Newly Published Data Highlights the Potential of Placenta-based Cell Therapy in Protecting the Heart Affected by Diabetes

Results from a peer-reviewed study in the peer-reviewed journal STEM CELLS Translational Medicine. showed that treating the heart with placenta-based cell therapy called PLX cells, led to improved diastolic function by significantly decreasing cardiomyocyte stiffness, endothelial inflammation, and improving vascularization in preclinical studies. The study’s authors believe the study holds the promise that PLX cells could potentially treat cardiac damage in diabetic patients, particularly in early-stage diabetic cardiomyopathy.

The article, titled “Placenta-derived adherent stromal cells improve diabetes mellitus-associated left ventricular diastolic performance”, highlights the ability of PLX cells, created by Haifa-based Pluristem Therapeutics, to significantly improve cardiac function and describes the underlying mechanism of action. Investigators from the Berlin-Brandenburg Center for Regenerative Therapies, (BCRT) and the Charité-Universitätsmedizin Berlin, Germany, led by Professor Carsten Tschöpe led the study.  Dr. Tschöpe is also a member of the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology.

Diastolic heart failure or diastolic dysfunction refers to a decline in performance of one or both ventricles of the heart during diastole, when the heart is filling with blood. The National Heart, Lung, and Blood Institute reports that approximately 4.8 million Americans suffer from heart failure, with approximately 400,000 new cases appearing annually. Additionally, it has been reported that 50% of these heart failure patients are afflicted with diastolic heart failure (Curr Cardiol Rep, 2017). Heart Failure with Preserved Ejection Fraction and Future Pharmacological Strategies: a Glance in the Crystal Ball. Tschöpe C, Van Linthout S, Kherad B. Curr Cardiol Rep. 2017 Aug;19(8):70

In the study, diabetes mellitus was induced in immune competent mice by streptozotocin application during 5 subsequent days. Seven days after the first streptozotocin injection, animals were intravenously (IV) treated with either PLX cells or saline (placebo). Cardiac parameters were assessed two weeks later. The treatment using PLX cells led to improved diastolic function as indicated by the heart-rate independent 1.2-fold (p<0.005) lower time constant of LV relaxation parameter Tau and the 1.2-fold (p<0.05) increase of the relaxation parameter dP/dtmin.

“Currently, there are limited treatment options for diastolic dysfunction and even fewer for diabetes-induced diastolic dysfunction,” said Dr. Tschöpe. “This study holds promise that PLX cells could potentially treat cardiac damage in diabetic patients, particularly in early-stage diabetic cardiomyopathy. PLX cells are particularly well suited for this indication because they can be used without the need for tissue matching or immunosuppression.”

“Diabetes-induced diastolic dysfunction is a chronic disease that represents a large unmet need. In this study, PLX cells were able to improve cardiac function when administered by simple IV injection. This opens a potentially new method for an effective, low risk treatment for diastolic dysfunction,” said Zami Aberman, Chairman and Co-CEO of Pluristem. “These new data, combined with findings published in the Journal of Surgical Research, which showed that PLX cells were effective in treating cardiac ischemia, suggest that PLX cells have the potential to address a wide range of cardiac disorders.”

FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma

This week, the U.S. Food and Drug Administration approved Yescarta (axicabtagene ciloleucel), a cell-based gene therapy, to treat adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment. Yescarta, a chimeric antigen receptor (CAR) T cell therapy, is the second gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma (NHL).

“Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases. In just several decades, gene therapy has gone from being a promising concept to a practical solution to deadly and largely untreatable forms of cancer,” said FDA Commissioner Scott Gottlieb, M.D. “This approval demonstrates the continued momentum of this promising new area of medicine and we’re committed to supporting and helping expedite the development of these products. We will soon release a comprehensive policy to address how we plan to support the development of cell-based regenerative medicine. That policy will also clarify how we will apply our expedited programs to breakthrough products that use CAR-T cells and other gene therapies. We remain committed to supporting the efficient development of safe and effective treatments that leverage these new scientific platforms.”

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL in adults. NHLs are cancers that begin in certain cells of the immune system and can be either fast-growing (aggressive) or slow-growing. Approximately 72,000 new cases of NHL are diagnosed in the U.S. each year, and DLBCL represents approximately one in three newly diagnosed cases. Yescarta is approved for use in adult patients with large B-cell lymphoma after at least two other kinds of treatment failed, including DLBCL, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.

Each dose of Yescarta is a customized treatment created using a patient’s own immune system to help fight the lymphoma. The patient’s T-cells, a type of white blood cell, are collected and genetically modified to include a new gene that targets and kills the lymphoma cells. Once the cells are modified, they are infused back into the patient.

“The approval of Yescarta brings this innovative class of CAR-T cell therapies to an additional group of cancer patients with few other options – those adults with certain types of lymphoma that have not responded to previous treatments,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER).

The safety and efficacy of Yescarta were established in a multicenter clinical trial of more than 100 adults with refractory or relapsed large B-cell lymphoma. The complete remission rate after treatment with Yescarta was 51 percent.

Treatment with Yescarta has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR-T cells causing high fever and flu-like symptoms, and for neurologic toxicities. Both CRS and neurologic toxicities can be fatal or life-threatening. Other side effects include serious infections, low blood cell counts and a weakened immune system. Side effects from treatment with Yescarta usually appear within the first one to two weeks, but some side effects may occur later.

Because of the risk of CRS and neurologic toxicities, Yescarta is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Yescarta be specially certified. As part of that certification, staff involved in the prescribing, dispensing or administering of Yescarta are required to be trained to recognize and manage CRS and nervous system toxicities. Also, patients must be informed of the potential serious side effects and of the importance of promptly returning to the treatment site if side effects develop.

To further evaluate the long-term safety, the FDA is also requiring the manufacturer to conduct a post-marketing observational study involving patients treated with Yescarta.

The FDA granted Yescarta Priority Review and Breakthrough Therapy designations. Yescarta also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The Yescarta application was reviewed using a coordinated, cross-agency approach. The clinical review was conducted by the FDA’s Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.

The FDA granted approval of Yescarta to Kite Pharma, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines, and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Newly described process in Parkinson’s protein as a potential new therapy route

An international group of researchers led by Professor Wim Versées (VIB-VUB) has unraveled the workings of an essential mechanism in ‘Parkinson’s protein’ LRRK2. Their study demonstrates a direct link between the protein’s ‘dimerization’ – two copies that are bound together -and mutations that lead to Parkinson’s disease. This process could eventually lead to a promising therapy route. This research has been published in the leading academic journal Nature Communications.

Approximately 4 million people worldwide currently suffer from Parkinson’s disease, and this number is only expected to increase. The most frequent genetic causes of the illness are mutations in the gene responsible for controlling the production of protein LRRK2, which includes two enzymes: a kinase and a GTPase. Because this kinase is at the root of neuronal problems, kinase inhibitors have already been clinically tested. However, these inhibitors eventually cause lung and kidney problems, making it imperative for scientists to seek alternative solutions.

Parkinson’s protein comes in a single or doubled state

In close collaboration with Prof. Arjan Kortholt (University of Groningen), the team of Prof. Wim Versées (VIB-VUB) sought a better understanding of LRRK2’s complex structure. It is already known that the kinase portion of the protein is active in the protein’s ‘dimeric’ or ‘double’ state, which involves two identical copies of the protein bound together. Using this information as a starting point, the team investigated how this binding is established. To do so, the scientists observed similar proteins occurring in certain bacteria.

