New inhibitor drug shows promise in relapsed leukemia

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Inhibitor drug improves overall survival in older radioiodine resistant thyroid cancer

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

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

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

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

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

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

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

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

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

Diabetes drug prevents stiffening of heart muscle in obese mouse model

Overconsumption of a Western diet high in fats and refined sugars has contributed to a global increase in obesity and Type 2 diabetes. Obese and diabetic premenopausal women are more at risk of developing heart disease — even more than men of similar age and with similar health issues. A study by researchers at the University of Missouri School of Medicine found that the diabetes medication linagliptin can protect against stiffening of the left ventricle of the heart in overweight female mice. The finding may have implications for management of cardiovascular diseases in humans.

“In previous studies, we showed that young, female mice consuming a Western diet, high in fat, sucrose and high fructose corn syrup, not only gained weight, but also exhibited vascular stiffening consistent with obese premenopausal women,” said Vincent DeMarco, Ph.D., a research associate professor of endocrinology at the MU School of Medicine and the lead author of the study. “Our current study sought to understand if linagliptin prevents cardiac stiffening caused by eating a Western-style diet.”

Linagliptin is a medication prescribed to lower blood glucose in patients with Type 2 diabetes. The medication works by blocking the enzyme dipeptidyl peptidase-4, or DPP-4. Previous studies have shown that DPP-4 inhibitors offer protection against vascular inflammation and oxidative stress — conditions associated with cardiovascular stiffening.

DeMarco’s team studied 34 female mice that were fed either a normal diet or a simulated Western diet for four months. Another group of mice were fed a Western diet containing a low dose of linagliptin. The team used an ultrasound system, similar to that used in humans, to evaluate the function of the left ventricle of the heart.

“A heartbeat actually is a two-part pumping action that takes less than a second in healthy humans,” DeMarco said. “The first part, known as diastole, involves relaxation of the left ventricle while it fills with oxygenated blood from the lungs. After the left ventricle fills with blood, it then contracts and pushes blood into the aorta. This part of the cardiac cycle is referred to as systole. If the left ventricle becomes stiffer it will not be able to relax normally, and diastole will be impaired. This form of heart disease is known as diastolic dysfunction, which is a risk factor for a more serious heart condition known as diastolic heart failure.”

The mice fed the Western diet alone gained weight, exhibited increased heart weight and developed diastolic dysfunction. However, the mice fed the Western diet along with linagliptin did not develop diastolic dysfunction. They also exhibited less oxidative stress and inflammation in their hearts compared to the mice fed the Western diet alone.

“Oxidative stress and inflammation are two factors that can promote excess accumulation of collagen, also known as fibrosis, in the walls of the left ventricle,” DeMarco said. “In our study, we found that Western diet-fed mice had increased fibrosis in the left ventricle that was prevented by linagliptin.”

The team also found that linagliptin suppressed not only DPP-4 activity, but also TRAF3IP2 production. TRAF3IP2 is a protein responsible for initiating tissue oxidative stress, inflammation and fibrosis in the heart.

“This was a major novel finding of our study,” DeMarco said. “However, further research is required to determine exactly how linagliptin affects the function of this important protein.”

DeMarco also cautioned that linagliptin, like other DPP-4 inhibitors, can be expensive without insurance coverage.

“Based on the results of this research and our previous studies, it is tempting to speculate that linagliptin could reduce the risk of cardiovascular complications associated with obesity and Type 2 diabetes,” DeMarco said. “However, ongoing clinical trials will help determine what, if any, cardio-protective role linagliptin could play in the management of obesity-related heart disease.”

Clinical trial shows experimental drug’s ability to knock down pancreatic cancer’s defense

By adding an experimental drug to a standard chemotherapy regimen, a subset of patients with metastatic pancreatic cancer had a significantly longer period before the cancer progressed as compared with those who received the standard treatment, according to a Phase 2 clinical trial led by an investigator at Fred Hutchinson Cancer Research Center.

The randomized, controlled trial found that when the experimental therapy was given to participants whose tumors had a lot of the drug’s target molecule, they had four months more of progression-free survival than participants in the control group who only had the chemo.

For anyone not familiar with the rapid deadliness of pancreatic cancer, it may be hard to see the significance of the few additional months before disease progression. But time is precious for patients with this cancer: Only about 8 percent of all pancreatic cancer patients survive five years after diagnosis.

Dr. Sunil Hingorani, the faculty member at Fred Hutch who led the trial, is scheduled to present the findings at 10:24 a.m., June 4, at the American Society of Clinical Oncology annual meeting in Chicago. ASCO abstract number 4008.

Hingorani said that the results reassure him that it was the right move to advance the drug, called PEGPH20, into the worldwide Phase 3 trial that opened last year.

“We still haven’t fully proven anything yet, strictly speaking, but I think [this strategy] is very rational,” he said. “Let me put it this way: I think it would be irresponsible not to finish the global Phase 3 trial as the most rigorous test of this hypothesis. I think we’re obligated now to answer the question.”

Hingorani consults for Halozyme, the PEGPH20 drugmaker and the sponsor of these trials. The company began this year to provide funding through Fred Hutch to support Hingorani’s research on the drug.

