized regenerative medicine therapy for the treatment of Hemophilia A patients by the HemAcure Consortium and confirmation of the second phase of funding of the Consortium by the European Commission.

The therapy being developed by international scientific Consortium members consisting of three European academic institutions, an enterprise for quality management and Sernova Corp is to treat severe Hemophilia A, a serious genetic bleeding disorder caused by missing or defective clotting factor VIII in the blood stream. This therapy consists of Sernova’s implanted Cell Pouch(TM) device transplanted with therapeutic cells, corrected to produce Factor VIII at a level sufficient to significantly reduce the side effects of the disease and improve patient quality of life.

“The international HemAcure Consortium team members are pleased with the ground breaking scientific advances achieved at this point and are on track for this regenerative medicine solution to advance into human clinical evaluation,” remarked Dr. Philip Toleikis, Sernova President and CEO.

Toleikis added, “Sernova’s Cell Pouch platform technologies are achieving important world first milestones in both diabetes and now hemophilia, two significant clinical indications which are being disrupted by its regenerative medicine approach aimed at significantly improving patient quality of life.”

“We are thrilled with the approval by the European Union of the next stage of funding for the HemAcure program based on our quality interim report. This is a strong validation of the Consortium’s dedication and teamwork and the importance of this regenerative medicine approach,” said Dr. Joris Braspenning, HemAcure Program Coordinator.

In summary, the following ground-breaking developments have been achieved by the Consortium:

  • A reliable procedure has been implemented to isolate and maintain required endothelial cells from a sample of the patient’s blood.
  • Using a novel gene correction process, the cells have been corrected and tuned to reliably produce the required Factor VIII to treat Hemophilia A.
  • The cells have been successfully scaled up to achieve the required therapeutic number, and cryopreserved for shipping and future transplant into the implanted Cell Pouch.
  • A preliminary study confirmed survival of the Factor VIII corrected human cells injected into the hemophilia model, achieving sustained therapeutic Factor VIII levels. This preliminary work is being used to aid in dosing of these cells in the Cell Pouch.
  • Safe Cell Pouch surgical implant and cell transplant procedures have been developed in the hemophilia A model in preparation for use in hemophilia patients.
  • Development of Cell Pouch vascularized tissue chambers suitable for Factor VIII producing cell transplant has been demonstrated in the hemophilia A model, expected to mimic the predicted findings in human patients.
  • In combination, this work is in preparation for safety and efficacy studies of the human hemophilia corrected Factor VIII producing cells in the Cell Pouch in a preclinical model of hemophilia.

This combination of advances by the HemAcure team represents a ‘first in world’ achievement towards developing a regenerative medicine therapy for the treatment of severe hemophilia A patients.

“In this regard, these fundamental advancements have set the stage for further optimization and implementation of cell production processes under controlled GMP conditions,” stated Martin Zierau, IMS member consortium team leader responsible for coordination of GMP processes.

With Factor VIII corrected cells, studies are ongoing to optimize cell dosing within the Cell Pouch and for study of safety and efficacy of hemophilia corrected Factor VIII cells in the hemophilia model. These studies are in support of the current extensive regulatory package already assembled for the Cell Pouch in anticipation of human clinical evaluation of the Cell Pouch with hemophilia corrected Factor VIII producing cells.

A big deal

Any discussions regarding advancing HemAcure’s plan, and more funding from Horizon 2020, had to be centered around success in these three areas:

  • CELLS ARE PRODUCING FACTOR VIII: The Consortium has successfully developed the process for isolating and maintaining the required cells from a sample of patient’s blood. Using a special technique these cells have been corrected and tuned to produce Factor VIII on a constant basis.
  • CORRECTED CELLS HAVE BEEN SCALED UP: The corrected cells have then been multiplied to demonstrate that the required number of cells can be produced. After testing, batches of corrected cells have been frozen, stored for later transplantation and successfully shipped, thawed and recovered. With further optimization and GMP production, this being the process anticipated to be used for future treatment of patients with hemophilia A.
  • CELLS PRODUCING THERAPEUTIC BLOOD LEVELS OF FACTOR VIII: In further preclinical tests, in a preliminary study, Factor VIII producing cells have been shown to produce therapeutic blood levels of Factor VIII. Studies have already shown that the Cell Pouch can produce vascularized tissue chambers in the hemophilia model and further studies will optimize dosing of hemophilic patient corrected cells that will then be transplanted into the Cell Pouch™ for evaluation of safety and efficacy in the preclinical model of hemophilia.