Prof. Wim Versées (VIB-VUB): “The GTPase enzyme, a component of LRRK2, regulates the state of the entire protein. In doing so, it determines whether a LRRK2 protein is in its inactive ‘single’ state, or its active ‘double’ state. In addition, we saw a clear link between the protein dimerization and genetic mutations in Parkinson’s disease. As a result, this regulation process bconstitutes an attractive new target for future drug development.”

Prof. Arjan Kortholt (Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen): “Our study is a milestone in the long-term scientific discussion covering the dimeric state of LRRK2 and its link with Parkinson’s. But although this is a significant step forward, it will be quite some time before we understand all the details enough to manipulate the process.”

Note: Wim Versées is part of the lab of Jan Steyaert of the VIB-VUB Center for Structural Biology

German research advances in cancer and blood disorders reported in human gene therapy

Virotherapy capable of destroying tumor cells and activating anti-tumor immune reactions, and the use of engineered hematopoietic stem cells (HSCs) to deliver replacement genes that have the potential to cure blood diseases are among the key areas of gene therapy being advanced by German researchers and highlighted in a special issue of Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The issue is available free on the Human Gene Therapy website.

The special focus issue entitled “German Gene Therapy Research — Part 1 ,” was developed by Guest Editors Christof von Kalle, MD, Boris Fehse, PhD, and Hildegard Büning, PhD. Dr. Büning, Hannover Medical School, is Editor of Human Gene Therapy Methods and serves as Chair of the 25th Anniversary ESGCT Congress, October 17-20, in Berlin.

In the special issue, Guy Ungerechts and Christine Engeland led a team of colleagues from Germany and Luxembourg in coauthoring the review article entitled “Virotherapy Research in Germany: From Engineering to Translation.” The researchers present the latest preclinical and clinical research activities to engineer oncolytic viruses, which selectively infect tumor cells, for use in tumor-targeted gene therapy. They discuss the different types of virus platforms being investigated–including adenovirus, arenavirus, measles vaccine virus, parvovirus, and vaccinia virus — and the potential to take advantage of the immunotherapeutic properties of oncolytic viruses and of their use in combination with other types of pharmaco-, radio-, and immunotherapy.

In the review article “Promises and Challenges in Hematopoietic Stem Cell Gene Therapy,” Saskia Kohlscheen, Halvard Bonig, and Ute Modlich, Paul-Ehrlich-Institute (Langen), Goethe University (Frankfurt), German Red Cross Blood Service Baden-Württemberg-Hessen (Frankfurt), Germany, and University of Washington, Seattle, describe the state-of-the-art in HSC-directed gene therapy, including viral vector delivery systems, transduction of HSCs, and protocols prior to HSC transplantation. The researchers discuss the main targets for this innovative approach, focusing on immunodeficiencies and inborn errors of metabolism, what has been learned to date from the limiting clinical studies performed, and how best to move forward to overcome the challenges the field still faces.

“The rapid pace of innovation among gene and cell therapy researchers in Germany is striking and significant,” says Editor-in-Chief Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School, Worcester, MA. “We are very proud to reflect the impact of German gene therapy science in this special issue of Human Gene Therapy.”

Blood pressure medication does not completely restore vascular function

Treatments for high blood pressure do not totally reverse its damaging effects on the vascular rhythms that help circulation of the blood say researchers.

The World Health Organisation says hypertension affects about 40% of those aged over 25 and is a major risk factor for heart disease, stroke and kidney failure.

An interdisciplinary group of scientists from Lancaster University found that conventional medication aimed at reducing high blood pressure restored normal vascular rhythms only in the largest blood vessels but not the smallest ones.

Professor Aneta Stefanovska said: “It is clear that current anti-hypertensive treatments, while successfully controlling blood pressure, do not restore microvascular function.”

Based on a networks physiology approach, the researchers compared a group aged in their twenties and two older groups aged around 70 – one with no history of hypertension and the other taking medications for high blood pressure.

In the older group being treated for high blood pressure the drug treatment restored normal function at the level of arterioles and larger vessels.

But when the researchers studied the nonlinear dynamical properties of the smallest blood vessels in the body, they found differences between the two older groups.

“Specifically, current hypertensive treatment did not fully restore the coherence or the strength of coupling between oscillations in the heart rate, respiration, and vascular rhythms (vasomotion).

“These are thought to be important in the efficient and adaptive behaviour of the cardiovascular system. Indeed, one aspect of ageing is the progressive physiological weakening of these links that keep the cardiovascular system reactive and functional.

“The results have not only confirmed previous observations of progressive impairment with age of the underlying mechanisms of coordination between cardiac and microvascular activity, but for the first time have revealed that these effects are exacerbated in hypertension.

“Current antihypertensive treatment is evidently unable to correct this dysfunction. Our novel multiscale analysis methods could help in optimising future drug developments that would benefit from taking microvascular function into account.”

A Dietary Supplement Dampens the Brain Hyperexcitability Seen in Seizures or Epilepsy

Seizure disorders — including epilepsy — are associated with pathological hyperexcitability in brain neurons. Unfortunately, there are limited available treatments that can prevent this hyperexcitability. However, University of Alabama at Birmingham researchers have found that inducing a biochemical alteration in brain proteins via the dietary supplement glucosamine was able to rapidly dampen that pathological hyperexcitability in rat and mouse models.

These results represent a potentially novel therapeutic target for the treatment of seizure disorders, and they show the need to better understand the physiology underlying these neural and brain circuit changes.

Proteins are the workhorses of living cells, and their activities are tightly and rapidly regulated in responses to changing conditions. Adding or removing a phosphoryl group to proteins is a well-known regulator for many proteins, and it is estimated that human proteins may have as many as 230,000 sites for phosphorylation.

A lesser-known regulation comes from the addition or removal of N-acetylglucosamine to proteins, which is usually controlled by glucose, the primary fuel for neurons. Several years ago, neuroscientist Lori McMahon, Ph.D., professor of cell, developmental and integrative biology at UAB, found out from her colleague John Chatham, D.Phil., a UAB professor of pathology and a cardiac physiologist, that brain cells had the second-highest amounts of proteins with N-acetylglucosamine, or O-GlcNAcylation, in the body.

At the time, very little was known about how O-GlcNAcylation might affect brain function, so McMahon and Chatham started working together. In 2014, McMahon and Chatham, in a study led by graduate student Erica Taylor and colleagues, reported that acute increases in protein O-GlcNAcylation caused long-term synaptic depression, a reduction in neuronal synaptic strength, in the hippocampus of the brain. This was the first time acute changes in O-GlcNAcylation of neuronal proteins were shown to directly change synaptic function.

Since neural excitability in the hippocampus is a key feature of seizures and epilepsy, they hypothesized that acutely increasing protein O-GlcNAcylation might dampen the pathological hyperexcitability associated with these brain disorders.

That turned out to be the case, as reported in the Journal of Neuroscience study, “Acute increases in protein O-GlcNAcylation dampen epileptiform activity in hippocampus.” The study was led by corresponding author McMahon and first author Luke Stewart, a doctoral student in the Neuroscience Theme of the Graduate Biomedical Sciences Program. Stewart is co-mentored by McMahon and Chatham.

“Our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics,” they wrote in their research significance statement. The researchers caution that the mechanism underlying the dampening is likely to be complex.