Hingorani’s earlier research led him to the drug because he believed it could address a challenge posed by many pancreatic cancers: The tumors have very high internal pressures that collapse local blood vessels and prevent cancer-killing drugs from getting in. PEGPH20 reduces those pressures so chemotherapies circulating in the blood can penetrate tumors.

The experimental drug, which was created from the blueprint of a naturally occurring enzyme, breaks down a molecule called hyaluronic acid that is produced in bulk by many pancreatic cancers.

Hyaluronic acid, or HA, is naturally found in the human body; it readily binds water to create a gel fluid, making it an excellent shock-absorber in your knees, for example. But in pancreatic tumors, it spells trouble. As the gel fluid builds up, it raises the tumor’s internal pressure, squeezing local blood vessels shut. Patients whose tumors have a lot of HA also tend to have a poor prognosis.

Hingorani and his team first conducted studies in mice that showed how PEGPH20, in combination with chemo, permanently reduced the amount of pressure-boosting HA inside the mouse tumors. It caused the tumors to shrink and increased the mice’s survival time.

In the Phase 2 trial, patients with late-stage pancreatic cancer were randomly assigned to receive a standard-of-care, first-line combination chemotherapy either with or without PEGPH20. When the results of all 234 evaluable patients on Halo 202 were grouped together, the apparent benefit of PEGPH20 was small ? a matter of just a couple extra weeks of progression-free survival.

“If this was all the potential that this strategy represented, I wouldn’t pursue this [research further],” Hingorani said. “That’s not enough for me.”

But a stark difference emerged when the results were divided up by how much of the drug’s target, HA, patients’ tumors contained: In the subset of 80 patients whose tumors had high levels of HA, adding PEGPH20 to chemo resulted in an average of 9.2 months before disease progression; with chemo alone, this timespan was just 5.2 months.

Hingorani also reported that the unexpected, elevated risk of blood clots associated with PEGPH20 ? which resulted in a temporary halt of the trial in 2014 ? equalized between the patients receiving PEGPH20 and those in the control group, and dropped overall, after the study was restarted, due to the addition of a blood thinner to all patients’ regimens.

“These are the real take-home messages to me, namely, the progression-free survival in target-rich [high-HA] patients and the ability to give the enzyme safely,” Hingorani said.

Because the Phase 2 trial results suggest that the benefit of the experimental drug is restricted to the patients with high levels of HA in their tumors, only patients with such tumors qualify for the new Phase 3 trial. And the Phase 3 trial is designed to offer a more stringent test of the benefits of the new drug than its predecessor: Aimed at advancing the drug toward potential FDA approval, the trial’s goal is to determine whether PEGPH20 actually increases participants’ lifespans, not just their time to disease progression. (It’s possible a treatment could achieve the latter without impacting the former.)

The investigators’ exploratory analysis of the Phase 2 trial data suggested that the experimental drug boosted the lifespans of patients with high-HA tumors to an average of nearly a year after diagnosis ? which, if shown definitively in the Phase 3 trial, could be a new benchmark for this cancer, Hingorani said.

Hingorani launched the Phase 3 trial before handing off its leadership to two other colleagues in the field, Dr. Margaret Tempero of the University of California, San Francisco and Dr. Eric Van Cutsem at the University of Leuven in Belgium. As he steps back from his leadership role on this project, Hingorani is satisfied by the solid scientific foundation the investigators have lain to justify moving forward with the development of this drug.

In light of the grim timelines associated with a pancreatic cancer diagnosis, he said, patients have no time to waste on anything less.

“Patients get one shot on goal, if that, with this cancer,” he said. “No cancer is more daunting than pancreas cancer.”

Treatment-related adverse events for trial participants included peripheral edema (63 percent of those receiving PEGPH20 vs. 26 percent for the control group), muscle spasms (56 percent vs 3 percent), neutropenia (34 percent vs 19 percent), and myalgia (26 percent vs. 7 percent).

Antidepressant May Enhance Drug Delivery to the Brain

NIH rat study suggests amitriptyline temporarily inhibits the blood-brain barrier, allowing drugs to enter the brain.

New research from the National Institutes of Health found that pairing the antidepressant amitriptyline with drugs designed to treat central nervous system diseases, enhances drug delivery to the brain by inhibiting the blood-brain barrier in rats. The blood-brain barrier serves as a natural, protective boundary, preventing most drugs from entering the brain. The research, performed in rats, appeared online April 27 in the Journal of Cerebral Blood Flow and Metabolism.

Although researchers caution that more studies are needed to determine whether people will benefit from the discovery, the new finding has the potential to revolutionize treatment for a whole host of brain-centered conditions, including epilepsy, stroke, human amyotrophic lateral sclerosis (ALS), depression, and others. The results are so promising that a provisional patent application has been filed for methods of co-administration of amitriptyline with central nervous system drugs.

According to Ronald Cannon, Ph.D., staff scientist at NIH’s National Institute of Environmental Health Sciences (NIEHS), the biggest obstacle to efficiently delivering drugs to the brain is a protein pump called P-glycoprotein. Located along the inner lining of brain blood vessels, P-glycoprotein directs toxins and pharmaceuticals back into the body’s circulation before they pass into the brain.

