UTHealth’s Lenard Lichtenberger Tests Effectiveness of Lipidic Aspirin Formulation Against Cancer

Scientists at The University of Texas Health Science Center at Houston (UTHealth) are testing the effectiveness of a soy-enriched aspirin formulation designed to fight colorectal cancer with fewer side effects.

Lenard Lichtenberger, Ph.D., professor of integrative biology and pharmacology at McGovern Medical School at UTHealth, is the principal investigator for the preclinical study funded with a $1.9 million grant from the National Cancer Institute (NCI). The grant was awarded to PLx Pharma Inc., the specialty pharmaceutical company developing this new form of aspirin.

While aspirin reduces the risk of colorectal cancer, daily use can cause ulcers and stomach bleeding. Colorectal cancer is a leading cause of cancer death in the United States claiming more than 50,000 lives in 2013, according to the Centers for Disease Control and Prevention.

First synthesized more than a century ago and hailed as a wonder drug, aspirin has been long known to reduce a person’s likelihood of heart disease and stroke. But, the research into its cancer protection benefits is relatively new.

For example, a popular medical search engine (PubMed) has less than 100 entries for the words aspirin and cancer between 1971 and 1974 compared to more than 4,000 since 2011.

The research into the chemopreventive action of aspirin is so conclusive that the U.S. Preventive Services Task Force recommends that people between the ages of 50 and 69 take low-dose aspirin on a daily basis to prevent colorectal  cancer so long as they consult with their physician first.

Custom built molecule shows promise as anti-cancer therapy

Scientists at the University of Bath funded by Cancer Research UK have custom-built a molecule which stops breast cancer cells from multiplying in laboratory trials, and hope it will eventually lead to a treatment for the disease.

But perhaps even more importantly the method they used to create the molecule has potential to be applied to develop new treatments for a wide range of cancers and other diseases.

The team, from the Department of Biology & Biochemistry, working with colleagues at the University of Queensland in Australia and the University of Bristol, modified a protein which can interfere with cell multiplication in many cancers, including breast cancer, by binding with another protein and rendering it inactive.

They took a small piece of the protein, called a peptide, that is known to be important in binding, and modified it to retain the structure otherwise lost when cut out. The modification has the additional advantage of protecting the peptide from being broken down within cells. The resulting molecule still binds to its target protein and inhibits cancer cell multiplication, but crucially can travel across cell membranes to get at it. The full-sized proteins, which the peptides are taken from, are usually too large to protect from breakdown or to cross protective cell membranes so this removes a literal barrier to developing treatments.

The study is published in the journal ACS Chemical Biology

Dr Jody Mason, one of the lead researchers on the project, said: “Peptides have the potential to be incredibly potent drugs which are exquisitely specific for their target. However they are easily broken down in the body, much like when we eat a steak. We have modified the peptides so that they retain the structure they have within the full-size protein and can therefore bind to the target “

Professor David Fairlie, from the University of Queensland added “This is a particularly challenging cancer target involving intertwined proteins and large surfaces that must be blocked. International collaborations like this one have the potential to combine resources and scientific skills from multiple disciplines to conquer difficult problems in targeting human disease.”

Dr Justine Alford, Cancer Research UK’s senior science information officer, said: “This early study may have laid the groundwork for a potential new treatment for certain cancers by creating a sophisticated designer molecule that can effectively block a cancer-fuelling target in cells.

“Cancer survival is improving, but people still die from their disease, so we need to develop innovative ways such as this that could help more people survive in the future.” The team now intend to continue to work on the molecule to improve its stability, with a long-term view to it eventually becoming a cancer drug, although this is still years away.

They are also interested in finding other candidate peptides for similar trials.

The researchers believe that other small peptides are a promising avenue of research to create new treatments for different types of cancer, and potentially other diseases such as Alzheimer’s disease

Alzheimer’s disease study links brain health and physical activity

People at risk for Alzheimer’s disease who do more moderate-intensity physical activity, but not light-intensity physical activity, are more likely to have healthy patterns of glucose metabolism in their brain, according to a new UW-Madison study.

Results of the research were published today online in Journal of Alzheimer’s Disease. Senior author Dr. Ozioma Okonkwo, assistant professor of medicine, is a researcher at the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Alzheimer’s Institute at the UW School of Medicine and Public Health. First author Ryan Dougherty is a graduate student studying under the direction of Dr. Dane B. Cook, professor of kinesiology and a co-author of the study, and Dr. Okonkwo. The research involved 93 members of the Wisconsin Registry for Alzheimer’s Prevention (WRAP), which with more than 1,500 registrants is the largest parental history Alzheimer’s risk study group in the world.

Researchers used accelerometers to measure the daily physical activity of participants, all of whom are in late middle-age and at high genetic risk for Alzheimer’s disease, but presently show no cognitive impairment. Activity levels were measured for one week, quantified, and analyzed. This approach allowed scientists to determine the amount of time each subject spent engaged in light, moderate, and vigorous levels of physical activity. Light physical activity is equivalent to walking slowly, while moderate is equivalent to a brisk walk and vigorous a strenuous run. Data on the intensities of physical activity were then statistically analyzed to determine how they corresponded with glucose metabolism–a measure of neuronal health and activity–in areas of the brain known to have depressed glucose metabolism in people with Alzheimer’s disease. To measure brain glucose metabolism, researchers used a specialized imaging technique called 18F-fluorodeoxyglucose positron emission tomography (FDG-PET).

Moderate physical activity was associated with healthier (greater levels of) glucose metabolism in all brain regions analyzed. Researchers noted a step-wise benefit: subjects who spent at least 68 minutes per day engaged in moderate physical activity showed better glucose metabolism profiles than those who spent less time.

“This study has implications for guiding exercise ‘prescriptions’ that could help protect the brain from Alzheimer’s disease,” said Dougherty. “While many people become discouraged about Alzheimer’s disease because they feel there’s little they can do to protect against it, these results suggest that engaging in moderate physical activity may slow down the progression of the disease.”

New inhibitor drug shows promise in relapsed leukemia

A new drug shows promise in its ability to target one of the most common and sinister mutations of acute myeloid leukemia (AML), according to researchers at the Perelman School of Medicine at the University of Pennsylvania and Penn’s Abramson Cancer Center. The Fms-like tyrosine kinase 3 (FLT3) gene mutation is a known predictor of AML relapse and is associated with short survival. In a first-in-human study, researchers treated relapsed patients with gilteritinib, an FLT3 inhibitor, and found it was a well-tolerated drug that led to frequent and more-sustained-than-expected clinical responses, almost exclusively in patients with this mutation. They published their findings today in The Lancet Oncology.

