First Large-Scale Genomic Analysis of Key Acute Leukemia Will Likely Yield New Therapies

A consortium including St. Jude Children’s Research Hospital and the Children’s Oncology Group has performed an unprecedented genomic sequencing analysis of hundreds of patients with T-lineage acute lymphoblastic leukemia (T-ALL). The results provide a detailed genomic landscape that will inform treatment strategies and aid efforts to develop drugs to target newly discovered mutations.

The data will also enable researchers to engineer better mouse models to probe the leukemia’s aberrant biological machinery.

The project’s 39 researchers were led by Charles Mullighan, M.D., MBBS, a member of the St. Jude Department of Pathology, with co-corresponding authors Jinghui Zhang, Ph.D., chair of the St. Jude Department of Computational Biology and Stephen Hunger, M.D., of the Children’s Hospital of Philadelphia. The research was selected for advance online publication today in the journal Nature Genetics.

“This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important,” Mullighan said. “Leukemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations.”

T-ALL is a form of leukemia in which the immune system’s T cells acquire multiple mutations that freeze the cells in an immature stage, causing them to accumulate in the body. ALL is the most common type of childhood cancer, affecting about 3,000 children nationwide each year. T-ALL constitutes about 15 percent of those cases. While about 90 percent of children with ALL can be cured, many still relapse and require additional treatment.

The multi-institutional effort involved sequencing the genomes of 264 children and young adults with T-ALL—the largest such group ever analyzed. The study involved sophisticated analysis of multiple types of genomic data, led by Yu Liu, Ph.D., a postdoctoral fellow in Zhang’s Computational Biology laboratory and first author of the study. Their analyses identified 106 driver genes—those whose mutations trigger the malfunctions that block normal T cell development and give rise to cancer. Half of those mutated genes had not been previously identified in childhood T-ALL.

The study enabled the researchers to compare the frequencies of mutations among patients whose cancerous cells were sequenced at the same detailed level, Mullighan said. Also important, he said, was that all the patients had uniform treatment, which enabled the researchers to draw meaningful associations between the genetics of their cancer and the response to different treatments. Such associations will enable better diagnosis and treatment of T-ALL with existing drugs.

Researchers analyzed the cancerous T cells as well as those that treatments had rendered non-cancerous. Comparing the two populations of cells could reveal valuable clues about why specific treatments were successful in thwarting particular cancer-causing mutations.

The findings revealed significant unexpected findings. “We went into this study knowing that we didn’t know the full genomic landscape of T-ALL,” Hunger said. “But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL, but not others.”

Cancers are driven by mutations in genes that are the blueprint for protein enzymes in signaling pathways in cells—the biological equivalent of circuits in a computer. While a cancer may arise from an initial founding mutation, that mutation triggers a cascade of other mutations that help drive the cancer.

The new genomic analysis confirmed that T-ALL was driven by mutations in known signaling pathways, including JAK–STAT, Ras and PTEN–PI3K.

However, the new analysis identified many more genetic mutations in those known pathways. The findings offered more targets for drugs to shut down the aberrant cells. “So the frequency of the patients that are potentially amenable to these targeted approaches is higher than we appreciated before,” Mullighan said.

The researchers also found cases in which the same T-ALL subtype had mutations in different pathways triggered by the same cancer-causing founding mutation. “We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective,” Mullighan said.

The multitude of new mutations uncovered in the new study will also enable researchers to use genetic engineering to create mouse models that more accurately reflect human cancer, he said. Such models are invaluable for understanding the biological machinery of T-ALL, as well as testing new drug strategies. “We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans,” Mullighan said.

The research also offers a broader lesson for genomic studies of cancers, Zhang said. “Our study is further evidence that if you systematically study a large enough population with careful, detailed genomic analysis, you will discover new mutational patterns of collaboration or exclusion across multiple genes unique to each T-ALL subtype,” she said.

The study was a collaboration between the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project, the Children’s Oncology Group (COG) and the National Cancer Institute’s Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. COG is a federally supported clinical trials group focused exclusively on childhood cancer. TARGET uses genomic analysis of COG samples to identify therapeutic targets and spur development of more effective treatment for childhood cancer.

Clinical Trial Results Marks a Significant Accomplishment for Medicortex Finland

Medicortex Finland Oy, a biotechnology company developing a diagnostic kit for brain injury detection based on a medical breakthrough biomarker, recently completed analyzing the results from the first clinical trial. Medicortex is working towards the validation of a Traumatic Brain Injury (TBI) biomarker and incorporating it into a quick and reliable diagnostic kit that can be easily used by the first responders and healthcare professionals, and by people with no medical profession.