Research details
Glucose, the major fuel for neurons, also controls the levels of protein O-GlcNAcylation on proteins. However, high levels of the dietary supplement glucosamine, or an inhibitor of the enzyme that removes O-GlcNAcylation, leads to rapid increases in O-GlcNAc levels.

In experiments with hippocampal brain slices treated to induce a stable and ongoing hyperexcitability, UAB researchers found that an acute increase in protein O-GlcNAcylation significantly decreased the sudden bursts of electrical activity known as epileptiform activity in area CA1 of the hippocampus. An increased protein O-GlcNAcylation in normal cells also protected against a later induction of drug-induced hyperexcitability.

The effects were seen in slices treated with both glucosamine and an inhibitor of the enzyme that removes O-GlcNAc groups. They also found that treatment with glucosamine alone for as short a time as 10 minutes was able to dampen ongoing drug-induced hyperexcitability.

In common with the long-term synaptic depression provoked by increased O-GlcNAcylation, the dampening of hyperexcitability required the GluA2 subunit of the AMPA receptor, which is a glutamate-gated ion channel responsible for fast synaptic transmission in the brain. This finding suggested a conserved mechanism for the two changes provoked by increased O-GlcNAcylation — synaptic depression and dampening of hyperexcitability.

The researchers also found that the spontaneous firing of pyramidal neurons in another region of hippocampus, area CA3, was reduced by increased O-GlcNAcylation in normal brain slices and in slices with drug-induced hyperexcitability. This reduction in spontaneous firing of CA3 pyramidal neurons likely contributes to decreased hyperexcitability in area CA1 since the CA3 neurons directly excite those in CA1.

Similar to the findings for brain slices, mice that were treated to increase O-GlcNAcylation before getting drug-induced hyperexcitability had fewer of the brain activity spikes associated with epilepsy that are called interictal spikes. Several drug-induced hyperexcitable mice had convulsive seizures during the experiments — this occurred in both the increased O-GlcNAcylation mice and the control mice. Brain activity during the seizures differed between these two groups: The peak power of the brain activity for the mice with increased O-GlcNAcylation occurred at a lower frequency, as compared with the control mice.

FDA Panel Approves Gene Therapy For A Form Of Childhood Blindness

An advisory board at the  Food and Drug Administration today endorsed the first gene therapy for an inherited disorder — a rare condition that causes a progressive form of blindness that usually starts in childhood.

The recommendation came in a unanimous 16-0 vote after a day full of hearings that included emotional testimonials by doctors, parents of children blinded by the disease and from children and young adults helped by the treatment.

The treatment will now progress to a final decision from the FDA and, if approved, will be the first gene therapy legally available in the United State for an inherited disorder. The FDA is under no obligation to follow the advisory board’s recommendation but usually does.

The treatment, which will be marketed as Luxturna, fixes a mutation in the RPE65 gene. It involves a single treatment to each eye, which introduces genetically engineered virus particles carrying a corrected version of the mutated gene. Spark Therapeutics, the treatment’s developer, estimates that 6,000 people around the world could benefit from this treatment. More than 90 percent of the patients treated in the study showed some improvement in eyesight within just a few days of treatment.

This is a huge step forward for the field of gene therapeutics. “[O]n multiple fronts, it’s a first and ushers in a new era of gene therapy,” assistant professor of ophthalmology at the Oregon Health and Science University, Paul Yang, told NPR.

Alone, this treatment could also be applied to other formally incurable genetic eye diseases. “There are a lot of retinal diseases like this, and if you added them together it’s a big thing because they are all incurable,” says lead researcher Albert Maguire in an interview with NPR before the hearing.

Sources: NPR

FDA awards 15 grants for clinical trials to stimulate product development for rare diseases

The U.S. Food and Drug Administration today announced that it has awarded 15 new clinical trial research grants totaling more than $22 million over the next four years to boost the development of products for patients with rare diseases. These new grants were awarded to principal investigators from academia and industry across the country.

“Given the often small number of patients facing certain rare diseases, there can be limited resources devoted to researching new drugs and unique challenges with recruiting and conducting the clinical trials needed to develop medicines targeted to rare conditions,” said FDA Commissioner Scott Gottlieb, M.D. “For more than 30 years, the FDA has been committed to investing in trials of potentially life-changing treatments for patients with rare diseases, especially in situations where commercial incentives may not be enough to foster the collection of quality data that can ultimately support efficient development and FDA-approval of treatments for patients who lack effective alternatives. By helping to support the cost of development of these potential new drugs, and reduce some of the financial risk, we also hope that these grants will lower the cost of the capital needed to develop these products, boost competition and translate into lower prices for successful medicines. This can help increase access to resulting therapies.”

The FDA awarded the grants through the Orphan Products Clinical Trials Grants Program, funded by Congressional appropriations, to encourage clinical development of drugs, biologics, medical devices, or medical foods for use in rare diseases. The grants are intended for clinical studies evaluating the safety and effectiveness of products that could either result in, or substantially contribute to, the FDA approval of products targeted to rare diseases.

Approximately 33 percent of the new grant awards fund studies to accelerate cancer research by enrolling patients with rare forms of cancer. Sixty percent of these studies target devastating forms of brain and peripheral nervous system cancers, including glioblastoma and anaplastic astrocytoma. One study recruits children as young as one year old with a particularly aggressive form of neuroblastoma.

Other studies span a broad range of diseases and address unmet needs like treating hyperphagia in Prader-Willi syndrome, a genetic disease that primarily affects children, and idiopathic osteoporosis in premenopausal women. Two studies recruit patients with unmet need in sickle cell disease. In addition, one study evaluates a new combination of existing antibiotics to treat pulmonary tuberculosis (TB), including multidrug-resistant TB. TB is a leading killer of HIV-positive patients, and, though not as common in the United States, one-third of the world’s population is infected with TB.

“The clinical trials grant program is an important part of the FDA’s ongoing commitment to encouraging and supporting the development of safe and effective therapies for rare diseases,” said Rachel Sherman, M.D., M.P.H, FDA’s principal deputy commissioner. “The grants awarded this year will support needed research in a range of rare diseases that have little, or no, treatment options for patients.”

A total of 76 grant applications were received for this fiscal year, with a funding rate of 20 percent. The grant recipients for fiscal year 2017 are the following:

  • AADi, LLC (Pacific Palisades, California), Neil Desai, Phase 2 Study of ABI-009 for the Treatment of Advanced Perivascular Epithelioid Cell Tumors — about $2 million over four years
  • Albert Einstein College of Medicine (Bronx, New York), Caterina Minniti, Phase 2 Study of Topical Sodium Nitrite for the Treatment of patients with Sickle Cell Disease & Leg Ulcers — about $2 million over four years
  • Albert Einstein College of Medicine (Bronx, New York), Eric Hollander, Phase 2 Study of Oxytocin for the Treatment of Hyperphagia in Prader-Willi Syndrome — about $1.5 million over three years
  • Alkeus Pharmaceuticals, Inc. (Cambridge, Massachusetts), Leonide Saad, Phase 2 Study of ALK-001 for the Treatment of Stargardt Disease – about $250,000 over one year
  • CereNova, LLC (Durham, North Carolina), Daniel Laskowitz, Phase 2A Study of CN-105 for the Treatment of Intracerebral Hemorrhage — about $1 million over two years
  • Columbia University Medical Center (New York), Elizabeth Shane, Phase 2 Study of Teriparatide for the Treatment of Idiopathic Osteoporosis in Premenopausal Women — about $1.9 million over four years
  • Columbia University Medical Center (New York), Gulam Manji, Phase 2 Study of PLX3397 + Sirolimus for the Treatment of Malignant Peripheral Nerve Sheath Tumors — $2 million over four years
  • Dana-Farber Cancer Institute (Boston), Steven Dubois, Phase 1 Study of dual PI3K/BRD4 Inhibitor SF1126 for the Treatment of Neuroblastoma — $750,000 over three years
  • Duke University (Durham, North Carolina), Allan Kirk, Phase 2 Study of Belatacept, Alemtuzumab, and Sirolimus in Renal Transplantation — about $1 million over three years
  • Johns Hopkins University (Baltimore), Susan Dorman, Phase 2a Study of Rifampin, Merrem and Augmentin for the Treatment of Pulmonary Tuberculosis — about $2 million over four years
  • New York Medical College (Valhalla, New York), Mitchell Cairo, Phase 2 Defibrotide for the Prevention of Complications in High-Risk Sickle Cell Disease Patients Following Allogeneic Stem Cell Transplantation – about $1.75 million over four years
  • Protalex, Inc (Florham Park, New Jersey), Richard Francovitch, Phase 1/2 Study of PRTX-100 for the Treatment of Immune Thrombocytopenia — about $500,000 over two years
  • Sloan-Kettering Institute for Cancer Research (New York), Ping Chi, Phase 2 Study of MEK162 & Imatinib for the Treatment of Gastrointestinal Stromal Tumors — $2 million over four years
  • Tocagen Inc. (San Diego), Asha Das, Phase 2/3 Study of Toca 511 +Toca FC versus SOC in Recurrent Glioblastoma and Anaplastic Astrocytoma — $2 million over four years
  • University of California, San Francisco (San Francisco), Marshall Stoller, Phase 2 Study of Lipoic Acid for the Treatment of Cystine Nephrolithiasis — about $2 million over four years

Since its creation in 1983, the Orphan Products Clinical Trials Grants Program has provided more than $390 million to fund more than 600 new clinical studies. At least 60 grants have supported the marketing approval of more than 55 orphan products. Three of the studies funded by this grants program supported product approvals in 2016 alone, including much needed treatments for aortic wall injury in patients with coarctation of the aorta and severe hepatic veno-occlusive disease (also known as sinusoidal obstructive syndrome).

Better ‘Mini Brains’ Could Help Scientists Identify Treatments for Zika-Related Brain Damage

UCLA researchers develop improved technique for creating brain tissue from stem cells

UCLA researchers have developed an improved technique for creating simplified human brain tissue from stem cells. Because these so-called “mini brain organoids” mimic human brains in how they grow and develop, they’re vital to studying complex neurological diseases.

In a study published in the journal Cell Reports, the researchers used the organoids to better understand how Zika infects and damages fetal brain tissue, which enabled them to identify drugs that could prevent the virus’s damaging effects.

The research, led by senior author Ben Novitch, could lead to new ways to study human neurological and neurodevelopmental disorders, such as epilepsy, autism and schizophrenia.

“Diseases that affect the brain and nervous system are among the most debilitating medical conditions,” said Novitch, UCLA’s Ethel Scheibel Professor of Neurobiology and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “Mini brain organoids provide us with opportunities to examine features of the human brain that are not present in other models, and we anticipate that their similarity to the real human brain will enable us to test how various drugs impact abnormal or diseased brain tissue in far greater detail.”

For about five years, scientists have been using human pluripotent stem cells, which can create any cell type in the body, to develop mini brain organoids. But the organoids they produced have generally been difficult to use for research because they had highly variable structures and inconsistent cellular composition, and because they didn’t correctly mimic the layered structure of the brain and were too small — often no bigger than the head of a pin. They also didn’t survive very long in the laboratory and contained neural tissue that was difficult to classify in relation to real human brain tissue.

The organoids developed by Novitch’s group have a stratified structure that accurately mimics the human brain’s onion-like layers, they survive longer and have a larger and more uniform shape.

To create the brain organoids, Novitch and his team made several modifications to the methods that other scientists used previously: The UCLA investigators used a specific number of stem cells and specialized petri dishes with a modified chemical environment; previous methods used varying amounts of cells and a different type of dish. And they added a growth factor called LIF, which stimulated a cell-signaling pathway that is critical for human brain growth.

The researchers found critical similarities between the organoids they developed and real human brain tissue. Among them: The organoids’ anatomy closely resembled that of the human cortex, the region of the brain associated with thought, speech and decision making; and a diverse array of neural cell types commonly found in the cortex were all present in the organoids, and they exhibited electrical activities and network function, meaning they were capable of communicating with one another much like the neural networks in the human brain do.

The UCLA scientists also found that they could modify their methodology to make other parts of the brain including the basal ganglia, which are involved in the control of movement and are affected by neurodegenerative conditions such as Parkinson’s disease and Huntington’s disease.

“While our organoids are in no way close to being fully functional human brains, they mimic the human brain structure much more consistently than other models,” said Momoko Watanabe, a UCLA postdoctoral fellow and the study’s first author. “Other scientists can use our methods to improve brain research because the data will be more accurate and consistent from experiment to experiment and more comparable to the real human brain.”

When the team exposed the organoids to Zika, they discovered specifically how the virus destroys neural stem cells, the cells from which the brain grows during fetal development. Novitch’s team found that there are four specific molecules, called receptors, on the outer surface of neural stem cells; previous studies have indicated that the Zika virus could bind to these receptors and infect the cells. The researchers then mapped the changes that occur in the neural stem cells after Zika infection, presenting a clearer picture of how the virus infiltrates and harms fetal brain tissue.

Zika is associated with an unusually high incidence of fetal brain damage, so understanding how neural stem cells are affected by the virus could be an important new step toward a treatment.

The researchers tested several drugs on the Zika-infected organoids. They found three that are effective at blocking the virus’s entry into the brain tissue, including two that protected neural stem cells by preventing the interaction between the virus and entry receptors on the neural stem cells. In previous studies by Novitch and other UCLA colleagues, one of those drugs reduced brain damage in fetal mice infected with Zika.

“Many neurological diseases or conditions arise from defects in the way one neuron communicates with another or from the way an external factor, such as a virus, interacts with neural cells,” Novitch said. “If we can focus in at the level of cellular communication, we should be able to model those undesirable cellular interactions and counteract them with drugs or other therapies.”

The team plans to continue using its improved organoids to better understand human brain development and to learn more about autism spectrum disorders, epilepsy and other neurological conditions.

The experimental drugs used in the preclinical study have not been tested in humans or approved by the Food and Drug Administration for treating Zika in humans.

Intermountain Healthcare Researchers Launch Major Three-Year Genomics Breast Cancer Study

Cancer researchers at Intermountain Medical Center and the Intermountain Healthcare Precision Genomics Program in Salt Lake City are launching a three-year study to determine if a blood test that looks for DNA from a cancer tumor can be used to complement mammography to improve the way breast cancer is diagnosed.

The goal of this new genomics study is to show whether screening patients for the presence of circulating tumor DNA, known as ctDNA, can successfully detect breast cancer using a blood draw.

Breast cancer is the second-leading cause of cancer deaths in women, behind only lung cancer, with an estimated 40,610 deaths each year from the disease. Nearly 253,000 new cases of invasive breast cancer are diagnosed each year, along with about 60,000 non-invasive, early-stage cases, according to the American Cancer Society.

