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Study Reveals Much-needed Strategy to Protect Against Deadly Liver Fibrosis

Chronic liver disease is a leading cause of death in the United States, in part because it often causes the formation of harmful scar tissue—a process known as fibrosis. A study published by Cell Press August 15 in the journal Immunity reveals the central role the immune molecule interleukin 33 (IL-33) plays in the formation of liver fibrosis. The findings suggest that drugs targeting this molecule could serve as a new treatment strategy to protect against liver fibrosis.

“Currently, the therapeutic options for liver fibrosis are limited and not curative,” says senior study author Stefan Wirtz of Friedrich-Alexander University Erlangen-Nuremberg. “We identified novel immunological factors that contribute to the development of liver fibrosis, opening up new avenues for the treatment of this serious condition.”

Liver fibrosis refers to the accumulation of harmful deposits of extracellular matrix (ECM) proteins, and it can eventually lead to organ failure. Past studies have suggested that this kind of damage is associated with abnormal immune responses in the liver, but very little was known about the molecules and cells that contribute to fibrosis.

In the new study, Wirtz and his team found that the amount of IL-33 in the blood was higher than normal in patients with liver disease. Following up on this observation, they discovered that injection of IL-33 into mice caused ECM proteins to build up in the liver, whereas mice that were genetically modified to lack IL-33 were largely protected from fibrosis. The researchers went on to identify the immune networks underlying IL-33’s harmful effects and discovered that this molecule activates immune cells called type 2 innate lymphoid cells (ILC2), which had never before been linked to liver disease.

“Our findings reveal IL-33 as a novel biomarker that could potentially lead to early detection of fibrosis in patients, which may be extremely valuable for preventing further damage to the liver,” Wirtz says. “Moreover, the study shows that drugs targeting IL-33 or ILC2 responses could be a promising strategy to protect against fibrosis and chronic liver disease.”

Study: Interleukin-33-Dependent Innate Lymphoid Cells Mediate Hepatic Fibrosis [Immunity]

Source: EurekAlert!

Unexpected Synergy Between Two Cancer-linked Proteins Offers Hope for Personalised Cancer Therapy

A team of scientists led by Associate Professor Zeng Qi from A*STAR’s Institute of Molecular and Cell Biology (IMCB) have discovered a new biomarker which will help physicians predict how well cancer patients respond to cancer drugs. Having the means to identify patients who are most likely to benefit from currently available cancer drugs not only reduces substantially the healthcare cost for the patient, it could mean saving precious lives by getting the right drugs to the right patient at the onset of the treatment. This study published and featured on August cover of the Journal of Clinical Investigation will boost the development of personalised medicine in cancer care and therapy.

Metastasis is the rapid and uncontrollable spread of cancer cells from the primary tumour to other parts of the body. It is often the leading cause of death in cancer patients. Increasingly, there is evidence to show that in many cancers that have metastasised, a protein called PRL-3 is often found to be present at unusually high levels. Since it was first identified in 1998 by Associate Professor Zeng, several other research groups have found evidence to support the strong link between elevated levels of PRL-3 protein and the metastasis of aggressive cancers in the lung, liver, colon and breast. This cancer-promoting action of PRL-3 makes it an ideal target for cancer diagnostics and treatment.

In this study, the IMCB team discovered a curious synergy between PRL-3 and EGFR, another well-known cancer-linked protein frequently associated with breast and lung cancers in humans. They found that cancer cells with higher levels of PRL-3 not only hyperactivate EGFR, but also develop an ‘addiction’ for it to survive. Consequently, by suppressing EGFR activity with EGFR inhibitor drugs, the scientists observed that cancer cells with higher levels of PRL-3 were more rapidly destroyed. To validate these findings in humans, the team collaborated with Associate Professor Wee Joo Chng from the National University Health System to run an analysis on pre-existing clinical data of colorectal cancer patients. The results confirmed that patients who respond better to EGFR inhibitor drugs were those suffering from cancers with abnormally high levels of PRL-3.

Associate Professor Zeng said, “This unexpected synergy has revealed a vulnerable spot of aggressive cancers and brought new hope of treating PRL-3 driven cancers successfully. The addiction phenomenon we observed in cancer cells is akin to depriving alcohol from an alcoholic, thereby inducing the severe ‘withdrawal effects’. In the same way, by selecting cancer patients with elevated levels of PRL-3 and greater ‘addiction’ of EGFR for anti-EGFR treatment, we can deliver more effective and targeted cancer therapy with the existing EGFR inhibitor cancer drugs.”