Conclusion

Being that all the companies in the HemAcure consortium are private, except SVA, and that they plan on ‘bringing breakthroughs, discoveries and world firsts from the lab to the market’ might not Sernova be a great way to leverage this in your portfolio?

And SVA is no one trick pony, the company is a leader in the regenerative space with their Cell Pouch™ and upon FDA clearance plan to initiate clinical trials in the United States for diabetes – expected to start patient enrollment this fall.

Add in developing local immune protection technology within the Cell Pouch™ and the company’s very own glucose responsive stem cell technology, you can see why your author thinks Sernova Corp might just be the best regenerative medicine pure play out there.

All of these reasons are why Sernova Corp. is on my radar screen. Is SVA on yours?

If not, maybe it should be.

Richard (Rick) Mills

aheadoftheherd.com

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New Therapeutic Approach for Difficult-to-Treat Subtype of Ovarian Cancer Identified

Scientists from The Wistar Institute demonstrate how a mutation in ovarian clear cell carcinoma can be exploited to design a targeted treatment.

A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Ovarian clear cell carcinoma accounts for approximately 5 to 10 percent of American ovarian cancer cases and about 20 percent of cases in Asia, ranking second as the cause of death from ovarian cancer. People with the clear cell subtype typically do not respond well to platinum-based chemotherapy, leaving limited therapeutic options for these patients.

Previous studies, including those conducted at The Wistar Institute, have revealed the role of ARID1A, a chromatin remodeling protein, in this ovarian cancer subtype. When functioning normally, ARID1A regulates expression of certain genes by altering the structure of chromatin – the complex of DNA and proteins in which DNA is packaged in our cells. This process dictates some of our cells’ behaviors and prevents them from becoming cancerous.

“Conventional chemotherapy treatments have proven an ineffective means of treating this group of ovarian cancer patients, meaning that alternative strategies based on a person’s genetic makeup must be explored,” said Rugang Zhang, Ph.D., professor and co-program leader in Wistar’s Gene Expression and Regulation Program and corresponding author of the study. “Therapeutic approaches based on the ARID1A mutation have the potential to revolutionize the way we treat these patients.”

Recent studies have shown that ARID1A is mutated in more than 50 percent of cases of ovarian clear cell carcinoma. Mutations of ARID1A and the tumor suppressor gene TP53 are mutually exclusive, meaning that patients with a mutation of ARID1A do not also carry a mutation of TP53. Despite this, the function of TP53, which protects the integrity of our genome and promotes programmed cell death, is clearly impaired as patients with the disease still have a poor prognosis.

In this study, Zhang and colleagues studied the connection between ARID1A and histone deacetylases (HDACs), a group of enzymes involved in key biological functions. They found that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. They were able to show that HDAC6 is typically inhibited by ARID1A, whereas in the presence of mutated ARID1A, HDAC6 levels increase. Because HDAC6 suppresses the activity of TP53, therefore inhibiting its tumor suppressive functions, higher level of HDAC6 allow the tumor to grow and spread.

Using a small molecule drug called rocilinostat that selectively inhibits HDAC6, the Zhang lab found that by blocking the activity of the enzyme in ARID1A-mutated cancers, they were able to increase apoptosis, or programmed cell death, in only those tumor cells containing the ARID1A mutation. This correlated with a significant reduction in tumor growth, suppression of peritoneal dissemination and extension of survival of animal models carrying ARID1A-mutated ovarian tumors.

“We demonstrated that targeting HDAC6 activity using a selective inhibitor like rocilinostat represents a possible therapeutic strategy for treating ovarian clear cell carcinoma and other tumors impacted by mutated ARID1A,” said Shuai Wu, Ph.D., a postdoctoral fellow in the Zhang lab and co-first author of the study. “Inhibitors like the one we used in this study have been well-tolerated in clinical trials, so our findings may have far-reaching applications.”