The Intermountain study is unique in that researchers will also help develop a specific test to check for ctDNA, and will have access to both mammography results and the DNA blood test results, which will allow a direct comparison of the “liquid-based biopsy” to be made.

The idea behind the science is simple, though researchers say the execution is not yet proven: Little pieces of DNA that come from dying cells end up in the peripheral blood stream, including circulating tumor cells. The goal of researchers is to use those markers to identify breast cancer, perhaps even before mammography can detect it, said Lincoln Nadauld, MD, PhD, co-lead investigator of the study and executive director of the Intermountain Healthcare Precision Genomics Program.

“As a tumor is growing, some of the cells will die and their DNA will end up in the peripheral blood stream,” Dr. Nadauld said. “We’re able to distinguish DNA from cancer vs. DNA from normal cells. The idea is to leverage DNA to see if we can detect that it comes from a tumor.”

In the study, patients with known breast cancer will be compared with those in a screening group.

“We don’t know what we’ll see yet,” said Brett Parkinson, MD, co-lead investigator of the study, who is also imaging director and medical director of the Intermountain Medical Center Breast Care Center in Murray. “We might find those who have breast cancer will have a negative blood test and learn it’s not a good screening tool.”

Even a successful blood test isn’t expected to replace mammography outright. If it detects the circulating tumor DNA, imaging would be needed to find the tumor. But it could help eliminate unneeded biopsies, Dr. Parkinson added.

Dr. Nadauld said cancers have mutations in their DNA that aren’t always unique.

“Sometimes those are the same whether it’s a breast cancer or a colon cancer. If we do create a blood test, it’s possible it would detect mutant DNA, but it might look so similar it would be hard to tell what kind of cancer it came from,” he said. “That’s part of what this trial is going to accomplish. We want to determine the signature for early breast cancer.”

If successful, a liquid biopsy might also be used to monitor a breast cancer survivor for recurrence, Dr. Nadauld said. It might even lead to development of similar tests for different types of cancer. But that would be a challenge for the future.

“We want to approach this with laser-like focus,” he said. “It’s needed to help us diagnose breast cancer. We need to detect it earlier, when it’s curable.”

Breast cancer survival depends largely on finding the disease early —and mammography is the only screening exam that’s been shown by multiple randomized clinical trials to reduce the mortality rate for breast cancer. Since 1991, the death rate from breast cancer is down 38 percent, largely because mammography screening tests lead to early detection.

Although mammography finds most breast cancers, it may not detect malignancy in women who have dense breast tissue, especially premenopausal women, or those under 50.

“We pick up most breast cancer in women with average breast density,” said Dr. Parkinson. “When breast tissue is denser, we can miss up to 30 percent of breast cancers.”

Mammography also has a false-positive or call-back rate of 10 percent, which may subject women to additional imaging and emotional duress. Plus, a mammogram can be uncomfortable, since breast tissue is compressed for imaging, which also exposes a woman to a small amount of radiation. Mammography may also be inconvenient, often requiring women to take time off work, he noted.

For those, and perhaps other reasons, mammography screening rates in the United States are low. In Utah, only about 65 percent of eligible women are screened, despite Intermountain Healthcare’s recommendations that women over 40 undergo yearly screening mammography. All major medical and advocacy organizations agree that screening every year after a woman is 40 saves more lives. About 20 percent of breast cancers occur in women under 50.

Dr. Nadauld said the unusual confluence of three factors weigh in Intermountain’s favor on this quest, starting with access to a lot of patients in one place who are getting mammograms, which are the gold standard screening test for breast cancer. Second, the researchers have access to the results of those mammograms; they know if the results were positive or negative. The third major factor is Intermountain’s genomic technology capability.

“This is the big conversation right now in all of oncology — the use of liquid biopsy to determine how to screen for breast cancer, a woman’s risk of recurrence, and how to monitor their treatment,” Dr. Nadauld said.

The study is being made possible by a generous donation from the Beesley Family Foundation.

Moffitt Researchers Discover New Targets for Approved Cancer Drug

New study shows ALK inhibitor ceritinib may have the ability to be used for more than ALK-rearranged non-small cell lung cancer

Developing new drugs to treat cancer can be a painstaking process taking over a decade from start to Food and Drug Administration approval. Scientists are trying to develop innovative strategies to identify and test new drugs quicker and more efficiently. A team of researchers at Moffitt Cancer Center used cellular drug screening, functional proteomics and computer-based modeling to determine whether drugs with well-known targets may be repurposed for use against other biological targets. They found that an FDA approved drug for non-small cell lung cancer called ceritinib has anti-cancer activity against previously unknown targets. Their results were published today in the journal, Nature Chemical Biology.

For the past 20 years, there has been an emphasis on targeted cancer therapy – targeting a specific driver of cancer development to minimize side effects typically seen with chemotherapy. This personalized approach has been successful in certain types of cancer that are primarily driven by a single DNA alteration, such as found in chronic myeloid leukemia. However, the majority of cancers are not caused by a single mutation; rather, cancer is more commonly caused by a large network of mutations and alterations. Some researchers, including those from Moffitt, are beginning to rethink the targeted approach to cancer therapy. They believe that developing drugs that act on multiple targets, called a polypharmacology approach, may more effectively treat those cancers that have a network of alterations.

In order to identify drugs that act on multiple targets, Moffitt researchers screened 240 drugs that are either FDA approved or in clinical development. They noticed that the drug ceritinib acts differently than other drugs in its class. Ceritinib targets a protein called ALK, and is approved to treat patients with ALK-rearranged metastatic non-small cell lung cancer. Their research found that ceritinib also inhibits the growth of lung cancer cells that do not have genetic alterations in the ALK gene.

After an extensive set of experiments to learn how ceritinib worked in cells without ALK rearrangements, they discovered the drug inhibits several other previously unknown targets, and that these signals converge onto a protein known to be responsible for causing drug resistance to paclitaxel. Importantly, the researchers showed that ceritinib combined with paclitaxel was more effective than either agent alone at reducing cell viability.

These findings suggest that ceritinib together with paclitaxel may be effective against other cancers that do not have ALK rearrangements, and that this drug combination may be used to target a network of changes in cancer.

“The results also demonstrate the benefits of using a combined screening, proteomics and computer-based modeling approach to identify drugs that act on multiple targets and to determine how they function,” said study lead author Uwe Rix, Ph.D., assistant member of the Drug Discovery Program at Moffitt. “In the future, this strategy may facilitate further drug repurposing efforts and lead to an increase in new therapy options for patients with difficult-to-treat diseases.”

Gene Identified That May Provide Potential Therapy for Cerebral Cavernous Malformations

Researchers at University of California San Diego School of Medicine, with national collaborators, have identified a series of molecular clues to understanding the formation of cerebral cavernous malformations (CCMs). The study offers the first genome-wide analysis of the transcriptome of brain microvascular endothelial cells after KRIT1 inactivation. Findings were published September 28 in the Journal of Experimental Medicine.

“These mouse studies reveal a critical mechanism in the pathogenesis of cerebral cavernous malformations and point to the possibility of using angiogenesis inhibitors, such as TSP1 for potential therapy,” said Mark H. Ginsberg, MD, professor of medicine, UC San Diego School of Medicine.

CCMs are collections of enlarged and irregular blood vessels in the central nervous system (CNS), for which there is no drug therapy. The vessels are prone to leakage causing headaches, seizures, paralysis, hearing or vision loss, or bleeding in the brain. There are two forms of the condition: familial and sporadic, affecting 1 in 200 patients in the U.S. The current treatment for CCMs involves invasive surgery, however, surgery is not possible for all patients due to location of vascular lesions within the CNS.