Professor Sir David Lane, Chief Scientist of A*STAR said, “This is an excellent example of how years of basic research lay the foundation for advancement in translational and clinical applications. I am pleased that the team is exploring the potentials of developing this new predictive biomarker into a rapid diagnostic kit for identifying patients who will respond favourably to current anti-EGFR treatment. I believe that this study will open new avenues for personalised medicine in cancer therapy.”

Study: Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells [Journal of Clinical Investigation]

Source: Agency for Science, Technology and Research (A*STAR)

Quest Diagnostics Introduces Comprehensive Opioid Therapy Genetic Test Based on CYP450 Biomarker License with Transgenomic

Quest Diagnostics (NYSE: DGX), the world’s leading provider of diagnostic information services, recently announced the availability of a new lab-developed genetic test to aid the delivery of personalized opioid pain-relieving treatment. It is believed to be the first clinical lab to offer testing for variants in all cytochrome P450 (CYP450) genes known to influence the CYP450 enzyme system, which affects metabolism of opioids and other medications.

Early Indicators of Lung Cancer Probed in New Study

Many of the critical processes underlying cancer formation and eventual metastasis to other organs remain mysterious. In the quest for earlier diagnoses and more effective treatment, intensive research efforts have been applied to the search for biomarkers—presymptomatic signs of disease detectable in blood, saliva, or other biofluids.

Chad Borges, an analytical biochemist working at Arizona State University’s Biodesign Institute has been studying a particularly promising class of potential biomarkers known as glycans. His new study, appearing in the journal Analytical Chemistry, investigates the formation of aberrant glycan molecules, which have been clinically implicated in a range of deadly cancers including ovarian, prostate, pancreatic, liver, multiple myeloma, breast, lung, gastric, thyroid and colorectal.

Indeed, as the authors note, nearly every known type of tumor cell displays abnormal glycans, making them a particularly attractive candidate for biomarker discovery and validation. Until now, however, detecting the source of aberrant glycans has been frustratingly difficult.

Borges is a member of Biodesign’s Molecular Biomarkers Unit, where proteins and protein modifications are examined for their potential as markers of human disease. “Our primary work has to do with extracting proteins from blood samples or other biofluids, purifying them and examining them in an intact state through mass spectrometry,” Borges says. “We look for variants in these proteins, which in many cases include glycosylation—the focus of this paper—except in this case we looked at global changes across all blood serum proteins.”

Glycans are biological sugar polymers, made up of several different types of sugar units—glucose, mannose, galactose and others. Glycans typically adorn the surfaces of cells and can act to modify proteins. Unlike other biological polymers like DNA and proteins, however, glycans are made “on-the-go,” without a preset template. This makes their formation and behavior trickier to predict.

As Borges explains, “glycans are assembled by enzymes through a first come, first build process. In cancer, the protein enzymes that form glycans—known as glycotranserases—get overexpressed. When that happens, you get these weird glycan structures that aren’t normal.” The study found, for the first time, at least two glycotransferases displaying aberrant activity in lung cancer samples, with other abnormal glycotransferase activity strongly implied as well.

The assembly of glycans is schematically similar to a tinker toy set in which glycotransferase enzymes act to connect various wheel-like sugar units via spoke-like branching elements. Overexpression of glycotransferases produces aberrant glycans, which tend to display bushier, more profuse branching patterns when compared with their normal counterparts. (see Figure 1).

These abnormal glycans can help facilitate metastasis of cancerous cells, because their presence on cell surfaces is differentially recognized by the immune system. Instead of destroying diseased cells, the immune system leaves them alone. The abnormal glycans can also help cancer cells traverse non-native tissues, i.e. metastasize.

In the current proof-of-concept study, archived plasma samples from 30 lung cancer patients were examined, along with 29 non-cancerous control samples matched by age, gender and smoking status. The study attempted to track the immediate upstream cause of aberrant glycans, namely the glycotransferase enzymes that build them—a process that takes place in the endoplasmic reticulum and Golgi apparatus of the cell.