To get an idea of how P-glycoprotein works, Cannon said to think of the protein as a hotel doorman, standing in front of a revolving door at a lobby entrance. A person who is not authorized to enter would get turned away, being ushered back around the revolving door and out into the street.

“For example, as good as vegetables are for us to eat, they have molecules that could be toxic if they slipped into the brain,” Cannon said. “They don’t get in, because of P-glycoprotein, but this same protector also keeps out helpful therapeutics.”

Cannon and his NIEHS colleagues initially found that amitriptyline significantly reduced P-glycoprotein’s pump activity in brain capillaries from wild-type rats. Later, they saw amitriptyline had the same effect in brain capillaries from genetically modified rats designed to mimic human ALS. In both rat models, amitriptyline turned off P-glycoprotein within 10-15 minutes. When amitriptyline was removed, P-glycoprotein pump activity returned to full-strength.

NIEHS postbaccalaureate fellow David Banks is lead author on the paper and described amitriptyline’s action on P-glycoprotein as rapid and reversible. It’s these advantages that make the therapy so appealing.

“Most inventions developed at the bench don’t make it to the clinic, but I’m hopeful that our findings will translate into better treatment options for doctors and their patients,” Banks said.

Cannon anticipates that administering amitriptyline along with a lower dose of an opioid could relieve pain and reduce the negative side effects, such as constipation and addiction, usually seen with higher doses of prescribed opioids.

“As our nation faces increases in Alzheimer’s disease, autism, and opioid abuse, we’re hopeful that this discovery will help address these serious health challenges,” said NIEHS Director Linda Birnbaum, Ph.D.

New Method for Tapping Vast Plant Pharmacopeia to Make More Effective Drugs

Cocaine, nicotine, capsaicin.

These are just three familiar examples of the hundreds of thousands of small molecules (also called specialized or secondary metabolites) that plants use as chemical ammunition to protect themselves from predation.

Unfortunately, identifying the networks of genes that plants use to make these biologically active compounds, which are the source of many of the drugs that people use and abuse daily, has vexed scientists for years, hindering efforts to tap this vast pharmacopeia to produce new and improved therapeutics.

Now, Vanderbilt University geneticists think they have come up with an effective and powerful new way for identifying these elusive gene networks, which typically consist of a handful to dozens of different genes, that may overcome this road block.

“Plants synthesize massive numbers of bioproducts that are of benefit to society. This team has revolutionized the potential to uncover these natural bioproducts and understand how they are synthesized,” said Anne Sylvester, program director in the National Science Foundation’s Biological Sciences Directorate, which funded the research.

The revolutionary new approach is based on the well-established observation that plants produce these compounds in response to specific environmental conditions.

“We hypothesized that the genes within a network that work together to make a specific compound would all respond similarly to the same environmental conditions,” explained Jennifer Wisecaver, the post-doctoral fellow who conducted the study.

To test this hypothesis, Wisecaver – working with Cornelius Vanderbilt Professor of Biological Sciences Antonis Rokas and undergraduate researcher Alexander Borowsky – turned to Vanderbilt’s in-house supercomputer at the Advanced Computing Center for Research & Education in order to crunch data from more than 22,000 gene expression studies performed on eight different model plant species.

“These studies use advanced genomic technologies that can detect all the genes that plants turn on or off under specific conditions, such as high salinity, drought or the presence of a specific predator or pathogen,” said Wisecaver.

But identifying the networks of genes responsible for producing these small molecules from thousands of experiments measuring the activity of thousands of genes is no trivial matter. That’s where the Vanderbilt scientists stepped in; They devised a powerful algorithm capable of identifying the networks of genes that show the same behavior (for example, all turning on) across these expression studies.

The result of all this number crunching – described in the paper titled “A global co-expression network approach for connecting genes to specialized metabolic pathways in plants” published online Apr. 13 by The Plant Cell journal – was the identification of dozens, possibly even hundreds of gene pathways that produce small metabolites, including several that previous experiments had identified.

Vered Tzin from Ben-Gurion University’s Jacoob Blaustein Institutes for Desert Research in Israel and Georg Jander from Cornell University’s Boyce Thompson Institute for Plant Research in Ithaca, NY, helped verify the predictions the analysis made in corn, and Daniel Kliebenstein from the Department of Plant Sciences at the University of California, Davis helped verify the predictions in the model plant system Arabidopsis.

The results of their analysis go against the prevailing theory that the genes that make up these pathways are clustered together on the plant genome. “This idea comes from the observation in fungi and bacteria that the genes that make up these specialized metabolite pathways are clustered together,” said Rokas. “In plants, however, these genes appear to be mostly scattered across the genome. Consequently, the strategies for discovering plant gene pathways will need to be different from those developed in the other organisms.”

The researchers argue that the results of their study show that this approach “is a novel, rich and largely untapped means for high-throughput discovery of the genetic basis and architecture of plant natural products.”

If that proves to be true, then it could help open the tap on new plant-based therapeutics for treating a broad range of conditions and diseases.