The trial consisted of patients that were hospitalized due to a head injury.  Medicortex collected body fluid samples of 12 patients who had sustained a head injury, and analyzed the presence of the novel biomarker between the patients and healthy control subjects.

“The biodegradation product we are targeting has never been used for TBI indication. The fact that we can readily find it in easily accessible body fluids such as urine and saliva enables us to develop a user-friendly diagnostic kit for TBI detection”, says Dr. Adrian Harel, Chief Executive Officer of Medicortex Finland.

“Collecting and testing human samples in a clinical trial is a significant accomplishment for us, and represents a meaningful step forward in the development of a fast and inexpensive diagnostic kit for head injuries,” added Dr. Harel. “Brain injuries are devastating, leading to mortality if not diagnosed. The opportunity to develop the first portable non-invasive kit to detect head injuries and concussion is so desperately needed,” added Harel.

Dr. Marten Kvist, Medical Director of Medicortex, says “We are excited of the clinical results which confirm the diagnostic potential of the unique biomarker, it will be further developed into a diagnostic aid for first responders and paramedics, it will help prioritize evacuation and reframe from administration of contraindicated medications.”

The clinical trial was supported and funded in part by Tekes (the Finnish Funding Agency for Innovation). Medicortex is currently raising money for the next step clinical development of the brain injury test. The planned multicenter clinical study including up to 160 study subjects will prove the validity of the new biomarker test for TBI diagnostics.

The general public can help contribute in the development of MediCortex’s diagnostic kit via a crowdfunding campaign at  Medicortex is issuing shares with the goal of raising capital to match funds the firm has already applied via Tekes.

Medicortex Finland Oy ( is a biotechnology company dedicated to improving the diagnostics and treatment of Traumatic Brain Injury (TBI). Its current focus is to develop biomarker diagnostics that evaluate the extent and severity of TBI. Once the company completes this test its next goal will be to develop an innovative drug to halt the progression of brain injury.

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.

Study Links Chemical In Plastics To Genital Abnormalities In Baby Boys

Doctors and researchers know that man-made chemicals commonly found in plastics, foods, personal care products and building materials can interfere with how hormones like estrogen and testosterone work in the body.

A new study published in the journal Environmental Research now shows that pregnant women’s exposure to a particular endocrine-disrupting chemical called diethylhexyl pthalate (DEHP) is directly linked to abnormalities in newborn boys’ reproductive organs.

Dr. Sheela Sathyanarayana, a pediatric environmental health researcher at Seattle Children’s Research Institute who led the study, sat down with On the Pulse to answer some questions about the findings.

Q: What did this study show about how phthalates can influence genital development in newborn boys?

This study showed a clear connection between a pregnant woman’s exposure to the endocrine-disrupting chemical DEHP and subsequent anomalies in a baby boy’s reproductive organs. We discovered this association by collecting urine samples from pregnant women and testing them for phthalates and doing physical exams of newborns.

While doctors and researchers have known that endocrine-disrupting chemicals interfere with hormones, it’s been difficult to prove clear health outcomes. Now, for the first time, we’ve shown that the higher the DEHP concentration in a mother’s urine, the more likely her boy would be born with of a genital anomaly.

Q: What complications did you identify in newborn boys?

The most common abnormality we found was hydrocele, a condition in which fluid builds up in the sac inside a boy’s scrotum. A newborn boy was more than twice as likely to develop this condition if his mother had high concentrations of DEHP in her urine.

While hydrocele is rarely a problem for boys who have it, this is significant because it is the first time that we have been able to show that exposure to an endocrine-disrupting chemical can result in changes to the reproductive system.

Q: Were there any findings about baby girls?

For this study we focused on newborn baby boys because the genital anomalies are easier to identify and record. More research is needed to understand how endocrine-disrupting chemicals may be impacting fetal development of females.

Q: Should pregnant women avoid exposure to endocrine-disrupting chemicals?

Yes. Pregnant women and families can take easy, common sense steps to reduce exposure to endocrine-disrupting chemicals. These chemicals, called phthalates, are most commonly found in plastics, personal care products like shampoos, makeup and perfumes, and in the U.S. food supply from things like jars, packaging, and other storage.

Tips to avoid endocrine-disrupting chemicals

• Buy low-fat dairy products like skim milk and low fat cheeses instead of high fat dairy products like cream and whole milk.
• Buy fresh or frozen fruits whenever possible, and avoid canned and processed foods.
• Look for items that are labeled phthalate or BPA-free.
• Minimize personal care products, and focus on simple products with clear ingredients.
• Use glass, stainless steel, ceramic or wood to hold and store foods instead of plastics, and do not microwave food in plastic.
• Do not heat a baby’s milk or food in plastics or put hot liquids in plastic products such as sippy cups.
• Check plastic symbols and avoid plastics known to contain these chemicals including numbers 3 (PVC and vinyl), 6 (polystyrene foam) and 7 (other, can contain BPA).
• Encourage frequent handwashing.
• Minimize handling of receipts.
• Take shoes off at home to avoid tracking dust in that may contain these chemicals.
• Keep carpets and windowsills clean because these products may contain these chemicals.