FLT3 is one of the most commonly mutated genes in AML patients. FLT3 mutations are found in about 30 percent of patients’ leukemia cells. Clinically, these mutations are associated with aggressive disease that often leads to rapid relapse, after which the overall survival is an average of about four months with current therapies. To avoid relapse, oncologists often recommend the most aggressive chemotherapy approaches for patients with FLT3 internal tandem duplication (FLT3-ITD), including marrow transplantation. But even that cannot always stave off the disease.

The FLT3 gene is present in normal bone marrow cells and regulates the orderly growth of blood cells in response to daily demands. When the gene is mutated in a leukemia cell, however, the mutated cells grow in an uncontrolled manner unless the function of FLT3 is turned off.

“Other drugs have tried to target these mutations, and while the approach works very well in the laboratory, it has proven very challenging to develop FLT3 inhibitors in the clinic for several reasons,” said Alexander Perl, MD, MS, an assistant professor of Hematology Oncology in Penn’s Abramson Cancer Center and the study’s lead author. “First, we’ve learned it takes unusually potent inhibition of the FLT3 target to generate clinical responses. Second, many of these drugs are not selective in their activity against FLT3. When they target multiple kinases, it can lead to more side-effects. That limits whether you can treat a patient with enough drug to inhibit FLT3 at all. Finally, with some FLT3 inhibitors, the leukemia adapts quickly after response and cells can develop new mutations in FLT3 that don’t respond to the drugs at all. So ideally, you want a very potent, very selective, and very smartly designed drug. That’s hard to do.”

For this phase 1/2 clinical trial, Perl and his team evaluated the drug gilteritinib – also known as ASP2215 – at increasing doses in patients whose AML had relapsed or was no longer responding to chemotherapy. The team focused on dose levels at 80mg and above, which were associated with more potent inhibition of the FLT3 mutation and higher response rates. They found these doses were also associated with longer survival. Of the 252 patients on this study, 67 were on a 120mg dose and 100 were on a 200mg dose. Seventy-six percent (191) of the patients on the trial had a FLT3 mutation. Overall, 49 percent of patients with FLT3 mutations showed a response. Just 12 percent of patients who didn’t have the mutation responded to the drug.

“The fact that the response rate tracked with the degree of FLT3 inhibition and was so much lower among patients who did not have an FLT3 mutation gives us confidence that this drug is hitting its target,” Perl said.

In leukemia cells, FLT3 itself can mutate again to a form called a D835 mutation that is resistant to several FLT3 inhibitors treatments. Gilteritinib, however, remains active against D835 mutations in laboratory models of leukemia. Clinical response rates from the trial appeared to be the same, whether patients had a FLT3-ITD alone or both a FLT3-ITD and a D835 mutation. The response rates also were similar in patients in whom gilteritinib was their first FLT3 inhibitor and those who previously were treated with other FLT3 inhibitors.

The drug was also generally well-tolerated. The three most common side effects attributed to the drug were diarrhea in 41 patients (16 percent), fatigue in 37 (15 percent), and abnormal liver enzyme tests in 33 (13 percent). These generally were mild in severity and discontinuation of gilteritinib for side effects was uncommon (25 patients, 10 percent).

“These look like data you want to see for a drug to eventually become a standard therapy,” Perl said, though he noted more research will be necessary.

A new multicenter trial, which compares gilteritinib to standard chemotherapy in patients with FLT3 mutations who relapsed or did not respond to initial therapy, is now underway, and Penn’s Abramson Cancer Center is one of the sites.

There are also studies underway that give the drug in combination with frontline chemotherapy and as an adjunct to bone marrow transplantation in hopes of preventing relapse altogether.

A patent study on the great new hope emerging from marine derived anticancer drugs

Microtubule dynamics govern crucial cellular functions and this is why microtubules are one of the most attractive anticancer drug targets. Microtubule targeting agents (MTAs) have the ability to treat a wide range of cancers. However, drug induced cytotoxicity and adverse side effects have hindered their development. Another major setback is multiple drug resistance in tumor cells. These limitations have prompted the need to develop novel MTAs from alternative sources, with better therapeutic efficacies. Recently, MTAs from marine sources have grabbed much attention due to their unique tubulin binding features and remarkable ability to reduce tumor progression.

The authors have summarized some of the most promising marine derived MTAs by systematically searching patent databases such as USPTO, Espacenet and WIPO for recent patents published from 2006 up to 2016. After a critical data analysis, only those patents focusing on the chemical synthesis and/or modifications of marine derived MTAs along with a significant demonstration of their in vitro and/or in vivo activity have been reviewed.

The survey of recent patents revealed that chemically modified versions of marine derived MTAs, overcoming drug resistance and their novel combination therapies increasing the overall efficacy, have positioned them as future anticancer blockbusters. Of particular interest are dolastatin, laulimalide, peloruside, hemiasterlin, halichondrin, eribulin mesylate, discodermolide, dictyostatin, cryptophycin and their analogs which have significant antiproliferative potency against a wide array of cancers and are also able to overcome multidrug resistance. A deeper understanding of the molecular mechanisms behind the specific drug interactions and of microtubule molecular biology in general, combined with innovative therapeutic regimen would lead to major advances in the field of cancer therapy.

Penn study details impact of antibiotics, antiseptics on skin microbiomes

The use of topical antibiotics can dramatically alter communities of bacteria that live on the skin, while the use of antiseptics has a much smaller, less durable impact. The study, conducted in mice in the laboratory of Elizabeth Grice, PhD, an assistant professor of Dermatology in the Perelman School of Medicine at the University of Pennsylvania, is the first to show the long-term effects of antimicrobial drugs on the skin microbiome. Researchers published their findings today in the journal Antimicrobial Agents and Chemotherapy.

The skin, much like the gut, is colonized by a diverse multitude of microorganisms which generally coexist as a stable ecosystem — many of which are harmless or even beneficial to the host. However, when that ecosystem is disturbed or destabilized, colonization and/or infection by more dangerous microbes can occur. Antiseptics, such as ethanol or iodine, are commonly used to disinfect the skin prior to surgical procedures or following exposure to contaminated surfaces or objects. Topical antibiotics may be used to decolonize skin of specific types of bacteria or for rashes, wounds, or other common conditions.