‘Neuron-Reading’ Nanowires Could Accelerate Development of Drugs to Treat Neurological Diseases

A team led by engineers at the University of California San Diego has developed nanowires that can record the electrical activity of neurons in fine detail. The new nanowire technology could one day serve as a platform to screen drugs for neurological diseases and could enable researchers to better understand how single cells communicate in large neuronal networks.

“We’re developing tools that will allow us to dig deeper into the science of how the brain works,” said Shadi Dayeh, an electrical engineering professor at the UC San Diego Jacobs School of Engineering and the team’s lead investigator.

“We envision that this nanowire technology could be used on stem-cell-derived brain models to identify the most effective drugs for neurological diseases,” said Anne Bang, director of cell biology at the Conrad Prebys Center for Chemical Genomics at the Sanford Burnham Medical Research Institute.

The project was a collaborative effort between the Dayeh and Bang labs, neurobiologists at UC San Diego, and researchers at Nanyang Technological University in Singapore and Sandia National Laboratories. The researchers published their work Apr. 10 in Nano Letters.

Researchers can uncover details about a neuron’s health, activity and response to drugs by measuring ion channel currents and changes in its intracellular potential, which is due to the difference in ion concentration between the inside and outside of the cell. The state-of-the-art measurement technique is sensitive to small potential changes and provides readings with high signal-to-noise ratios. However, this method is destructive — it can break the cell membrane and eventually kill the cell. It is also limited to analyzing only one cell at a time, making it impractical for studying large networks of neurons, which are how they are naturally arranged in the body.

“Existing high sensitivity measurement techniques are not scalable to 2D and 3D tissue-like structures cultured in vitro,” Dayeh said. “The development of a nanoscale technology that can measure rapid and minute potential changes in neuronal cellular networks could accelerate drug development for diseases of the central and peripheral nervous systems.”

The nanowire technology developed in Dayeh’s laboratory is nondestructive and can simultaneously measure potential changes in multiple neurons — with the high sensitivity and resolution achieved by the current state of the art.

The device consists of an array of silicon nanowires densely packed on a small chip patterned with nickel electrode leads that are coated with silica. The nanowires poke inside cells without damaging them and are sensitive enough to measure small potential changes that are a fraction of or a few millivolts in magnitude. Researchers used the nanowires to record the electrical activity of neurons that were isolated from mice and derived from human induced pluripotent stem cells. These neurons survived and continued functioning for at least six weeks while interfaced with the nanowire array in vitro.

Silicidation is usually used to make contacts to transistors, but this is the first time it is being used to do patterned wafer bonding, Dayeh said. “And since this process is used in semiconductor device fabrication, we can integrate versions of these nanowires with CMOS electronics.” Dayeh’s laboratory holds several pending patent applications for this technology.
To overcome this hurdle, researchers invented a new wafer bonding approach to fuse the silicon nanowires to the nickel electrodes. Their approach involved a process called silicidation, which is a reaction that binds two solids (silicon and another metal) together without melting either material. This process prevents the nickel electrodes from liquidizing, spreading out and shorting adjacent electrode leads.

Dayeh noted that the technology needs further optimization for brain-on-chip drug screening. His team is working to extend the application of the technology to heart-on-chip drug screening for cardiac diseases and in vivo brain mapping, which is still several years away due to significant technological and biological challenges that the researchers need to overcome. “Our ultimate goal is to translate this technology to a device that can be implanted in the brain.”

New Arsenal Against MRSA: New Study Reports Cannabinoids Effective Against Antibiotic-Resistant MRSA

Researchers have found that cannabinoid-based therapies have unique anti-bacterial properties that fight MSRA and other infectious bacteria. In vitro studies demonstrated that bactericidal synergy was achieved against multiple species of methicillin-resistant Staphylococcus aureus (MRSA) utilizing a proprietary cannabinoid-based therapeutic platform. MRSA species tested included community acquired- (CA-MRSA), healthcare-acquired- (HA-MRSA), and mupirocin-resistant (MR-MRSA) strains of MRSA.

Researchers also found that using unique strategic cannabinoid-based cocktails, fractional-inhibitory concentration (FIC) levels demonstrating synergy between mixtures of individual cannabinoid-based components ranged from 0.06 to 0.28. FIC findings below 0.5 indicate significant killing potential of the mixture. The work was led by NEMUS BIoscience, Inc. and the company’s discovery and research partner, the University of Mississippi (UM).

Dr. Mahmoud ElSohly, professor at the National Center for Natural Products Research (NCNPR) at the University of Mississippi commented: “Historically, many types of anti-infective compounds are derived from plants so to have a series of cannabinoid-related compounds exhibit activity against this dangerous pathogen is in keeping with prior efforts of drug development. I believe that these compounds, in addition to the bacterial killing capability, could also offer benefits associated with anti-inflammatory and anti-fibrotic properties that could enhance healing, especially against an organism associated with skin and soft tissue infections. The University, in conjunction with Nemus, is looking to expand the anti-infective capabilities of this series of compounds.”