No symptoms, but could there be cancer? Our chemosensor will detect it!

Many cancers could be successfully treated if the patient consulted the doctor sufficiently early. But how can a developing cancer be detected if it doesn’t give rise to any symptoms? In the near future, suitably early diagnosis could be provided by simple and cheap chemical sensors – thanks to special recognizing polymer films developed at the Institute of Physical Chemistry of the Polish Academy of Sciences in Warsaw.

These days, cancer is no longer a death sentence for the patient. However, the best chances of recovery are when the correct treatment is undertaken at an early stage of the disease. This is where the trouble starts, because many tumours develop over a long period without any symptoms. One solution to this problem could be diagnostic tests available to everyone that could be performed by people themselves and on a relatively regular basis. A step bringing us closer to this sort of personalized medical diagnosis and cancer prophylaxis is the chemical sensor devised and fabricated by Prof. Wlodzimierz Kutner’s group from the Institute of Physical Chemistry of the Polish Academy of Sciences (IPC PAS) in Warsaw using a grant from the National Science Centre, in collaboration with the team of Prof. Francis D’Souza of the University of North Texas in Denton TX, USA.

The most important element of the chemosensor devised at the IPC PAS is a thin film of the polymer that detects molecules of neopterin. Neopterin – in chemical terminology known as 2-amino-6-(1,2,3-trihydroxypropyl)-1H-pteridin-4-one) – is an aromatic compound present in human body fluids, such as serum, urine, and cerebrospinal fluid. Produced by the immune system, it is regarded as a universal marker in medical diagnosis. The concentration of this biomarker rises significantly particularly in the case of certain neoplastic diseases, e.g., malignant lymphoma, although elevated levels of neopterin are also seen in some viral and bacterial infections, as well as in diseases of parasitic aetiology. In turn, in transplant patients, increased levels of neopterin signal probable rejection.

“How can we detect the presence of neopterin? A reasonable approach is to use special recognizing materials for this purpose, prepared by molecular imprinting. This technique involves ‘stamping out’ molecules of the desired compound – their shape, but also at least some of the chemical characteristics – in a carefully designed polymer,” explains Dr. Piyush Sindhu Sharma (IPC PAS), the lead author of an article published in the Biosensors and Bioelectronics journal.

During the preparation of the polymer film, molecules of the substance being detected – in this case neopterin – are in a working solution in which their binding sites have to link with recognizing sites of so-called functional monomers. In turn, these monomers should be able to form connections with another monomer, a cross-linking agent which together, after polymerization, form a rigid support structure of the polymer. Next, the molecules of the compound used as a template are washed out from the structure. The result is a durable polymer with molecular cavities of a shape and chemical properties ensuring the capture of molecules of the desired compound from its surroundings.

The basic difficulty in molecular imprinting is the selection of the appropriate functional and cross-linking monomers as well as solvents, their proportions and reaction conditions. PhD student Agnieszka Wojnarowicz (IPC PAS) explains: “With the aid of quantum-chemical calculations, we first check whether there is bonding between our template molecule and selected functional monomers, and whether they will be stable in the solvent used. We also check whether the molecular cavities formed are sufficiently selective, i.e., whether they will primarily capture the molecules we are detecting, and not any that are similar to them. When the calculation results confirm our expectations, that is when we proceed to their experimental confirmation.”

At the IPC PAS a recognizing polymer film with molecular cavities from neopterin has been produced on the surface of an electrode. After immersion in artificial blood serum spiked with neopterin, the film on the electrode captured molecules of the latter, thus leading to a decrease in electrical potential in the connected measuring system. The tests showed that the molecular cavities of the polymer were almost entirely filled with molecules of neopterin despite the presence of molecules of similar structure and properties. This result means that the probability of false positive detection (detecting the presence of neopterin in body fluids not containing it) is negligibly small. The new chemical sensor therefore mainly reacts to what it should react to – and nothing else.

“At present, our chemosensor is a piece of laboratory equipment. However, the production of its key element, that is, the recognizing polymer film, does not pose major problems, and the electronics responsible for electrical measurements can easily be miniaturized. There is nothing standing in the way of building simple and reliable diagnostic equipment, based on our development, in just a few years’ time, which would be affordable not only for medical institutions and doctors’ surgeries, but also for the public in general,” predicts Prof. Kutner (IPC PAS).