The most common cause of familial cavernous malformations is mutations of KRIT1. The protein produced from this gene is found in the junctions connecting neighboring blood vessel cells. Loss of function mutations in KRIT1 result in weakened contacts between blood vessel cells and CNS vascular abnormalities as seen in CCMs.

“Inactivation of KRIT1 in endothelial cells causes a cascade of changes in the expression of genes that regulate cardiovascular development,” said Ginsberg. “What we learned is that reduced expression of a protein encoded by one of these genes, TSP1, contributes to the growth of CCMs. Loss of one or two copies of THBS1, the gene that encodes TSP1, makes a mouse model of the disease much worse. Conversely, administration of 3TSR, a fragment of TSP1, reduces lesions in this mouse model. This means that replacement of TSP1 by 3TSR or other angiogenesis inhibitors may be a preventative for CCMs or treatment of the disease.”

Combination Treatment Targeting Glucose in Advanced Brain Cancer Shows Promising Results in Preclinical Study

UCLA scientists have discovered a potential combination treatment for glioblastoma, the deadliest form of brain cancer in adults. The three-year study led by Dr. David Nathanson, a member of UCLA’s Jonsson Comprehensive Cancer Center, found that the drug combination tested in mice disrupts and exploits glucose intake, essentially cutting off the tumor’s nutrients and energy supply. This treatment then stimulates cell death pathways—which control the cancer cells’ fate—and prevents the glioblastoma from getting bigger.

The combination treatment works by manipulating sugar metabolism with the FDA-approved drug erlotinib against one of the most common genetic alterations in glioblastoma, a cell surface protein known as EGFR. The researchers found that erlotinib treatment reduces sugar uptake in the majority of glioblastomas studied, thereby creating a metabolically vulnerable state for these brain tumors. The researchers then exploited this metabolic deficiency with an experimental drug called idasanutlin, which activates a protein called p53 to promote glioblastoma cell death and stimulate tumor regression in mice. Nathanson and his team also demonstrated that positron emission tomography, or PET, imaging can predict which tumors would respond best to this combination treatment.

BACKGROUND 

These findings build on previous research by Nathanson, who was a co-author of the initial study in 2013. That research showed that EGFR genetic alterations promote sugar uptake in glioblastomas. The researchers also found they could not directly attack sugar metabolism in the brain, due to potential side effects, since normal tissue requires sugar to survive.

Glioblastoma is one of the most lethal human cancers, with a median survival rate in adults of just 15 months after diagnosis.

METHOD

Researchers conducted the study using 19 human glioblastoma cells from different people. Some of the cells were implanted in the mice to analyze the effectiveness of the drug combination treatment. The researchers used PET imaging to predict which tumors would benefit from the drug combination.

The researchers also used an assay, or an assessment tool, developed by collaborators at Harvard University to measure how close a brain tumor cell is to the death threshold while targeting sugar metabolism.

IMPACT

The next stage of research will be to test the combination treatment on people with glioblastomas in clinical trials. Eventually, the researchers might design a new strategy involving the combination treatment that would attack and kill the glioblastoma altogether.

Good-Guy Bacteria May Help Cancer Immunotherapies Do Their Job

Individuals with certain types of bacteria in their gut may be more likely to respond well to cancer immunotherapy, researchers at the Harold C. Simmons Comprehensive Cancer Center found in a study of patients with metastatic melanoma.

The incidence of melanoma has been increasing over the past 40 years. Immunotherapies have dramatically improved the outlook for patients with metastatic melanoma in the past half-dozen years, but still only about half of these patients go into remission.

UT Southwestern cancer researchers analyzed the gut bacteria of 39 melanoma patients who were treated with immunotherapies and found a strong association between a good response and the presence of particular bacteria.

“Our research suggests there were certain good-guy bacteria that are needed to optimize the effectiveness of checkpoint inhibitors. These bacteria somehow prime your immune system so that it’s better able to attack cancer cells and kill them,” said senior author Dr. Andrew Koh, Associate Professor of Pediatrics and Microbiology with the Simmons Cancer Center.

Rick Spurr, former CEO of Zix, a company that provides email encryption services for banks and health care facilities, volunteered for the study that helped identify the link. The grandfather of six was diagnosed with metastatic melanoma, which was discovered on his lungs while he was fighting off a bout of pneumonia.

Mr. Spurr was treated with an every-other-week infusion of nivolumab, an immunotherapy drug that acts by lifting a brake on the immune system, allowing the body’s natural defenses to go into overdrive.

“I felt virtually no side effects from the treatment,” he said. “I started the treatment in the summer and I was skiing in November.”

Researchers found he had the beneficial gut bacteria and suspect this microbiome contributed to the outcome. As a group, patients who responded well to the immunotherapy had three specific bacteria:

  • Bacteroides thetaiotaomicron
  • Faecalibacterium prausnitzii
  • Holdemania filiformis

All three are common normal flora in the human intestinal tract.

After identifying the link, researchers looked for a potential reason for the association between the helper bacteria and immunotherapy effectiveness. “Is it something the bacteria are making? We examined metabolites in these subjects and found the strongest correlation between anacardic acid, present in cashews and mangoes, and the beneficial bacteria,” Dr. Koh said.

Researchers plan to follow up on the current research, which appears in the journal Neoplasia, with larger clinical studies.

“While these preliminary observations do not establish a firm causal connection between gut microbes and immunotherapy efficacy, they may lead eventually to a probiotic cocktail that could be given along with immunotherapy to enhance the chance of response,” said Dr. Koh, Director of Pediatric Hematopoietic Stem Cell Transplantation at UT Southwestern.

The research was supported by the Roberta I. and Norman L. Pollock Fund, the Melanoma Research Fund, the T. Boone Pickens Cancer Research Fund, the Cancer Prevention and Research Institute of Texas, and the National Institutes of Health.

The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 49 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year.

Bariatric surgery lowers cancer risk for severely obese patients

Severely obese patients who undergo bariatric surgery lower their risk of developing cancer by at least a third, according to a University of Cincinnati (UC) College of Medicine researcher leading a large retrospective cohort study of patients in the western United States.

“We found having bariatric surgery is associated with a reduced risk of cancer, especially obesity-associated cancers including postmenopausal breast cancer, endometrial cancer, pancreatic cancer and colon cancer,” explains Daniel Schauer, MD, associate professor in the UC Division of General Internal Medicine and lead researcher. “What’s surprising is how great the risk of cancer was reduced.”

The findings were recently published online in the Annals of Surgery.

The study reviewed medical data of 22,198 individuals who had bariatric surgery and 66,427 nonsurgical patients between 2005 and 2012 with follow-up through 2014. It pulled data from large integrated health insurance and health care delivery systems from five study sites operated by Kaiser Permanente–Southern California, Northern California, Oregon, Colorado and Washington.

More than 80 percent of patients in the study were women.

Patients undergoing bariatric surgery had a 33 percent lower risk of developing any cancer during follow-up, according to the published findings. Schauer says the benefit is greatest among obesity-associated cancers. The risk of postmenopausal breast cancer dropped by 42 percent and while the risk for endometrial cancer dropped 50 percent in severely obese patients. The risk of colon cancer dropped 41 percent while the risk of pancreatic cancer was lowered by 54 percent.

“Cancer risks for postmenopausal breast cancer and endometrial cancer are closely related to estrogen levels,” says Schauer. “Having weight loss surgery reduces estrogen level.”