Recently, the World Health Organization (WHO) placed MRSA on their list as one of the top six organisms that pose a global public health threat. “This anti-infective platform will constitute the NB3000 series of Nemus molecules and formulations.  While there are a number of compounds in the development pipeline against MRSA, we believe that this family of drug candidates could possess an excellent safety profile in addition to efficacy in neutralizing this bacterium,” stated Brian Murphy, M.D., C.E.O. and Chief Medical Officer of Nemus. “These unique botanically derived components establish an anti-infective platform which could potentially be expanded into other types of bacteria, as well as viruses, and fungi.”

The University of Mississippi, the state’s flagship institution, is among the elite group of R-1: Doctoral Universities – Highest Research Activity in the Carnegie Classification. The university has a long history of producing leaders in public service, academics, research and business. Its 15 academic divisions include a major-medical school, nationally recognized schools of accountancy, law and pharmacy, and an Honors College acclaimed for a blend of academic rigor, experiential learning and opportunities for community action.

Nemus will work with Dr. Elsohly, the University lead researcher on this project, to have this data submitted to a future scientific meeting and anticipates performing further testing against a variety of other bacterial species. Commercially, the company looks to actively pursue partnering opportunities for these candidate molecules. “This work highlights the importance of Nemus’ relationship with the University which has significant experience and intellectual capital related to cannabinoid chemistry and physiology, dating back to 1968,” added Dr. Murphy.

Nemus Bioscience is a biopharmaceutical company, headquartered in Costa Mesa, California, focused on the discovery, development, and commercialization of cannabinoid-based therapeutics for significant unmet medical needs in global markets. Utilizing certain proprietary technology licensed from the University of Mississippi, NEMUS is working to develop novel ways to deliver cannabinoid-based drugs for specific indications, with the aim of optimizing the clinical effects of such drugs, while limiting potential adverse events. NEMUS’s strategy is to explore the use of natural and synthetic compounds, alone or in combination with partners. The Company is led by a highly-qualified team of executives with decades of biopharmaceutical experience and significant background in early-stage drug development.

For more information, visit http://www.nemusbioscience.com.

Zika Virus Protein Mapped to Speed Search for Cure

A recently-published study shows how Indiana University scientists are speeding the path to new treatments for the Zika virus, an infectious disease linked to birth defects in infants in South and Central America and the United States.

Cheng Kao, a professor in the IU Bloomington College of Arts and Sciences‘ Department of Molecular and Cellular Biochemistry, has mapped a key protein that causes the virus to reproduce and spread.

“Mapping this protein provides us the ability to reproduce a key part of the Zika virus in a lab,” Kao said. “This means we can quickly analyze existing drugs and other compounds that can disrupt the spread of the virus. Drugs to target the Zika virus will almost certainly involve this protein.”

The World Health Organization reports that more than 1 million people in 52 countries and territories in the Americas have been infected with the Zika virus since 2015. The disease has also been confirmed to cause microcephaly in more than 2,700 infants born to women infected with the virus while pregnant. Symptoms include neurological disorders and a head that is significantly smaller than normal.

The virus is also transmissible through sexual activity and can trigger an autoimmune disease in adults called Guillain-Barre syndrome.

The IU-led study, conducted in collaboration with Texas A&M University, revealed the structure of the Zika virus protein NS5, which contains two enzymes needed for the virus to replicate and spread. The first enzyme reduces the body’s ability to mount an immune response against infection. The other enzyme helps “kick off” the replication process.

“We need to do everything we can to find effective drugs against the Zika virus, as changes in travel and climate have caused more tropical diseases to move into new parts of the globe,” said Kao, who has also spent 15 years studying the virus that causes hepatitis C.

“We’ve learned a lot of lessons about how to fight this class of virus through previous work on hepatitis C, as well as other work on the HIV/AIDS virus,” he added.

In addition, Kao said, the study showed that the Zika virus protein is similar in structure to proteins from viruses that cause dengue fever, West Nile virus, Japanese encephalitis virus and hepatitis C, which prompted the team to test several compounds that combat those diseases. The team also tested other compounds to disrupt the virus’s replication.

“Drugs approved to treat hepatitis C and compounds in development to treat other viral diseases are prime candidates to use against the Zika virus,” Kao said. “We’re continuing to work with industry partners to screen compounds for effectiveness against the NS5 protein.”

Other IU Bloomington authors on the study were Guanghui Yi and Yin-Chih Chuang in the Department of Molecular and Cellular Biochemistry and Robert C. Vaughan in the Department of Biology. Additional authors were Baoyu Zhao and Pingwei Li of Texas A&M University and Banumathi Sankaran at Lawrence Berkeley National Laboratory.

The method used to reproduce the virus protein in the lab is the subject of a U.S. patent application filed by the IU Research and Technology Corp.

The study appears in the journal Nature Communications. It was supported in part by the Johnson Center for Innovation and Translational Research at IU Bloomington.

Rogue Breast Tumor Proteins Point to Potential Drug Therapies

For patients with difficult-to-treat cancers, doctors increasingly rely on genomic testing of tumors to identify errors in the DNA that indicate a tumor can be targeted by existing therapies. But this approach overlooks another potential marker — rogue proteins — that may be driving cancer cells and also could be targeted with existing treatments.