In the gut, research shows medication that alters microbial communities can lead to complications like Clostridium difficile, or C. diff — which causes diarrhea and is the most common hospital-acquired infection. But when it comes to the skin, the impact of these medications on bacteria strains like Staphylococcus aureus, or S. aureus — the most common cause of skin infections — is still largely unstudied.

“We know antibiotics and antiseptics can be effective in stopping the growth of certain bacteria, but we wanted to know about the larger impact these treatments can have on the resident microbial communities on the skin,” said the study’s lead author, Adam J. SanMiguel, PhD, a researcher in the Grice Laboratory at Penn.

Researchers treated the skin of hairless mice with a variety of antibiotics, including a narrowly targeted mupirocin ointment and a broadly applicable triple-antibiotic ointment (TAO) containing bacitracin, neomycin, and polymyxin B. All of the antibiotics changed the makeup of the microbial communities, and, in a key finding of the study, the impact of that change lasted for days after treatment stopped.

“The problem in this case isn’t antibiotic resistance, but instead, how long the disruption of the skin microbiomes continues,” SanMiguel said. “That disruption opens the door for colonization by an unwanted strain.”

The researchers similarly evaluated antiseptics, using alcohol or povidone-iodine and comparing those treatments with two control groups – mice treated with water and mice entirely untreated. They found neither antiseptic caused responses similar enough to cluster the mice together into groups based on their microbiomes. They also found no clear difference between the treatment groups and the control groups when comparing the relative number of individual bacteria strains.

“We thought antiseptics would be even more disruptive to microbial communities than antibiotics since they are less targeted, but it turns out the opposite is true,” SanMiguel said. “It shows how stable the skin microbiome can be in the face of stress.”

However, both antibiotic and antiseptic treatments removed skin resident bacteria that compete against the pathogenic S. aureus to colonize the skin. Colonization with S. aureus is a risk factor for developing a skin infection.

“This gives us a better understanding of how topical antimicrobials affect the skin microbiome and what kind of impact their disturbance can have in the context of pathogenic colonization,” said Grice, the study’s senior author. “This helps us anticipate their potential effects.”

The researchers say this work can provide the foundation for greater understanding of how the skin defends against infection. They have already begun similar testing in humans.

Genetic modifier for Huntington’s disease progression identified

A team led by UCL and Cardiff University researchers has developed a novel measure of disease progression for Huntington’s disease, which enabled them to identify a genetic modifier associated with how rapidly the disease progresses.

“We’ve identified a gene that could be a target for treating Huntington’s disease. While there’s currently no cure for the disease, we’re hopeful that our finding could be a step towards life-extending treatments,” said Dr Davina Hensman Moss (UCL Huntington’s Disease Centre, UCL Institute of Neurology), one of the lead authors of the Lancet Neurology study.

Huntington’s disease (HD) is a fatal neurological disease caused by a genetic mutation. Larger mutations are linked to rapidly progressing disease, but that does not account for all aspects of disease progression. Understanding factors which change the rate of disease progression can help direct drug development and therapies.

The research team used the high quality phenotypic data from the intensively studied TRACK-HD cohort of people with the HD gene mutation. They established that different symptoms of disease progress in parallel, so they were able to combine the data from 24 cognitive, motor and MRI brain imaging variables to generate their progression score for genetic analysis.

They then looked for areas of the genome associated with their progression measure, and found a significant result in their sample of 216 people, which they then validated in a larger sample of 1773 people from a separate cohort, the European Huntington’s Disease Network (EHDN) REGISTRY study.

The genetic signal is likely to be driven by the gene MSH3, a DNA repair gene which has been linked to changes in size of the HD mutation. The researchers identified that a variation in MSH3 encodes an amino acid change in the gene. MSH3 has previously been extensively implicated in the pathogenesis of HD in both mouse and cell studies. The group’s findings may also be relevant to other diseases caused by repeats in the DNA, including some spinocerebellar ataxias.

Dr Hensman Moss said: “The gene variant we pinpointed is a common variant that doesn’t cause problems in people without HD, so hopefully it could be targeted for HD treatments without causing other problems.”

Professor Lesley Jones (Cardiff University), who co-led the study, said: “The strength of our finding implies that the variant we identified has a very large effect on HD, or that the new progression measure we developed is a much better measure of the relevant aspects of the disease, or most likely, both.”

The researchers say their study demonstrates the value of getting high quality data about the people with a disease when doing genetic studies.

Professor Sarah Tabrizi (UCL Huntington’s Disease Centre), who co-led the study said: “This is an example of reverse translation: these novel findings we observed in people with HD support many years of basic laboratory work in cells and mice. Now we know that MSH3 is critical in the progression of HD in patients, we can focus our attention on it and how this finding may be harnessed to develop new therapies that slow disease progression.”

Study Shows How an Opportunistic Microbe Kills Cancer Cells and Identifies Specialized Vesicles Responsible for Cell Reproduction

New study results show for the first time how dying cells ensure that they will be replaced, and suggests an ingenious, related new approach to shrinking cancerous tumors. A research team from Rush University Medical Center will publish a new paper this week in the journal Developmental Cell that describes two groundbreaking discoveries.

“I believe this discovery is going to have important ramifications on cancer biology and cancer drug development, and on the treatment of other diseases such as diabetic foot ulcers,” says Sasha Shafikhani, PhD, associate professor of Hematology, Oncology and Cell Therapy at Rush Medical College, who headed up the study.

The team made its two-pronged discovery while investigating how an opportunistic microbe kills cancer cells. For years, Shafikhani’s lab has been studying Pseudomonas aeruginosa, a bacterium that can be lethal, but only to people who are already wounded or sick. This pathogenic bacterium secretes several toxins that allow it to cause infection. One such toxins, ExoT, inhibits cell division and can severely impede wound healing, but it’s also known to kill cancer cells.

The researchers were trying to figure out ExoT’s lethal mechanisms against cancer when they unlocked, almost by accident, a mystery researchers have been trying to solve for years, Shafikhani says. For at least 20 years, medical researchers have wondered how cells, before they die in the normal process of apoptosis, manage to alert their neighbors of the need to replace them and compensate for their demise, so to ensure the organism’s survival. While shining a light on the lethal habits of Pseudomonas aeruginosa, Shafikhani’s team discovered what actually happens in that “compensatory proliferation signaling” (CPS) process.

