New Treatment Leaves Liver Cancer Cells In Limbo

Scientists have shown that a mutation in a gene called Arid1b can cause liver cancer. The gene normally protects against cancer by limiting cell growth, but when mutated it allows cells to grow uncontrollably. The researchers have shown that two existing drugs can halt this growth in human cells. This points to a new approach to treating liver cancer.

These early results could be translated into a treatment relatively quickly, says Jesus Gil of the MRC Clinical Sciences Centre (CSC), based at Imperial College London, and who led the study. This is because the drugs are already used to treat other types of cancer. Gemcitabine is used on bladder, pancreas and ovary cancer, whilst DON has been tested in clinical trials. Both are known to be safe in people so will not require the usual toxicity testing.

According to MacMillian Cancer Support, 4200 people in the UK are diagnosed with liver cancer annually. “Liver cancer is a deadly disease,” says Luca Tordella, a postdoctoral researcher at the CSC who played a key role in the study. He says the new treatment will be most effective in people who have a mutation in the Arid1b gene. “It’s important to better classify patients into groups, according to their genes. One advance of personalised medicine is to understand which drug will work best on you, and which on me.”

The CSC team began by looking for mutations in the DNA of 100 people with liver cancer. They focused in on genes known to regulate a cellular state called senescence. This is a built-in safety mechanism that helps to protect the cell against cancer. Senescence is triggered when a cell grows abnormally fast and, once induced, it acts to keep the cell in limbo, such that it is alive but can no longer grow or divide. Bypassing senescence is a hallmark of many types of cancer.

It has previously been suggested that the Arid1b gene plays a role in liver cancer. The CSC team are the first to show that it does so by disrupting senescence. Working with researchers at the University of Tübingen, Germany, they mutated Arid1b in mice and human cells, and this stopped the cells from entering senescence. When Arid1b was mutated in mice that also had a mutation in the gene Ras, the mice developed liver cancer.

The researchers also identified exactly how Arid1b stimulates senescence. In healthy cells, Arid1b is part of a bigger complex (called SWI/SNF) that regulates the activity of hundreds of genes. One of these genes produces an enzyme that breaks down the building blocks of DNA. Without these blocks, the cell cannot continue to grow and divide so enters senescence. But if Arid1b is mutated, the blocks cannot be degraded and the cell continues to grow, bypassing senescence and potentially growing out of control.

Gil and Tordella have shown that it’s possible to induce senescence by treating human cells, which have an Arid1b mutation, with either gemcitabine or DON. Both drugs inhibit the synthesis of these blocks, called nucleotides, and thereby induce senescence and stop cancer in its tracks.

“Around 20% of patients with liver cancer have mutations on the genes encoding for components of the SWI/SNF complex. What we suggest is if we treat these people with drugs that target the degradation of nucleotides, they will respond,” says Gil. “We plan to continue to research this in the lab to develop treatments to target liver cancer.”

Fatty Liver: Turning Off TAZ Reverses Disease

Scientists at Columbia University Medical Center (CUMC) have identified a factor in liver cells that is responsible for turning a relatively benign liver condition, present in 30 percent of U.S. adults, into a serious disease that can lead to liver failure.

The study was published online today in Cell Metabolism.

With the rise of obesity in the U.S., the incidence of nonalcoholic fatty liver disease (NAFLD)—in which excess fat fills the liver—has risen to epidemic levels. The extra liver fat is generally benign, but in one in five people, NAFLD evolves into a more serious condition, nonalcoholic steatohepatitis (NASH).

In NASH, the liver becomes inflamed and criss-crossed by fibrous scar tissue, and liver cells start dying. Patients with NASH are at risk of liver failure and liver cancer, but there are no drugs on the market that can slow or stop the disease.

Because the amount of fibrosis in the liver is associated with a greater risk of death from NASH, Xiaobo Wang, PhD, associate research scientist in the Department of Medicine at CUMC working in the lab of Ira Tabas, MD, PhD, looked for ways to stop fibrosis in a mouse model of NASH.