If DNA can be described as the body’s genetic blueprint, proteins can be thought of as the construction workers who carry out the plan. Studying the blueprint can be vital to understanding genetic diseases, including cancer, but that focus also means that some problems arising with the workers may be missed.

Studying mice with breast tumors transplanted from patients, researchers at Washington University School of Medicine in St. Louis, The Broad Institute of MIT and Harvard, and Baylor College of Medicine have analyzed the proteins present in these tumors. The researchers demonstrated that some protein alterations can be used to identify drugs that may work against some cancers. The work is part of the National Cancer Institute’s (NCI) Clinical Proteomic Tumor Analysis Consortium efforts.

The study is published March 28 in Nature Communications.

“Proteins carry out most of the biological functions in the cell,” said senior author Li Ding, PhD, an associate professor of medicine at Washington University. “Knowing the DNA sequence does not automatically tell us everything about the proteins doing work in the cells. This is another layer of tumor complexity that we need to explore to identify new therapies.”

Ding said recent advances in a technology called mass spectrometry and in techniques to analyze massive quantities of data have made complex studies of the proteins in tumor cells possible. Another reason to prioritize the systematic study of proteins in tumors — cancer proteomics — is that the vast majority of cancer therapies developed from genetic studies actually target proteins.

“Identifying the rogue proteins of cancer is an important pathway toward developing new drugs,” said co-author R. Reid Townsend, MD, PhD, a professor of medicine and director of the Proteomics Shared Resource at Washington University.

“We can use proteomics to confirm and validate our genomics findings,” said Ding, also an assistant director of The McDonnell Genome Institute at Washington University School of Medicine. “In addition, it’s another tool to uncover additional events that drive cancer and are specific to individual patient tumors, including the amount of the ‘rogue’ protein, its specific form, or the type and extent of chemical modifications of the proteins that we know are treatable with approved or investigational drugs. We also can test these therapies in the mice before we evaluate them in patients.”

Steven A. Carr, PhD, of the Broad Institute, said the team analyzed a chemical modification called phosphorylation, which plays a central role in how healthy, as well as diseased, cells communicate.

“Disruption or enhancement in such signaling is often directly related to disease mechanism and can be targeted for therapy,” Carr said.

The researchers studied 24 tumor samples from breast cancer patients after the samples were transplanted into mice. Twenty-two of the transplanted samples retained their genetic and proteomic identities as specific types of breast cancer. A proteomic analysis of the tumors also identified multiple protein targets that have the potential to respond to drugs.

For example, the researchers showed dialed-up activity of multiple protein pathways that could be targeted with investigational drugs called PI3K inhibitors and mTOR inhibitors, separately and in combination, depending on the tumor. They also showed that drugs against a type of breast tumor called HER2 positive breast cancer — such as the dual ERBB2/EGFR inhibitor lapatinib — potentially could benefit more patients than currently receive them, if analysis of the tumor proteins is taken into consideration.

While most of these tumor models recapitulated specific types of breast cancer, Ding said the scientists were surprised to see that two of the 24 tumors evolved into a completely different type of cancer after transplantation into the mice. Instead of breast cancer, they resembled lymphoma and were driven by the cancer-causing virus Epstein-Barr, according to the researchers. Lymphomas are cancers of immune cells that may have arisen from lymphatic tissue present in the breast tumors transplanted into the mice.

The analysis of the lymphoma-like cancers was the first proteomic study of this type of tumor. Though unintentional, Ding said the analysis provides an explanation for why investigational drugs that inhibit a protein called BTK have been effective in treating patients with lymphoma.

“Since it is the proteins that interact directly with drugs, the strength of studying proteomics in patient-derived tumor models is the ability to test drug treatment in the mice,” Ding said. “With advances in cancer proteomics that increase the speed of measurement, we are moving toward a future that includes genomic and proteomic analyses of patient tumors.”

Co-author Matthew J. Ellis, MD, PhD, of Baylor, agreed. “The mouse work is promising enough to adapt these technologies for real time analysis of patient materials so that clinical trials can be designed to test this new diagnostic and drug selection approach,” he said.

Other key contributors to this project are Kuan-lin Huang, a PhD student in genomics and bioinformatics at Washington University; Shunqiang Li, PhD, an assistant professor of medicine at Washington University; Philipp Mertins, PhD, of The Broad Institute; and Sherri Davies, a senior scientist at Washington University.

First in Human’ Trial Defines Safe Dosage for Small Molecule Drug ONC201 for Solid Cancer Tumors

Research from Rutgers Cancer Institute of New Jersey examines oral drug that targets cancer cells and spares healthy tissue

A ‘first in human’ clinical trial examining the small molecule drug ONC201 in cancer patients with advanced solid tumors shows that this investigational drug is well tolerated at the recommended phase II dose. That’s according to Rutgers Cancer Institute of New Jersey investigators and colleagues whose research also showed early signs of clinical benefit in patients with advanced prostate and endometrial cancers. The work appears in the ‘OnlineFirst’ section of Clinical Cancer Research (DOI: 10.1158/1078-0432.CCR-16-2658).