For the first time, the investigators saw — and have shown in amazing videos they produced — that during CPS, dying cells release “microvesicles” containing the CrkI protein, which travel to neighboring cells and cause them, upon contact, to create new cells to replace the ones that are dying.

Apoptosis is part of life. “In the course of normal tissue turnover in humans, about one million cells die every second, through a highly-regulated process of apoptotic programmed cell death (PCD),” the new paper states. Apoptosis is not the only type of cell death, and not all cells dying of apoptosis are capable of CPS.

Not only that, but Shafikhani and his colleagues have demonstrated that if they knocked out the CrkI protein during CPS, either genetically or with the ExoT toxin, they could stop cell compensatory proliferation cold. That’s a trick P. aeruginosa uses to take advantage of damaged tissues, but it has exciting possibilities for disease treatment as well.

Apoptosis is of particular interest to cancer researchers because majority of the current cancer drugs kill cancer cells by apoptosis.

However, CPS can dog apoptosis in cancer treatment. Yes, treated cancer cells can be induced to die, but before they do, they call on nearby cancer cells to replace them, so the drug loses its effectiveness and the tumor persists. But if the communication between the dying cancer cells and neighboring cancer cells is blocked, Shafikhani says, the hope is that the treated cancer cells would not be replaced when they die, and hopefully the tumor would disappear.

“If it’s possible to uncouple CPS from apoptosis, we can develop new drugs that would improve the effectiveness of treatments already in use,” Shafikhani says.

In cancer cells, the CPS process and communication would need to be interrupted to prevent the development of new cancer cells; but in other conditions, the CPS process could be enhanced to accelerate the healing process. One of the possible long-term benefits of the discoveries set out in the new Developmental Cell article could be to use of these vesicles to encourage cell proliferation — in diabetic wounds where healing is not going well because tissue cells are dysfunctional and have reduced ability to regenerate, for example, Shafikhani says.

All the researchers on the new study were from Rush University Medical Center.

Risk of infection higher for patients with obesity after bypass surgery: University of Alberta research

Patients with obesity have a higher risk of infection within 30 days after receiving heart bypass surgery, according to a series of studies conducted by University of Alberta researchers at the Faculty of Rehabilitation Medicine.

The team analyzed data from 56,722 patients in the provincial registry to examine associations between body mass index (BMI) and various outcomes following coronary artery bypass grafting (CABG) surgery and percutaneous coronary intervention (PCI), also known as coronary angioplasty.

“Compared to patients with normal BMI, we found that patients with BMI greater than 30 were 1.9 times more likely to report infections after bypass surgery,” said Tasuku Terada, a rehabilitation science postdoctoral research fellow who recently presented the series of studies at the Canadian Obesity Summit. “A better understanding is needed in order to improve clinical outcomes for patients with obesity and heart disease.”

In addition, another study in the series published in the Canadian Journal of Cardiology found that 88 per cent of patients who received PCI were classified as obese, compared to 55 per cent of the patients who received CABG. PCI is a non-surgical procedure that opens up narrowed arteries in the heart due to plaque buildup. The physician places a small stent to keep the artery open and help to prevent re-narrowing.

Terada says the risk of infection following CABG may explain why patients with obesity are more likely to receive PCI.

“We need to look at why there is more infection following CABG and whether more patients with obesity are receiving PCI because they should be, or because the risk is a factor in the decision made by health-care professionals,” he says.

Postsurgical infection means an increase in the length of stay at the hospital for patients, resulting in increased medical costs and use of resources. Knowing the risks and potential outcomes can help health-care providers and patients make more informed choices on treatment and better use of resources.

Mary Forhan, obesity expert and assistant professor in occupational therapy at the Faculty of Rehabilitation Medicine, believes that further investigation will help researchers develop tools to help decrease the risk of infection, and to ensure that patients are receiving proper care.

“For example, are the chest binders that are used after surgery the right size and are they working the right way?” she says. “Our team is currently looking at the re-design of postsurgical chest binders so that patients have better outcomes following bypass surgery.”

Tumor immune fitness determines survival of lung cancer patients

In recent years, immunotherapy, a new form of cancer therapy that rouses the immune system to attack tumor cells, has captivated the public’s imagination. When it works, the results are breathtaking. But more often than not it doesn’t, and scientists still don’t know why.

Publishing in the June 19, 2017, issue of Nature Immunology, researchers at La Jolla Institute for Allergy and Immunology, identify a subpopulation of T cells in tumors known as tissue-resident memory T cells (TRM) as an important distinguishing factor between cancer patients whose immune system mounts an effective anti-tumor response and those who are unable to do so. Their finding emerged from the first large-scale effort to profile the gene expression patterns of cytotoxic T cells isolated directly from patients’ tumors.

“Systematically studying cancer patients’ immune cells reveals a lot of information,” says LJI Associate Professor and William K. Bowes Jr. Distinguished Professor Pandurangan Vijayanand, M.D., Ph.D., who co-directed the study with Professor Christian Ottensmeier at the University of Southampton, England. “It could be a baseline test to predict whether a patient will respond to immunotherapy and guide the choice of immunotherapy that is most likely to be effective. It is almost like judging tumor immune fitness,” adds Vijayanand. The systematic profiling of tumor-infiltrating T cells will also provide new insight into their basic biology revealing new potential immunotherapy drug targets.

Scientists initially found that when T cells were swarming a patient’s tumor that patient lived longer. Over time, however, they found that T-cells lose their fervor and cancer cells gain the upper hand. In the last decade they discovered why: Inhibitory molecular signals emitted from a tumor or its environment undercut the immune response, making tumor cells invisible to the immune system. One class of cancer immunotherapy drugs, known as checkpoint blockade inhibitors, disables either PD-1 or CTLA-4, two known molecules that allow cancer cells to live and multiply undetected by the immune system.

“The challenge with immunotherapy based on PD-1 and CTLA-4 is that if they work, they work miraculously, but they only work in about 30 percent of patients,” says the study’s first author, Anusha-Preethi Ganesan, M.D., Ph.D., a physician in the Division of Pediatric Hematology and Oncology at Rady’s Children’s Hospital, UC San Diego. “If we are doing all these immunotherapies based on activating T cells to kill tumor cells it is really important to know what the transcriptional profiles of these T cells are, what molecules do they make?”