He found that in liver cells, TAZ, a previously unknown factor in NASH, plays a critical role in initiating fibrosis, and that fibrosis stops in mice with NASH when TAZ is inactivated in liver cells. With TAZ shut down, existing fibers in the liver also dissolved, essentially reversing the disease. Two other critical features of NASH, inflammation and cell death, were also reduced when TAZ was turned off. Fat accumulation in the liver was unaffected.

Based on their examination of liver biopsies from NAFLD and NASH patients, Drs. Wang and Tabas believe that TAZ works in the same way in people.

“We think that by stopping fibrosis through TAZ and its partners, we may be able to prevent the serious consequences of NASH, including liver failure and liver cancer,” said Ira Tabas, Richard J. Stock Professor and vice-chair of research in the Department of Medicine and professor of pathology & cell biology (in physiology and cellular biophysics) at CUMC.

Scientists Uncover Why Hepatitis C Virus Vaccine Has Been Difficult To Make

Researchers have been trying for decades to develop a vaccine against the globally endemic hepatitis C virus (HCV). Now scientists at The Scripps Research Institute (TSRI) have discovered one reason why success has so far been elusive.

Using a sophisticated array of techniques for mapping tiny molecular structures, the TSRI scientists analyzed a lab-made version of a key viral protein, which has been employed in some candidate HCV vaccines to induce the body’s antibody response to the virus. The researchers found that the part of this protein meant as the prime target of the vaccine is surprisingly flexible. Presenting a wide variety of shapes to the immune system, it thus likely elicits a wide variety of antibodies, most of which cannot block viral infection.

“Because of that flexibility, using this particular protein in HCV vaccines may not be the best way to go,” said co-senior author TSRI Associate Professor Mansun Law.

“We may want to engineer a version that is less flexible to get a better neutralizing response to the key target site and not so many off-target responses,” said co-senior author Ian A. Wilson, TSRI’s Hansen Professor of Structural Biology and a member of the Skaggs Institute for Chemical Biology at TSRI.

The report, published online ahead of print by the Proceedings of the National Academy of Sciences the week of October 24, 2016, is likely to lead to new and better HCV vaccine designs.

A Great Need

A working vaccine against this liver-infecting virus is needed desperately. HCV infection continues to be a global pandemic, affecting an estimated 130 to 150 million people worldwide and causing about 700,000 deaths annually from liver diseases including cancer. Although powerful antiviral drugs have been developed recently against HCV, their extremely high costs are far beyond the reach of the vast majority of people living with HCV infection. Moreover, antiviral treatment usually comes too late to prevent liver damage; HCV infection is notorious for its ability to smolder silently within, producing no obvious symptoms until decades have passed.

The Law and Wilson laboratories have been working together in recent years to study HCV’s structure for clues to successful vaccine design. In 2013, for example, the team successfully mapped the atomic structure of the viral envelope protein E2, including the site where it binds to surface receptors on liver cells.

Because this receptor-binding site on E2 is crucial to HCV’s ability to infect its hosts, it has an amino-acid sequence that is relatively invariant from strain to strain. The receptor-binding site is also relatively accessible to antibodies, and indeed many of the antibodies that have been found to neutralize a broad set of HCV strains do so by targeting this site.

For all these reasons, HCV’s receptor-binding site has been considered an excellent target for a vaccine. But although candidate HCV vaccines mimicking the E2 protein have elicited high levels of antibodies against the receptor-binding site, these antibody responses—in both animal models and human clinical trials—have not been very effective at preventing HCV infection of liver cells in laboratory assays.

Enormous Flexibility

To understand why, the Law and Wilson laboratories teamed up with TSRI Associate Professor Andrew Ward and used electron microscopy and several other advanced structural analysis tools to take a closer look at HCV’s E2 protein, in particular the dynamics of its receptor binding site. Their investigations focused on the “recombinant” form of the E2 protein, produced in the lab and therefore isolated from the rest of the virus. Recombinant E2 is a prime candidate for HCV vaccine design and is much easier to purify and study than E2 from whole virus particles.

One finding was that recombinant E2, probably due to its many strong disulfide bonds, has great structural stability, with an unusually high melting point of 85°C. However, the TSRI scientists also found evidence that, within this highly buttressed construction, the receptor binding site portion is extraordinarily loose and flexible in the recombinant protein.