At focus is the investigational drug ONC201 that targets a dopamine receptor, a member of the G protein-coupled receptor superfamily residing on the surface of cancer cells, to cause their destruction. ONC201 is the first of a new family of therapeutic compounds called imipridones. Previous research on the study drug conducted by Rutgers Cancer Institute and Oncoceutics, Inc. – which is also supporting this trial – suggests that ONC201 may be capable of turning off proteins that maintain tumor growth and and may help kill cancer cells while sparing normal ones. Pre-clinical study demonstrated ONC201 was effective in laboratory models against a number of solid tumors including colon cancer, brain cancer, triple-negative breast cancer and non-small cell lung cancer.

In this phase I dose-escalation study, 10 patients over age 18 with advanced solid tumors that were resistant to standard therapies were enrolled through Rutgers Cancer Institute between January and July 2015. Participants received a starting dose of 125mg of the study drug, which was taken orally via capsule every 21 days (one cycle). The dosage for this cohort was increased incrementally up to a maximum dose of 625mg, which is five-fold above the dose that was effective in laboratory models. An additional 18 patients were enrolled in an expansion phase between August 2015 and February 2016 and treated at the recommended phase II dose of 625mg in order to collect additional safety, pharmacokinetic and pharmacodynamic information.

There were no drug-related adverse events over Grade 1 in either the dose escalation phase or the expansion phase. The few low grade events that were recorded (nausea, fever) were resolved quickly, note the authors. While the study achieved the aim of identifying the recommended phase II dose of the drug, findings also showed tumor regression in patients with metastatic disease. Results also demonstrated prolonged stable disease following more than nine cycles (27 weeks) of treatment – particularly in prostate and endometrial cancer patients that had lymph node, bone and lung lesion involvement. Out of the 28 participants, 10 completed at least four cycles of treatment with two patients receiving at least nine cycles. The authors note while a 90-year old prostate cancer patient saw his primary tumor and metastatic bone lesion shrink by about 25 percent after taking two 625mg doses of ONC201, a 72-year old patient with advanced clear cell endometrial cancer had a mixed response after two doses, with multiple nodes decreasing by more than 30 percent but experiencing the development of new nodes.

“By exploring a novel agent that targets the cancer but leaves non-cancerous tissue untouched, we have an opportunity to not only provide a new treatment option for patients who have exhausted standard forms of therapy without the typical toxicities associated with anticancer treatment, but to also offer them a therapeutic that may result in a better quality of life since healthy cells are not impacted,” notes Rutgers Cancer Institute medical oncologist Mark Stein, MD, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School and lead investigator of the work. “While meaningful to confirm the safety profile of this dosage for ONC201, it is noteworthy that our findings also showed some evidence of clinical benefit to some patients.”

Drug Developed at University of Minnesota Increases Survival in Dogs with Cancer

A breakthrough trial at the University of Minnesota testing a new UMN-developed drug resulted in improved survival rates for dogs diagnosed with a cancer called hemangiosarcoma (HSA). The results were published today in the journal Molecular Cancer Therapeutics.

“This is likely the most significant advance in the treatment of canine HSA in the last three decades,” said study co-author Jaime Modiano, V.M.D., Ph.D. professor in the University of Minnesota College of Veterinary Medicine and member of the Masonic Cancer Center, University of Minnesota.

Canine HSA is a common, aggressive, incurable sarcoma. It is remarkably similar to angiosarcoma, which affects humans. Both cancers typically spread before diagnosis and the survival time for affected patients is extremely short, even with aggressive treatment. Only 50% of humans diagnosed with angiosarcoma live longer than 16 months and the prognosis for dogs with HSA is similarly dire: less than 50% will survive 4-6 months and only about 10% will be alive one-year after their diagnosis.

The study tested a drug called eBAT, invented by study senior author Daniel Vallera, Ph.D., professor at the University of Minnesota Medical School and Masonic Cancer Center.

“eBAT was created to specifically target tumors while causing minimal damage to the immune system. HSA is a vascular cancer, meaning it forms from blood vessels. eBAT was selected for this trial because it can simultaneously target the tumor and its vascular system,” said Vallera.

Traditional cancer treatments have side effects that can be very hard on patients. “In this trial we aimed for a sweet spot by identifying a dose of eBAT that was effective to treat the cancer, but caused no appreciable harm to the patient. Essentially we’re treating the cancer in a safer and more effective way, improving quality of life and providing a better chance at survival,” lead study author Antonella Borgatti, D.V.M., M.S., associate professor with the University of Minnesota College of Veterinary Medicine said.

eBAT was tested on 23 dogs of various breeds, both large and small, with HSA of the spleen. Dogs received three treatments of eBAT after surgery to remove the tumor and before conventional chemotherapy. The drug treatment improved the 6-month survival rate to approximately 70%. Furthermore, five of the 23 dogs that received eBAT treatment lived more than 450 days.

The positive results for canine patients, the similarities between this cancer and angiosarcoma in humans, and the fact that many other tumor types can be targeted by eBAT, make a strong case for translating this drug into clinical trials for human cancer patients. The researchers want these results to bring hope to those touched by this disease.