New Technology Is Life-Saving Voice for Premature or Critically Ill Infants

A new technology in the Neonatal Intensive Care Unit (NICU) at UC San Diego Health is able to predict the risk of life-threatening infections up to 24 hours before they appear in severely premature or critically ill infants. Infection is the leading cause of death in this fragile patient population.

The Heart Rate Observation system, or HeRO, is an innovative monitoring technology that uses an algorithm to detect slight changes in a baby’s heartbeat that could be an early sign of a major infection, like sepsis — a bacterial infection that is highly dangerous to babies born three pounds or less.

“The challenge with diagnosing sepsis is a lot of symptoms for the early stages of the infection are subtle and nonspecific,” said Erika Fernandez, MD, director of the NICU at UC San Diego Health. “With the HeRO technology, we can detect symptoms of sepsis up to 24 hours before the infection actually happens. This allows us to begin an investigation and intervene with treatment before a baby becomes critically ill.”

UC San Diego Health is the first health care provider in San Diego County to use the technology, which can detect infections in the blood stream and intestines. Historically, physicians and nurses have relied upon their own observations to detect signs of infection. The new system reports vital sign trends much earlier than the human eye or traditional equipment and requires no additional wiring to the baby.

“This state-of-the-art technology lets babies be babies, and mothers can breastfeed without worrying about tangling up or unplugging wires,” said Lawrence Prince, MD, PhD, chief in the Division of Neonatology at UC San Diego Health. “It makes for a much less intimidating experience for families and a highly improved monitoring approach for medical staff.

The HeRO system uses a zero-to-seven surveillance score generated after a heart rate is analyzed, with anything higher than a two considered an alert for possible infection. Prince says the technology is expected to reduce mortality rates in the NICU by 20 percent.

“Physicians and nurses can evaluate a situation much more thoroughly,” said Prince. “When I look at the data on the monitor, I can ask myself, ‘is there something more going on with the patient and do we need to do further testing?’”

Fernandez added that the monitoring system represents part of the next generation of technology to save lives and help achieve the ultimate goal in the NICU: “To provide the highest quality of comprehensive and compassionate care to NICU babies so they can thrive and go home with their families as soon as possible.”

New Funding Sought for Development of Diagnostic Test and Therapeutic Drug for Traumatic Brain Injury (TBI)

Medicortex Finland Oy, a start-up biotechnology company focused on the diagnosis and treatment of neurodegenerative conditions has recently launched a funding round and is seeking investors to help fund research and development of a therapeutic drug and companion diagnostic test for Traumatic Brain Injury (TBI). The company aims to identify a TBI biomarker and, on this basis, develop a diagnostic test for the evaluation of TBI presence and severity. The Company’s other mission is to develop a drug that would limit the long-term effects of TBI, including post-traumatic stress disorder and chronic traumatic encephalopathy.

Numerous studies show that even one mild TBI, also called concussions, can lead to long-term neurodegeneration, which can manifest as sleep disturbance, problems with concentration, nausea, and seizures. When left untreated, these symptoms can develop into more severe neurodegenerative conditions, such as Alzheimer’s or Parkinson’s diseases. As a result of repeated head trauma, many football players, boxers, and ice hockey players suffer from impaired memory and early-onset dementia.

The insidious and devastating consequences of TBI result from the cascade of physiological events that follow the trauma. In the hours, days, and weeks after TBI, the increased permeability of the neuronal membrane allows for an excessive influx of metal ions and circulating free radicals into the brain. These cause a series of protein degradation cascades and oxidation, leading to widespread molecular damage and neuronal cell death. In short, the damage expands and permanent neurodegeneration takes place if TBI is left untreated. Unfortunately, no drug or proper diagnostic test exist for TBI sufferers.

The people most likely to suffer from TBI include, among others, soldiers, athletes and sports professionals. Certainly, the world remembers Michael Schumacher, race car driver and Formula One winner, who suffered a ski accident and fought a serious TBI. No matter how much attention these stories receive, the real story of sports-related TBI lies in the sheer magnitude of the problem. The total annual costs of TBI in Europe exceed €100 billion and the costs show no decrease because the incidence of TBI is increasing steeply. The incidence rate is estimated to be 262 per 100,000 annually, but the true incidence might be even higher because of the lack of proper TBI diagnostics.

Medicortex Finland is working towards the identification of a TBI biomarker and incorporating it into a quick and reliable diagnostic kit that can be easily used by the first responders and healthcare professionals, but also by people with no medical profession. The ideal kit will not only diagnose the presence of TBI, but it will also quantify the severity of injury so that the recovery can be monitored. In the future, the kit will advance the TBI drug development that will again alleviate or even arrest the long-term neurodegeneration after TBI. The company is currently in the human proof-of-concept stage, is seeking an investment to support the fast evaluation of a TBI biomarker from human samples.