To uncover the underlying reasons why some patients see little or no benefit and to identify those patients most likely to respond, Ganesan utilized advanced genomics tools to define the molecular features of a robust anti-tumor immune response using freshly resected tumors from patients with cancer. Comparing gene expression profiles of cytotoxic T cells (CTLs) isolated from 41 head and neck tumors and 36 untreated, early stage lung tumors with CTLs isolated from adjacent normal lung tissue, Ganesan identified a shared molecular fingerprint between different tumor types suggesting extensive reprogramming of CTLs infiltrating tumor tissue.

Beyond their shared molecular signature, tumor-infiltrating CTLs differed widely in their expression of molecules associated with T cell activation and known immune checkpoints. “There is a huge deal of heterogeneity, which has a lot of implications for immunotherapy,” says Ganesan. “We see the traditional immunotherapy targets but they are not expressed in every single patient, which means not every patient is a candidate for currently available immunotherapies targeted at PD-1 or CTL4-1. That’s why having the full transcriptional profile is so important to understand the entire complexity of the immune network and to identify novel targets.”

Interestingly, gene expression patterns that signal the presence of tissue resident memory T cells (TRM) corresponded with better anti-tumor activity. The only recently identified tissue resident memory T cells act as local first responders that provide rapid onsite immune protection. A large scale analysis in an independent cohort of 689 lung cancer patients confirmed that patients with a high density of TRM cells in tumor tissue survived significantly longer, demonstrating that these cells serve a critical role in protecting against tumor recurrence.

“Any time you remove a tumor, the patient is a ticking time bomb after that. In some people it will come back and it others it won’t,” says Vijayanand. “Our study suggests that the presence of these tissue resident memory cells is an important factor in determining whether somebody is having an effective immune response against cancer and whether they will live longer.”

Pre-Clinical Study Suggests Parkinson’s Could Start in Gut Endocrine Cells

Recent research on Parkinson’s disease has focused on the gut-brain connection, examining patients’ gut bacteria, and even how severing the vagus nerve connecting the stomach and brain might protect some people from the debilitating disease.

But scientists understand little about what’s happening in the gut — the ingestion of environmental toxins or germs, perhaps — that leads to brain damage and the hallmarks of Parkinson’s such as tremors, stiffness and trouble walking.

Duke University researchers have identified a potential new mechanism in both mice and human endocrine cells that populate the small intestines. Inside these cells is a protein called alpha-synuclein, which is known to go awry and lead to damaging clumps in the brains of Parkinson’s patients, as well as those with Alzheimer’s disease.

According to findings published June 15 in the journal JCI Insight, Duke researchers and collaborators from the University of California, San Francisco, hypothesize that an agent in the gut might interfere with alpha-synuclein in gut endocrine cells, deforming the protein. The deformed or misfolded protein might then spread via the nervous system to the brain as a prion, or infectious protein, in similar fashion to mad cow disease.

“There is abundant evidence that misfolded alpha-synuclein is found in the nerves of the gut before it appears in the brain, but exactly where this misfolding occurs is unknown,” said gastroenterologist Rodger Liddle, M.D., senior author of the paper and professor of medicine at Duke. “This is another piece of evidence that supports the hypothesis that Parkinson’s arises in the gut.”

Alpha-synuclein is the subject of much ongoing research on Parkinson’s, as it’s the main component of Lewy bodies, or toxic protein deposits that take up residence in brain cells, killing them from the inside. The clumps form when alpha-synuclein develops a kink in its normally spiral structure, making it ‘sticky,’ and prone to aggregating, Liddle said.

But how would a protein go from traveling through the inner-most ‘tube’ of the intestine, where there are no nerve cells, into the nervous system? That’s a question Liddle and colleagues sought to answer in a 2015 manuscript published in the Journal of Clinical Investigation. Although the main function of gut endocrine cells is to regulate digestion, the Duke researchers found these cells also have nerve-like properties.

Rather than using hormones to communicate indirectly with the nervous system, these gut endocrine cells physically connect to nerves, providing a pathway to communicate with the brain, Liddle said. The researchers demonstrated this in a stunning time-lapse video (2015, Journal of Clinical Investigation) in which a gut endocrine cell is placed under the microscope near a neuron. In just a few hours, the endocrine cell moves toward the neuron and fibers appear between them as they establish communication.

Liddle and other scientists were astonished at the video, he said, because the endocrine cells — which are not nerves — were behaving like them. This suggests they are able to communicate directly with the nervous system and brain.

With the new finding of alpha-synuclein in endocrine cells, Liddle and colleagues now have a working explanation of how malformed proteins can spread from the inside of the intestines to the nervous system, using a non-nerve cell that acts like a nerve.

Liddle and colleagues plan to gather and examine the gut endocrine cells from people with Parkinson’s to see if they contain misfolded or otherwise abnormal alpha-synuclein. New clues about this protein could help scientists develop a biomarker that could diagnose Parkinson’s disease earlier, Liddle said.

New leads on alpha-synuclein could also aid the development of therapies targeting the protein. Scientists have been investigating treatments that could prevent alpha-synuclein from becoming malformed, but much of the research is still in its early stages, Liddle said.

“Unfortunately, there aren’t great treatments for Parkinson’s disease right now,” he said. “It’s conceivable down the road that there could be ways to prevent alpha-synuclein misfolding, if you can make the diagnosis early.”

In addition to Liddle, study authors include Rashmi Chandra of Duke, Annie Hiniker and Yien-Ming Kuo of the University of California, San Francisco (UCSF), and Robert L. Nussbaum of UCSF and the Invitae Corporation.

Inhibitor drug improves overall survival in older radioiodine resistant thyroid cancer

The drug lenvatinib can significantly improve overall survival rates in a group of thyroid cancer patients whose disease is resistant to standard radioiodine treatment, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The study, published today in the Journal of Clinical Oncology, is the first to show lenvatinib has a definitive impact on overall survival (OS). Researchers found OS improves in patients older than 65 years of age and that the drug is well-tolerated.

“Due to limitations of study design, it has been hard to prove that multikinase inhibitors improve overall survival, although we have suspected it,” said the study’s lead author Marcia Brose, MD, PhD, an associate professor of Otorhinolaryngology and a member of Penn’s Abramson Cancer Center. “These findings put that doubt to rest for the group of patients over 65 treated with lenvatinib.”

Most cases of differentiated thyroid cancer (DTC) are treated with radioiodine therapy. Since the thyroid absorbs nearly all of the iodine in the human body, radioactive iodine given to a patient will concentrate in thyroid cancer cells, killing them with little effect on the rest of the body. The treatment can be curative, but about 15 percent of DTC patients have cancers that are resistant to the therapy.