“This drug was invented here at the University of Minnesota, developed here, manufactured here, tested here and showed positive results here. We would also like this drug to achieve positive outcomes for humans here,” Modiano said.

“The ultimate goal for all of us is to create a world in which we no longer fear cancer,” Modiano said.

This project is an example of the remarkable progress that is being made through collaborations among the multiple colleges and schools within the University of Minnesota’s Academic Health Center.

Funding was provided by many sources, including various foundations and individuals along with the National Institutes of Health, showing the broad interest in identifying cures for these devastating cancers.

Cancer Drug Could Double as a Weapon Against Heart Disease, Promoting Regeneration of Damaged Heart Tissue

An anticancer agent in development promotes regeneration of damaged heart muscle – an unexpected research finding that may help prevent congestive heart failure in the future.

Many parts of the body, such as blood cells and the lining of the gut, continuously renew throughout life. Others, such as the heart, do not. Because of the heart’s inability to repair itself, damage caused by a heart attack causes permanent scarring that frequently results in serious weakening of the heart, known as heart failure.
For years, Dr. Lawrence Lum, Associate Professor of Cell Biology at UT Southwestern Medical Center, has worked to develop a cancer drug targeting Wnt signaling molecules. These molecules are crucial for tissue regeneration, but also frequently contribute to cancer. Essential to the production of Wnt proteins in humans is the porcupine (Porcn) enzyme, so-named because fruit fly embryos lacking this gene resemble a porcupine. In testing the porcupine inhibitor researchers developed, they noted a curiosity.

“We saw many predictable adverse effects – in bone and hair, for example – but one surprise was that the number of dividing cardiomyocytes (heart muscle cells) was slightly increased,” said Dr. Lum, senior author of the paper, and a member of UTSW’s Hamon Center for Regenerative Science and Medicine. “In addition to the intense interest in porcupine inhibitors as anticancer agents, this research shows that such agents could be useful in regenerative medicine.”

Based on their initial results, the researchers induced heart attacks in mice and then treated them with a porcupine inhibitor. Their hearts’ ability to pump blood improved by nearly twofold compared to untreated animals.

The study findings were published online this week in Proceedings of the National Academy of Sciences.

“Our lab has been studying heart repair for several years, and it was striking to see that administration of a Wnt inhibitor significantly improved heart function following a heart attack in mice,” said Dr. Rhonda Bassel-Duby, Professor of Molecular Biology and Associate Director of the Hamon Center for Regenerative Science and Medicine.
Importantly, in addition to the improved pumping ability of hearts in the mice, the researchers noticed a reduction in fibrosis, or scarring in the hearts. Collagen-laden scarring that occurs following a heart attack can cause the heart to inappropriately increase in size, and lead to heart failure.

“While fibrotic responses may be immediately beneficial, they can overwhelm the ability of the heart to regenerate in the long run. We think we have an agent that can temper this fibrotic response, thus improving wound healing of the heart,” said Dr. Lum, a Virginia Murchison Linthicum Scholar in Medical Research and Associate Director of Basic Research at the Harold C. Simmons Comprehensive Cancer Center.
Additionally, Dr. Lum said, preliminary experiments indicate that the porcupine inhibitor would only need to be used for a short time following a heart attack, suggesting that the unpleasant side effects typically caused by cancer drugs might be avoided.

“We hope to advance a Porcn inhibitor into clinical testing as a regenerative agent for heart disease within the next year,” Dr. Lum said.

Researchers Find Fungus-Fighting Compound in Drug Discovery Center Library

Researchers with the Virginia Tech Center for Drug Discovery have identified a compound that blocks the growth of a fungus that causes deadly lung infections and allergic reactions in people with compromised immune systems.

The research team targeted the switch that allows the fungus Aspergillus fumigatus to survive in iron-deficient conditions like the human body. Specifically, they targeted an enzyme known as SidA, which is essential for the synthesis of molecules called siderophores that are made during infection to steal iron from human proteins.

Furthermore, by performing high-throughput screening in the center’s Drug Discovery Screening Laboratory, they found a compound called Celastrol that blocks the growth of iron-producing organelles in the fungus.

The results were published in the journal ACS Chemical Biology.

“This project shows what an asset the screening lab is to the community,” said Pablo Sobrado, a professor of biochemistry in the College of Agriculture and Life Sciences and director of the screening laboratory. “Without the robots and chemical libraries available at the screening lab, this work would not have been possible. We are very fortunate at Virginia Tech to have this facility.”

Aspergillus fumigatus is common and is typically found in soil and decaying organic matter. Most people are exposed to it daily with little consequence, but it can cause lung damage in people with compromised immune systems, such as organ transplant recipients and people with AIDS or leukemia. The mortality rate of this population, when exposed to the fungus, is more than 50 percent, according to the authors.

“Growing antibiotic resistance is demanding the development of target-directed therapies,” said Julia S. Martin del Campo, a postdoctoral research scientist in Sobrado’s lab. “This approach requires the discovery of enzyme inhibitors that block essential pathogen pathways. The discovery of Celastrol as a SidA inhibitor represents the first building block in the development of drugs against A. fumigatus and related pathogens.”