“It adopts a very wide range of conformations,” said study first author Leopold Kong, of TSRI at the time of the study, now at the National Institutes of Health.

Prior studies have shown that HCV’s receptor binding site adopts a narrow range of conformations (shapes) when bound by virus-neutralizing antibodies. A vaccine that elicited high levels of antibodies against only these key conformations would in principle provide effective protection. But this study suggests that the E2 protein used in candidate vaccines displays far too many other binding-site conformations—and thus elicits antibodies that mostly do nothing to stop the actual virus.

Law and Wilson and their colleagues plan to follow up by studying E2 and its receptor binding site as they are presented on the surface of the actual virus. They also plan to design a new version of E2 or even an entirely different scaffold protein, on which the receptor binding site is stabilized in conformations that will elicit virus-neutralizing antibodies.

Liver Cancer Drug May Treat NASH, a Disease Projected to Reach Epidemic Proportions

There is no U.S. FDA approved therapy on the market today for Nonalcoholic steatohepatitis (NASH), a chronic liver disease found in adults and children. Between 5.6 and 8.4 million Americans are living with NASH today and this number is expected to jump to 25 million by 2025, driven by rising obesity rates. NAFLD, the liver disease which is a precursor to NASH, afflicts an estimated 30 million people today.

These numbers are astounding, considering the fact that diabetes is widely considered an epidemic because it impacts 29 million Americans. NAFLD and NASH can lead to cirrhosis, and in later stages, to liver cancer and liver failure.

Israel based Can-Fite BioPharma’s CF102, a drug currently in a Phase 2 trial treating hepatocellular carcinoma (HCC), the most common form of liver disease, is headed into clinical trials for the treatment of NAFLD/NASH. While about 40,000 Americans are diagnosed with liver cancer today, this number may increase with the rising incidence of NASH.

Several other companies are developing potential treatments for NAFLD and NASH. As these drugs come to market, Deutsche Bank projects their annual sales to be in the $35 – $40 billion range by 2025. The CEO of Allergan, Brent Saunders, one of the companies developing NAFLD/NASH drugs described the situation, “With the increasing rates of diabetes, obesity and other metabolic conditions in the U.S. and in developed nations globally, NASH is set to become one of the next epidemic-level chronic diseases we face as a society. It is important that we invest in new treatments today so that healthcare systems, providers and patients have treatment options to face this challenge in the coming years.”

CF102 is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR). A3AR is highly expressed in diseased cells whereas low expression is found in normal cells. Preclinical studies have shown CF102’s efficacy in reducing liver fat in NASH models as compared to placebo, improving liver function, and regenerating liver cells.

Can-Fite reported it has submitted the clinical trial protocol for its Phase 2 study of CF102 in the treatment of NAFLD to leading Institutional Review Boards in Israel. Top medical centers in Israel, including Hadassah Medical Center and Rabin Medical Center are expected to participate in the planned study by enrolling and treating patients.

The multicenter, randomized, double-blinded, placebo-controlled, dose-finding study will enroll 60 patients with NAFLD, with or without NASH. The study will have three arms, including two different dosages of CF102 and a placebo, given via oral tablets twice daily. The study’s primary endpoints will be percent change from baseline in liver triglyceride (fat) concentration. Can-Fite’s drugs, based on A3AR, have been studied in over 1,000 patients.

Given the size and scope of the NAFLD/NASH patient population in the U.S. and around the world, healthcare systems can benefit from several different drugs for this indication. A few drugs are in Phase 3 and some others are in Phase 2. Can-Fite’s CF-102 could emerge as a safe and effective choice.

Technique May Identify Patients With Fast-Progressing Fibrosis In Nonalcoholic Fatty Liver Disease

Combining multiple non-invasive measures, researchers at University of California San Diego School of Medicine describe a novel method to quantify the progression of nonalcoholic fatty liver disease (NAFLD) to its more dangerous and deadly states — advanced fibrosis and cirrhosis.

The findings are published in the Oct 5 online issue of Hepatology.

Roughly one-quarter of all Americans — an estimated 100 million adults and children — have NAFLD, which occurs when fat accumulates in liver cells due to causes other than excessive alcohol use. The precise cause is not known, but obesity, diabetes, diet and genetics play substantial roles.