Levatinib is one of two first-line therapies approved by the U.S. Food and Drug Administration for patients who are resistant to radioiodine treatment. The drug is a multi- kinase inhibitor (MKI) — meaning it targets the specific enzymes that are required for growth in DTC.

“It was approved based on previous trials that showed it had a benefit for progression-free survival, but until now, nobody has shown it also has a benefit for overall survival,” Brose said.

Brose and her team participated in the SELECT trial to study the effects of levatinib on DTC, and Brose directed the further analysis published in this report which specifically looked at OS and safety of lenvatinib in younger and older patients. Patients were divided into two groups: Those 65 or younger, and those older than 65. The median age of the younger group was 56. For the older group, it was 71. Each group contained patients on the drug and patients receiving a placebo.

Researchers found significant differences in overall survival between those on the drug and those on the placebo in the older age group. Among the older cohort, those on the placebo had an OS of 18.4 months. For patients receiving the drug, OS was not reached, but confidence intervals show the expected survival would exceed 22 months. In the younger cohort, overall survival was not reached for either group.

“There’s a belief that these drugs should be withheld from older patients due to concerns about toxicity and other medical concerns, but our results show just the opposite,” Brose said. “Not only do older patients benefit from these drugs, but they generally tolerate them well.”

Brose says the results of this study can have an immediate impact in clinical care, and several other studies are ongoing to find new uses for lenvatinib in other types of thyroid cancer.

Cardiac stem cells from heart disease patients may be harmful

Patients with severe and end-stage heart failure have few treatment options available to them apart from transplants and “miraculous” stem cell therapy. But a new Tel Aviv University study finds that stem cell therapy may, in fact, harm heart disease patients.

The research, led by Prof. Jonathan Leor of TAU’s Sackler Faculty of Medicine and Sheba Medical Center and conducted by TAU’s Dr. Nili Naftali-Shani, explores the current practice of using cells from the host patient to repair tissue — and contends that this can prove deleterious or toxic for patients. The study was recently published in the journal Circulation.

“We found that, contrary to popular belief, tissue stem cells derived from sick hearts do not contribute to heart healing after injury,” said Prof. Leor. “Furthermore, we found that these cells are affected by the inflammatory environment and develop inflammatory properties. The affected stem cells may even exacerbate damage to the already diseased heart muscle.”

Tissue or adult stem cells — “blank” cells that can act as a repair kit for the body by replacing damaged tissue — encourage the regeneration of blood vessel cells and new heart muscle tissue. Faced with a worse survival rate than many cancers, many heart failure patients have turned to stem cell therapy as a last resort.

“But our findings suggest that stem cells, like any drug, can have adverse effects,” said Prof. Leor. “We concluded that stem cells used in cardiac therapy should be drawn from healthy donors or be better genetically engineered for the patient.”

Hope for improved cardiac stem cell therapy

In addition, the researchers also discovered the molecular pathway involved in the negative interaction between stem cells and the immune system as they isolated stem cells in mouse models of heart disease. After exploring the molecular pathway in mice, the researchers focused on cardiac stem cells in patients with heart disease.

The results could help improve the use of autologous stem cells — those drawn from the patients themselves — in cardiac therapy, Prof. Leor said.

“We showed that the deletion of the gene responsible for this pathway can restore the original therapeutic function of the cells,” said Prof. Leor. “Our findings determine the potential negative effects of inflammation on stem cell function as they’re currently used. The use of autologous stem cells from patients with heart disease should be modified. Only stem cells from healthy donors or genetically engineered cells should be used in treating cardiac conditions.”

The researchers are currently testing a gene editing technique (CRISPER) to inhibit the gene responsible for the negative inflammatory properties of the cardiac stem cells of heart disease patients. “We hope our engineered stem cells will be resistant to the negative effects of the immune system,” said Prof. Leor.

Talking Breast Cancer for Men’s Health Awareness Week

Males account for less than 1 percent of all breast cancer cases in the United States. In 2017, an estimated 2,470 American men will be diagnosed with the disease; 460 will die.

While rare among men, breast cancer symptoms, diagnosis and survival are similar for both genders. Men experience many of the same primary symptoms or signs of breast cancer: a lump or swelling in the chest area or new irregularities on the skin or nipples, such as redness, scaliness or puckering. Because male breasts generally have less tissue than female, it’s easier to detect lumps. However, some men with breast cancer never display obvious signs of the disease or fail to notice them.

“Both men and women benefit from being aware of their bodies and seeking care with their primary care providers for changes,” said Richard Schwab, MD, oncologist with Moores Cancer Center at UC San Diego Health.

The earlier breast cancer is detected, the better the chances of recovery and survival. In the earliest stages, the five-year survival rate (the percentage of people who live at least five years after diagnosis, excluding other causes of death) is 99 percent. If the cancer has spread to local lymph nodes, the 5-year survival rate drops to 85 percent. If the cancer metastasizes to more distant parts of the body, the rate falls to 27 percent.

As with women, men have a higher risk of developing cancer if they have a family history of breast disease or a mutation in a breast cancer risk gene, such as BRCA1 or BRCA2. In addition, age, high levels of radiation, elevated levels of estrogen (which can be caused by genetic conditions), other diseases, some kinds of medical treatment and lifestyle can increase a man’s risk of breast cancer.

International study identifies new genetic risk factors for testicular cancer

Testicular cancer is relatively rare with only 8,850 cases expected this year in the United States. A majority of testicular cancer, 95 percent of all cases, begins in testicular germ cells, which are the cells responsible for producing sperm. Testicular germ cell tumors (TGCT) are the most common cancer in men aged 20 to 39 years in the U.S. and Europe. Peter Kanetsky, Ph.D., M.P.H., chair of the Cancer Epidemiology Department at Moffitt Cancer Center, and colleagues from the International TEsticular CAncer Consortium (TECAC), launched a large analysis of five major testicular cancer studies to investigate genetic risk factors linked to TGCT. Their results, which uncovered eight new genetic markers associated with TGCT, were published in the June 12 issue of Nature Genetics.

The incidence of TGCT has been increasing around the world throughout the past 50 years. Between 1973 and 2003, the number of men diagnosed with TGCT rose by 54 percent. TGCT is also more prevalent in certain populations. Men who are of Northern European ancestry have the highest incidence of TGCT, while men of African decent have the lowest incidence.

Scientists are unsure why the incidence of TGCT has been increasing or why it is more prevalent in certain populations. Their goal is to identify risk factors for TGCT to increase their understanding of how it arises and to identify those patients who may develop TGCT to prevent progression and treat the disease earlier.