Bariatric surgery helps reduce the risk of diabetes and insulin levels which may be a risk factor for pancreatic cancer, while the mechanisms for colon cancer are more complicated, says Schauer.

“I think considering cancer risk is one small piece of the puzzle when considering bariatric surgery, but there are many factors to consider. Reductions in diabetes, hypertension and improvements in survival and quality of life are reason enough,” says Schauer. “The study provides an additional reason to consider bariatric surgery.”

The study found no significant association between bariatric surgery and cancer risk among men. Schauer says that may be because the vast majority of study patients are female and at least two of the cancers most impacted by bariatric surgery, postmenopausal breast cancer and endometrial cancer, affect women only.

Multivariable Cox proportional-hazards models were used to examine the incidence of cancer up to 10 years after bariatric surgery compared to the matched nonsurgical patients. After a mean follow-up of 3.5 years, researchers identified 2,543 incident cancers.

About 15 million adults in the United States suffer from severe obesity, which is defined as having a body mass index of greater than 35 kg/m2. Obesity and cancer are closely linked. Obesity is associated with up to 40 percent of all cancers diagnosed in the United States, says Schauer.

Tests with topical treatment strategy for fighting skin cancer yield positive results

Researchers at the University of São Paulo (USP), in Brazil, are testing a technique in mice that combines low-intensity electric current with a formulation containing nanoencapsulated chemotherapy to treat skin cancer.

Applying a low-intensity unidirectional current is one of the ways to ensure that chemical substances penetrate the skin, pushed into the bloodstream through the electric field using a technique known as iontophoresis.

According to preliminary results of the study, cancer-induced mice which received the formulation combined with iontophoresis presented a significantly greater reduction in the size of the tumor than those that received it through injection.

“One of the challenges involved in this type of topical treatment is ensuring that the drug penetrates the stratum corneum – the outermost layer of the epidermis, composed mainly of dead cells. It is an important tissue barrier against the entry of microorganisms, but it also makes it more difficult for medicines to penetrate,” explained Renata Fonseca Vianna Lopez, who supervises the Thematic Project supported by the São Paulo Research Foundation – FAPESP and is also a at the School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP-USP).

In the case of skin cancer, however, the intent is not that the drug penetrates the tissue to get into the bloodstream, but rather that it becomes concentrated in the area below the stratum corneum that requires treatment. This is the reason why, in the study led by Lopez, she chose to place the chemotherapeutic agent inside nanoparticles.

In vivo tests

Using mice, the researchers induced the formation of a tumor associated with one of the most common types of skin cancer – squamous cell carcinoma – through a subcutaneous injection of human tumor cells that overexpress the epidermal growth factor receptor (EGFR). Lopez explained that the presence of this protein causes the tumor to become more aggressive.

The treatment was conducted using a formulation containing chemotherapy agent 5-fluorouracil encapsulated in a nanoparticle (liposome) that functions as an anti-EGFR antibody. The malignant cells are able to capture a larger quantity of the drug encapsulated in these liposomes.

One group of rodents received the tumor formulation through subcutaneous injections and another group received it through topical application combined with iontophoresis. Lopez compared both methods and thus assessed:

“In addition to reducing the size of the tumor, the topical treatment left the tumor less aggressive. We believe that this method combined with iontophoresis allows the drug to be dispersed over the entire area of the tumor, whereas the subcutaneous application causes it to be concentrated in a single location,” Lopez noted.

Versatile technique

In another study, Lopez’ group used a stiffer type of polymeric nanoparticle, one containing the anti-inflammatory dexamethasone associated with iontophoresis for the treatment of uveitis – an inflammation of the eye tissue. The results, published in 2015 in the Journal of Controlled Release, is the outcome of the doctoral thesis of Joel Gonçalves Souza, winner of the 2015 Capes Thesis Award in Pharmacy.

“When we apply the medicine directly to the eye, it is quickly eliminated through the defense mechanisms, such as tears. Increased penetration and better results are obtained by using the application method combined with iontophoresis,” Lopez said.

Currently, in dissertation research by Camila Lemos, the group plans to test a method that uses iontophoresis in the treatment of chronic wounds such as those that develop in patients with diabetes.

“In this case, we are not dealing with the stratum corneum barrier. We use iontophoresis to assess its influence on release of the substance of interest in a formulation, and to investigate its effect on the growth of microorganisms,” Lopez explained.

The strategy consists of placing a peptide having anti-inflammatory properties on a film made of fibers extracted from the cocoon of a silkworm (fibroin). The film is placed on the wound as a dressing, to which an electric current is then applied.

“When we placed the peptide directly on the wound, it degraded very quickly. When placed on the film, however, release occurs in a slower and more sustained way. Iontophoresis allows a larger amount of the peptide to be released from the film at the start of treatment to accelerate healing,” the researcher explained.

Lopez went on to say that preliminary results suggest that iontophoresis also stops the proliferation of some types of microorganisms (particularly gram-positive bacteria) that could aggravate wounds.

Blood Test for HPV May Help Predict Risk in Cancer Patients

A blood test for the human papillomavirus, or HPV, may help researchers forecast whether patients with throat cancer linked to the sexually transmitted virus will respond to treatment, according to preliminary findings from the University of North Carolina Lineberger Comprehensive Cancer Center.

HPV can cause oropharyngeal cancer, which is a cancer of the throat behind the mouth, including the base of the tongue and tonsils. Studies have shown that patients with HPV-positive oropharyngeal cancer have better outcomes than patients whose cancer is not linked to the virus.

Preliminary findings presented at this year’s American Society for Radiation Oncology Annual Meeting suggest a genetic test for HPV16 in the blood could be useful to help assess risk for patients, and could help identify patients suitable for lower treatment doses.

“Our work on this blood test is ongoing, but we are optimistic that ‘liquid biopsy’ tests such as ours may be useful in the personalization of therapy for many patients with HPV-associated oropharyngeal cancer,” said the study’s senior author Gaorav P. Gupta, MD, PhD, UNC Lineberger member and assistant professor in the UNC School of Medicine Department of Radiation Oncology.

To avoid over-treating patients and to spare them from toxic treatment side effects, UNC Lineberger’s Bhisham Chera, MD, an associate professor in the radiation oncology department, led studies testing whether favorable-risk patients with HPV-positive oropharyngeal cancer can be treated successfully with lower doses of radiation and chemotherapy. A phase II clinical trial using this de-intensified regimen have shown “excellent” cancer control, Chera said.

The researchers used a number of selection criteria to identify patients who can benefit from lower-doses: patients had to be positive for HPV, and they had to have smoked fewer than 10 pack years. Chera said this system is not perfect, however. The researchers have seen cancer recur in non-smoking patients as well as “excellent” cancer control in longtime smokers.

“This has led us to question whether we can get better prognostication with other biomarkers,” Chera said.

They developed a test that can detect HPV16 circulating in the blood, and found that circulating HPV16 DNA was detectable using the test in the majority of a group of 47 favorable-risk oropharyngeal cancer patients.

In a finding that seems counterintuitive, they discovered that very low or undetectable HPV16 pretreatment levels in their blood actually had higher risk of persistent or recurrent disease for chemotherapy and radiation treatment. In contrast, patients with high pretreatment levels of HPV16 in their blood had 100 percent disease control.

They hypothesized that, potentially, the patients with undetectable/low pre-treatment HPV16 levels in the blood may have different, more radiation/chemotherapy resistant cancers.