Most people with NAFLD exhibit few or no symptoms, but the condition can progress to nonalcoholic steatohepatitis (NASH), a more extreme form of the disease, which in turn can result in cirrhosis or liver cancer. One driver of the disease is excessive production of collagen, an extracellular structural protein that in over-abundance can lead to harmful scarring and dysfunction in affected tissues; in this case, the liver.

“Progression of the condition, from NAFLD to NASH or from mild fibrosis (thickening and scarring of tissue) to cirrhosis, varies greatly from patient to patient,” said Rohit Loomba, MD, professor of medicine at UC San Diego School of Medicine and director of the Nonalcoholic Fatty Liver Disease Research Center at UC San Diego Health. “Having a diagnostic technique that can effectively predict individual clinical fibrotic disease progression quickly — which patients are more likely to develop serious liver health problems — would obviously be extremely valuable.”

The current gold standard for monitoring fibrosis progression are repeat liver biopsies, but these are problematic for several reasons. They are invasive. There is a related health risk, including the chance of death. And sampling may miss or not fully capture a liver’s full fibrotic state.

In recent years, non-invasive scanning technologies, such as magnetic resonance imaging (MRI), have been used to measure liver stiffness (an indicator of fibrosis), but they assess only disease status in the moment and cannot provide a more kinetic assessment of metabolic process of the rate of scarring.

“As a result, patients with fast-progressing fibrotic disease are typically identified only when they are in the late stages of the condition,” said Loomba, when treatments and effectiveness are more limited.

In their study, Loomba and colleagues asked 21 patients with suspected NAFLD to ingest “heavy water,” (a form of water that contains deuterium, a “heavier” form of hydrogen) two to three times daily for three to five weeks prior to a liver biopsy. The heavy water was used to label and measure collagen growth. Additionally, blood samples from study participants were measured for collagen synthesis rates and MRIs taken to assess liver stiffness. They found that all of these assessment tools — some used for the first time to provide direct, immediate measurements — correlated with established risks for fibrotic disease progression.

“If confirmed in larger, longer studies, these findings have potential implications for charting the prospective course of disease and managing patients’ treatment accordingly,” said Loomba.

Largest HIV Transmission Study Conducted

A new study has found that neither gay men nor heterosexual people with HIV transmit the virus to their partner, provided they are on suppressive antiretroviral treatment.

The PARTNER study, which is the world’s largest study of people with HIV who have had condomless sex with their HIV negative partners, was conducted by investigators from the University of Liverpool, University College London, Royal Free NHS and Rigshospitalet (one of the largest hospitals in Denmark).

This work was funded by the National Institute for Health Research (NIHR) and was sponsored by UCL (University College London).

More than 800 couples monitored

The study monitored 888 couples from 14 different European countries, in which one of the partners was on effective treatment for HIV. Of the 888 couples, 548 were heterosexual and 340 were gay men.

All the couples had sex regularly without using a condom. They have now been monitored for several years and not one instance of transmission of the virus has been recorded. The results have just been published in the prestigious Journal of the American Medical Association.

In the period following the study, a total of 11 HIV-negative partners were infected with HIV. Led by Professor Anna Maria Geretti, researchers from the University of Liverpool‘s Institute of Infection and Global Health undertook phylogenetic analyses of the 11 new HIV cases and their partners’ virus.

No HIV transmission between couples

Professor Geretti, said: “The HIV virus can be divided into several sub-groups, each with its own genetic characteristics, and this makes it possible to see whether the virus is genetically similar to a partner’s. In all cases the results showed that the virus came from someone other than the partner under treatment.

“This research is vital for us to gain an even better understanding the risks associated with this particular virus.”

Professor Jens Lundgren from Rigshospitalet, senior author of the study and head of CHIP (the Centre for Health and Infectious Diseases), said: “The results clearly show that early diagnosis of HIV and access to effective treatment are crucial for reducing the number of new HIV cases. As soon as a patient with HIV is on treatment with a suppressed viral load, the risk of transmission becomes minimal.”

More data on the way

Gay couples in the study will continue to be monitored for three more years to obtain even more data in this area for anal sex.