It is believed that some TGCT risk factors may be inherited. Men who have a father with TGCT are four times more likely to develop it, and the risk increases eight-fold if they have a brother with TGCT. Approximately 30 genetic risk factors have been identified so far, but these do not completely account for all of the potential heritable risks.

TECAC combined data from five previous genome-wide association studies, providing researchers with more than 3,500 TGCT cases internationally to review. Their analysis identified eight new genetic markers that are associated with an increased risk of developing TGCT and refined four previously reported susceptibility regions.

“Our findings substantially increase the number of known susceptibility genes associated with TGCT. This moves the field closer to a comprehensive understanding of the underlying genetic architecture and development of the disease,” Kanetsky said.

Altered virus may expand patient recruitment in human gene therapy trials

For many patients, participating in gene therapy clinical trials isn’t an option because their immune system recognizes and fights the helpful virus used for treatment. Now, University of Florida Health and University of North Carolina researchers have found a solution that may allow it to evade the body’s normal immune response.

The discovery, published May 29 in the Proceedings of the National Academy of Sciences, is a crucial step in averting the immune response that prevents many people from taking part in clinical trials for various disorders, said Mavis Agbandje-McKenna, Ph.D., a professor in the University of Florida College of Medicine department of biochemistry and molecular biology and director of the Center for Structural Biology.

During gene therapy, engineered viruses are used to deliver new genes to a patient’s cells. While the recombinant adeno-associated virus, or AAV, is effective at delivering its genetic cargo, prior natural exposure to AAV results in antibodies in some people. As many as 70 percent of patients have pre-existing immunity that makes them ineligible for gene therapy clinical trials, Agbandje-McKenna said.

The findings provide a road map for designing virus strains that can evade neutralizing antibodies, said Aravind Asokan, Ph.D., an associate professor in the department of genetics at the University of North Carolina, who led the study. At UF Health, the structural “footprints” where pre-existing antibodies interact with the virus were identified using cryo-electron microscope resources provided by the UF College of Medicine and the UF Office of Research’s Division of Sponsored Programs. The UNC researchers then evolved new viral protein shells. Using serum from mice, rhesus monkeys and humans, the researchers showed that the redesigned virus can slip past the immune system.

“This is the blueprint for producing AAV strains that could help more patients become eligible for human gene therapy. Now we know how to do it,” Agbandje-McKenna said.

While the findings prove that one variation of AAV can be evolved, further study in preclinical models is needed before the approach can be tested in humans. Next, the immune profile of one particularly promising virus variant will need to be evaluated in a larger number of human serum samples, and dose-finding studies are needed in certain animal models. Researchers may also need to study whether the same virus-manipulating technique can be used in a broader range of gene therapy viruses, Agbandje-McKenna said.

Although human gene therapy remains an emerging field and has yet to reach patients on a wide scale, researchers elsewhere have used AAV therapy to successfully treat hemophilia, a blood-clotting disorder, in a small trial. It has also been or is now being studied as a way to treat hereditary blindness, certain immune deficiencies, neurological and metabolic disorders, and certain cancers.

The latest findings are the result of more than 10 years of studying the interactions between viruses and antibodies and a long-standing collaboration with Asokan, who heads the synthetic virology group at the UNC Gene Therapy Center, according to Agbandje-McKenna.

Study discovers proteins which suppress the growth of breast cancer tumors

Researchers at the University of Birmingham have found that a type of protein could hold the secret to suppressing the growth of breast cancer tumours.

The research, published today in Oncogenesis, examined the role Proline-Rich Homeodomain protein (PRH) can play in the progression of breast cancer tumours and could, in turn, help to better determine the prognosis for patients with the disease.

Dr Padma Sheela Jayaraman, of the University of Birmingham’s Institute of Cancer and Genomic Sciences, said: “PRH is a protein that controls and regulates when genes are switched on or off.

“However, prior to our research, the role of this protein in breast cancer has been poorly understood.

“Public databases show that, in a large number of breast cancer patients with a poor prognosis, the activity of the PRH gene had decreased.

“However, it was not known whether the amount of PRH protein was also lower in these patients as protein levels had not been recorded.”

The researchers used a special staining process on breast cancer tissue removed during biopsy to observe the levels and location of PRH proteins in breast cancer cells. They found that in a small study there were changes in PRH proteins in tumour cells compared to normal cells that were consistent with the decreased activity of the PRH gene in the public database.

Dr Jayaraman added: “In the laboratory, we found that when PRH protein levels are reduced in a breast tumour the cells are more able to divide, speeding up the progression of the tumour.

“Moreover, we identified some of the genes which are regulated by PRH and specifically contribute to the increased cell division.”

The researchers also carried out tests in a tumour model of mammary cancers, increasing PRH levels to observe the effect.

“We made the significant finding that high levels of PRH actually blocked the formation of the tumours, therefore our data suggests that PRH can block tumour formation in some breast cancers,” added Dr Jayaraman.

“We propose that monitoring PRH protein levels or activity in patients with breast cancer could be particularly important for assessing their prognosis.

“In addition, since PRH is known to be important in multiple cell types, this work has important implications for other types of cancer.

“We are now working to investigate the importance of PRH in prostate cancer and in cancer of the bile duct, a type of liver cancer.”

Researching Radiosensitizers, a New Class of Drugs That Would Make Tumors More Vulnerable to Radiation Therapy

Two out of three cancer patients are treated with radiation, but the therapy often fails to wipe out the tumor or slow its growth. Southern Research is working to develop a new class of drugs that will help the radiation deliver a more powerful punch to the disease.

Dr. Bo Xu, M.D., Ph.D., Distinguished Fellow and Chair of Southern Research’s Oncology Department, said a radiosensitizer would greatly benefit cancer patients by improving the success rate of radiation by reducing resistance to the treatment.

“Our project focuses on making those tumor cells more vulnerable to radiation by targeting a critical survival mechanism that allows them to recover from the effects of radiation,” Xu said.

It’s a challenging project, in the works for almost a decade. It got started when Southern Research scientists began looking at fundamental biology concepts to identify a pathway that could play a role in the ability of cancer cells to survive radiation.

They discovered that disrupting the tumor’s self-protection mechanism – in this case, an interaction between two specific proteins – makes the cancer more sensitive to radiation treatment, Xu said.