“Most glycomics efforts look at intact glycans, but often this is not a good molecular surrogate for the activity of glycotranferases because glycotranferases work on hundreds of growing glycan polymers,” Borges notes. “Our new, bottom-up approach looks at glycans in a different way.” To evaluate glycotranferase activity, the study pooled together the glycan polymer branching points or nodes for all of the aberrant glycan structures observed. Specific sugar subunits and linkage types characterize these glycan nodes.

A technique known as gas chromatography/mass spectrometry was used to detect glycan node levels, which were then combined to infer glycotransferase activity. The study demonstrated that a number of glycan nodes exhibited a 1:1 molecular correspondence with particular glycotranferases. The technique was used to accurately pinpoint lung cancer in blood samples with 76-88 percent reliability.

While a number of hurdles must be addressed in future research, the new technique holds the promise of a simple test capable of analyzing multiple glycotransferases simultaneously and linking abnormal activity with the aberrant glycans formed by these enzymes. The test can be carried out without the need for enzyme or antibody reagents and provides a potential means of finally harnessing aberrant glycans as useful disease biomarkers.

The method’s effectiveness is expected to further improve once information from large data sets of known patient outcome are applied and analyzed. This will hopefully permit the development of disease-specific biomarkers for a range of ailments including cancers and other inflammation-related diseases.

Applying the glycan-node strategy directly to cancerous fluids or tissues, rather than plasma/serum (where normal glycans tend to dilute the desired signal) may further enhance the test’s sensitivity. “The interesting thing is that we see widely different glycan profiles for different biofluids and different tissues, suggesting that they will be able to provide information above and beyond what blood serum alone can provide,” Borges says.

The method, once refined, may offer clinicians an extra piece of evidence on which to base decisions concerning invasive procedures (like lung biopsy or pancreatectomy) for confirming cancer diagnosis and charting appropriate treatment.

Source: Multiplexed surrogate analysis of glycotransferase activity in whole biospecimens.

Source: Arizona State University Biodesign Institute

Matrix-Bio Options Metabolite Biomarker Technology from Purdue University to Evaluate Opportunities for New Cancer Diagnostic Tests

Matrix-Bio Inc., a diagnostics company that uses metabolite profiling to detect cancer and other diseases, has signed an exclusive agreement with the Purdue Research Foundation optioning metabolite biomarker technology and eight patent applications to evaluate the commercial potential of cancer diagnostics tests based on the technologies.

The optioned technologies include metabolite biomarkers for detecting esophageal, liver, pancreatic and colon cancer; for identifying liver cancer in patients with hepatitis C; and for predicting preoperative chemotherapy effectiveness for breast cancer treatment. Matrix-Bio’s agreement is for one year with an option to extend the agreement. No other terms of the agreement were released.

The new agreement builds on the existing master license agreement between Matrix-Bio and Purdue Research Foundation for breast cancer biomarkers and metabolite profiling technology developed by Dan Raftery, Matrix-Bio chief scientific officer and founder, while he was a member of the Purdue University research faculty. Raftery is now director of the Northwest Metabolomics Research Center at the University of Washington in Seattle, and is also a member of the Fred Hutchinson Cancer Research Center in Seattle, one of the world’s leading cancer research centers.

Matrix-Bio CEO Eric Beier said the agreement will enable the company to significantly expand its pipeline of cancer detection and monitoring tests, further advancing the company’s leadership in metabolomics-based cancer diagnostic technologies.

“Metabolite profiling is an emerging field of diagnostics that looks at the changes in small molecule biomarkers in cells. Patterns of these metabolite biomarkers in the blood are altered when cancer is present,” Beier said. “Dr. Raftery’s technology identifies metabolic changes with very high sensitivity and specificity, and can detect various cancers in early, more treatable stages more accurately than currently available tests. Studies have also demonstrated that metabolite profiling can assist in monitoring cancer treatment.”

The announcement comes on the heels of an exclusive global licensing and marketing agreement for metabolomic biomarkers Matrix-Bio signed with Quest Diagnostics (NYSE: DGX), the world’s leading provider of diagnostic information services. Under the agreement, Quest Diagnostics has the rights to use the Matrix-Bio biomarkers for the future, potential development of a clinical lab-developed test to aid in the detection of breast cancer recurrence. Quest Diagnostics also has the option to pursue an appropriate regulatory pathway for an in vitro diagnostic version of the test. Additional terms were not disclosed.

Source: Business Wire