“Our current theory is that these patients with low or undetectable levels of HPV16 have a different genetic makeup—one that is perhaps less driven purely by HPV, and thus potentially less sensitive to chemotherapy and radiation,” Gupta said. “We are performing next generation sequencing on these patients to search for additional genetic markers that may give us a clue regarding why they have a worse prognosis.”

They also identified a subset of patients who rapidly cleared the HPV16 from their blood. Researchers hypothesize that they could use their findings to further stratify patients who may be eligible for lower intensity treatment.

“A tantalizing – and yet currently untested – hypothesis is whether this subset of ultra-low risk patients may be treated with even lower doses of chemoradiotherapy,” Gupta said.

Genetic Targets to Chemo-Resistant Breast Cancer Identified

Research led by Dr. Carlos Arteaga, Director of the Harold C. Simmons Comprehensive Cancer Center, has identified potential targets for treatment of triple negative breast cancer, the most aggressive form of breast cancer.

Increased activity of two genes, MCL1 and MYC, is associated with the development of chemotherapy resistance. The increased action of these two genes boosts mitochondrial oxidative phosphorylation, which promotes the growth of chemotherapy-resistant cancer stem cells, the research showed.

“Alterations in these two genes are easily detectable with tumor gene tests in current use. Combinations of drugs that inhibit MCL1 or MYC, or both, have the potential to reduce the development of chemotherapy resistance and should be studied in clinical trials,” said Dr. Arteaga, Professor of Internal Medicine at UT Southwestern Medical Center. Dr. Arteaga holds The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology.

Most breast cancers can be treated with hormone therapy, but about 15 percent of cases are triple negative breast cancer, meaning the cancer cells are not influenced by hormones like estrogen or progesterone. These triple negative breast cancers must, therefore, be treated with chemotherapy, which is toxic to healthy cells as well as cancer cells. Furthermore, most triple negative breast cancers eventually become resistant to chemotherapy and the cancer then spreads unchecked.

Drugs that inhibit activity of the MCL1 or MYC genes are in development, Dr. Arteaga said. These drugs, given in conjunction with standard chemotherapies, could potentially slow or even prevent the development of chemotherapy resistance, improving the outlook for this aggressive form of breast cancer.

The research was conducted at Vanderbilt-Ingram Cancer Center and appears in the journal Cell Metabolism. The research was supported by the Susan G. Komen for the Cure Foundation, the Breast Cancer Research Foundation, a National Institutes of Health Breast Cancer SPORE grant, and a Vanderbilt-Ingram Cancer Center Support Grant.

The Simmons Cancer Center at UT Southwestern is one of 49 NCI-designated Comprehensive Cancer Centers in the U.S. and the only one in North Texas. It is also one of 30 U.S. cancer research centers to be designated by the National Cancer Institute as a National Clinical Trials Network Lead Academic Site.

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year.

A New Clinical Trial for a Novel Brain Injury Biomarker

The challenge with diagnosing chronic traumatic encephalopathy (CTE), a condition that shows up in the overwhelming majority of American football players and other athletes who frequently sustain injuries to the head, is that it can only be diagnosed through an autopsy.

Researchers at Medicortex Finland Oy, are working on a diagnostic kit that could detect CTE in a living person with a simple blood test or other body fluids. Actually being able to diagnose CTE while athletes are alive would mean they could take steps to mitigate the disease before it’s exacerbated with even more hit. The test based on a medical breakthrough biomarker, recently was granted clearance to begin a multi-center clinical trial. The trial will consist of patients that are admitted to emergency rooms due to a head injury.

“Collecting and testing human samples in a clinical trial is a significant accomplishment for Medicortex, and represents a meaningful step forward in the development of a fast-inexpensive diagnostic kit for brain injury detection,” said Dr. Adrian Harel, Chairman and Chief Executive Officer of Medicortex Finland. “Brain injury is a devastating condition with mortality if not diagnosed. The opportunity to develop the first portable non-invasive kit for brain injury and concussion to help the patients and families that so desperately need it is remarkable.”

Samples of body fluids such as blood, urine and plasma will be collected from the study subjects and will be analyzed for a novel biomarker using a biochemical and analytical assay from Medicortex. A special focus will be in catching the patients as soon as possible after the accident and time tracking of the biomarker levels following the injury.

In this clinical trial, Medicortex intends to collect body fluid samples of up to 160 patients who have sustained a head injury, and analyze for the existence of a brain injury biomarker between the patients and healthy control subjects. Based on our earlier laboratory animal tests and the phase one clinical test we can expect positive result from the study.

Dr. Marten Kvist, Medical Director of Medicortex: “We are excited to begin a second clinical study after the promising results of the first trial completed earlier this year. The study is to confirm the clinical relevance of this unique biomarker, and it will lead to development of a diagnostic aid for first responders and paramedics, it will help prioritize evacuation and refrain from administration of contraindicated medications.”

Medicortex Finland Oy is a biotechnology company dedicated to developing diagnostics and treatments for brain injury and concussion. One of the company’s missions is to identify a new biomarker in order to reliably assess the severity and extent of brain injury. Medicortex was founded by Dr. Adrian Harel in Turku, Finland, in 2014 and it operates as a privately owned company. Dr. Harel is a neurobiologist and he has a track record in the business management and leadership of early-stage biotechnology companies.

By Decoding How HPV Causes Cancer, Researchers Find a New Potential Treatment Strategy

A study that teases apart the biological mechanisms by which human papillomaviruses (HPV) cause cancer has found what researchers at Georgetown University Medical Center say is a new strategy that might provide targeted treatment for these cancers.

HPVs are responsible for the majority of cervical cancer and a substantial portion of head and neck and anal cancers, but therapy available to date is surgery and non-specific chemotherapy.

The new study, published Oct. 2 in the journal Oncotarget, found that E6, an oncoprotein produced by the virus, interacts with several other molecules in host cells in a manner that ensures infected cells cannot die. If they are immortal and continue to multiply, cancer develops.

“There is no targeted treatment now for these cancers since German virologist Harald zur Hausen, PhD, discovered in 1983 that HPV can cause cervical cancer. Recently, the numbers of HPV-linked head and neck cancers have increased in the U.S. Now we have a chance to develop and test a very specific, potentially less toxic way to stop these cancers,” says the study’s lead author, Xuefeng Liu, MD, associate professor of pathology at Georgetown University Medical Center.  Liu is director of Telomeres and Cell Immortalization for the medical center’s Center for Cell Reprogramming.

Liu and his team have previously found that the HPV E6 oncoprotein interferes with the well-known p53 tumor suppressor to increase telomerase activity that extends the life span of infected cells. A telomerase is a protein that allows a cell to divide indefinitely when it would have stopped after a certain number of divisions.

In this study, researchers found that E6 also interacts with myc, a protein produced by the Myc gene, which controls gene expression in all healthy cells. They concluded that telomerase activity is dependent on E6-myc proteins hooking on to each other.

This means, says Liu, that designing a small molecule that stops E6 from joining up with myc should shut down persistent activation of telomerase. A small molecule could bind to E6 in the same spot that myc would, or bind on to myc in the same spot that E6 would, thus preventing an E6-myc complex.

“This small molecule would not be toxic to all normal cells or, importantly, to master stem cells, because myc would not be affected,” says Liu. “It could be a unique treatment, targeted specifically to HPV cancers.”

Georgetown researchers are now working on a prototype chemical to interfere with E6/Myc binding.