“The whole idea is to use this strategy to find a new drug that can be used by patients who receive radiation. This drug wouldn’t have toxicity because if it got into the cell it wouldn’t mess up the major functions of the protein network,” he said.

“It would only work when radiation is delivered, and that radiation would be more effective. It’s like a catalyst.”

Using funding from the Alabama Drug Discovery Alliance (ADDA), a partnership with the University of Alabama at Birmingham, Southern Research scientists recently scanned thousands of compounds to identify potential drug candidates. The focus now is to validate the results of those scans and to identify lead compounds for more testing.

“Our hope is that in three years, we can identify a novel class of radiosensitizers that can help the approximately two-thirds of cancer patients who will eventually receive radiotherapy,” Xu said.

While some forms of cancer, such as lymphoma, are sensitive to radiation therapy, many others are not. Solid tumors with a low supply of oxygen, called hypoxic tumors, are tough to treat with radiation. So are cancer cells with a high DNA-repair capability.

To develop a radiosensitizer, Xu is taking aim at a protein that binds to DNA and recognizes the damage being done by radiation. The protein then joins forces with an enzyme to initiate a molecular repair job.

“If that recruitment is successful, then the DNA damage will be repaired, and the cancer cell will survive,” Xu said. “What we’re trying to do is to block this protein from finding the other one, so that the repair process will be diminished or affected. That way, the tumor cells will die.”

To prevent the DNA repair job from getting started, Xu is investigating a small peptide mimic, a small sequence of amino acids that is similar to a human protein but just a fraction of its size. These strands get to the site to block the interaction of the two natural, full-size proteins.

“This interference makes the cancer cell more vulnerable to radiation treatment,” he said.

Radiosensitizers are in demand, but they have proved difficult to develop. While the concept has been around for half a century, very few radiosensitizers have actually become available, according to Xu.

“While there are compounds that work synergistically with radiation, there are few drugs that were developed as a pure radiosensitizer,” he said.

In addition to the ADDA, the National Institutes of Health and the Department of Defense prostate cancer program have provided Southern Research with funding for this research over the years.

Study reveals sweetened drinks during pregnancy puts infants at higher risk for obesity

A recent Danish study of children born to women with gestational diabetes, found that maternal daily consumption of artificially-sweetened beverages during pregnancy was associated with a higher body mass index score and increased risk of overweight/obesity at 7 years.

Artificial sweeteners are widely replacing caloric sweeteners, due to the health concern related to sugar-sweetened beverages (SSBs) within the general population. Artificially sweetened beverages have been considered as potential healthier alternatives, although this study suggests contrary. This study looks to investigate the long-term impact of ASBs consumption during pregnancy on offspring obesity risk in relation to offspring growth through age 7 years among children born to women with gestational diabetes .

In particular, children born to women with gestational diabetes –the most common pregnancy complication affecting approximately 16% of pregnancies worldwide–represent a high-risk phenotype, which may serve as a unique model to study the early origins of obesity. Further evidence has linked nutritional biological disruptions during pregnancy to fetal development and obesity risk in later life. Thus, the authors argue it is important to identify modifiable dietary factors that may prevent offspring obesity and maternal complications.

The study investigated 918 mother and child pairs from the Danish National Birth Cohort. Enrolled participants completed four telephone interviews at gestational weeks 12 and 30, and 6 and 18 months postpartum, which collected data on sociodemographic, perinatal, and clinical factors. In addition, maternal dietary intake was assessed by a food questionnaire during pregnancy. Offspring body mass index scores and overweight/obesity status were calculated using weight and length/height at birth, 5 and 12 months, and 7 years. When the children were 7 years old, a follow-up questionnaire about the child’s health and development was delivered to the parents.

Results showed that approximately half (45.4%) of women reported consuming artificially sweetened beverages during pregnancy. Whereas 68.7% reported consuming SSBs, artificially sweetened beverage consumption–compared to never consuming artificially sweetened beverages–by pregnant women with gestational diabetes was associated with a 1.57 increased risk of being overweight for gestational age babies and a 1.93-fold increase in overweight/obesity risk at 7 years after adjustment for major maternal and offspring risk factors.

Associations were more pronounced in male than female offspring. Substituting SSBs with artificially sweetened beverages was associated with an increased risk of offspring overweight/obesity at 7 years whereas substitution of artificially sweetened beverage with water was associated with a 17% reduced risk. The findings illustrated a positive association between uterus exposure to artificially sweetened beverages and birth size and risk of overweight/obesity at 7 years.

New cellular imaging paves way for cancer treatment

Researchers at the Universities of York and Leiden have pioneered a technique which uses florescent imaging to track the actions of key enzymes in cancer, genetic disorders and kidney disease.

Scientists hope this new development will aid drug design for new anti-cancer, inflammation and kidney disease treatments.

It will also provide diagnostic tools for disease identification and allow medical professionals to measure the effectiveness of drug treatment regimes in an easy laboratory manner.

Studying heparanase – a key enzyme in the development and metastasis of human cancers – scientists unveiled new fluorescent imaging agents that detect enzyme activity in healthy and diseased tissues.

The research, published this week in Nature Chemical Biology, builds upon previous work revealing heparanase’s three-dimensional structure.

Heparanase is a long-studied protein in human tissues involved in breaking down the complex sugars of the “extracellular matrix” – the material surrounding cells that provides structure and stability.

Heparanase dysfunction is linked to the spread of cancers both through the breakdown of this matrix and via the subsequent release of “growth factors” – chemicals that promote tumour development.

Through its remodelling of the matrix, heparanase is also a key player in inflammation and kidney disease. It is therefore a major drug, and diagnostic probe, target.

Gideon Davies, Professor of Structural Enzymology and Carbohydrate Chemistry at the University of York, said: “Heparanase is a key human enzyme. Its dysregulation is involved in inherited genetic disorders, and it is also a major anti-cancer target and increasingly implicated in kidney disease.

“Our work allows us to probe the activity of heparanase in human samples – allowing early disease identification and a direct measure of the success of drugs in humans.

“This work is a great example of the power of EU collaboration and science funding from the European Research Council.”

Hermen Overkleeft, Professor of Bio-Organic Synthesis at Leiden University, added: “This work reveals the power of activity-based protein profiling: the probe described here at once enables screening for heparanase inhibitors from large compound collections and is a lead compound for drug development in its own right.

“While the road to heparanase-targeting clinical drugs is long and fraught with risks, with this work we believe to have taken a major step in realizing the therapeutic potential of this promising clinical target.”