Developing a pediatric leukemia super drug

Illustration of gene expression. Credit: Northwestern University

Fourth study published over two-year span that analyzes key leukemia protein

Northwestern Medicine scientists have discovered two successful therapies that slowed the progression of pediatric leukemia in mice, according to three studies published over the last two years in the journal Cell, and the final paper published Dec. 20 in Genes & Development.

When a key protein responsible for leukemia, MLL, is stabilized, it slows the progression of the leukemia, the most recent study found. The next step will be to combine the treatments from the past two years of research into a pediatric leukemia “super drug” to test on humans in a clinical trial.

The survival rate is only 30 percent for children diagnosed with MLL-translocation leukemia, a cancer that affects the blood and bone marrow. Patients with leukemia have a very low percentage of red blood cells, making them anemic, and have approximately 80 times more white blood cells than people without cancer.

30%Current survival rate for pediatric leukemia patients.

“These white blood cells infiltrate many of the tissues and organs of the affected individuals and is a major cause of death in leukemia patients,” said senior author Ali Shilatifard, the Robert Francis Furchgott Professor of Biochemistry and Molecular Genetics and Pediatrics, the chairman of biochemistry and molecular genetics and the director of Northwestern’s Simpson Querrey Center for Epigenetics. “This is a monster cancer that we’ve been dealing with for many years in children.”

There are several types of leukemia. This research focused on the two most common found in infants through teenagers: acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL).

For the past 25 years, Shilatifard’s laboratory has been studying the molecular function of MLL within its complex known as COMPASS (Complex Proteins Associated with Set1). Most recently, it was demonstrated that COMPASS components are one of the most frequently identified mutations in cancer.The next step of this work will be to bring the drug to a clinical trial setting, which Shilatifard said he hopes will happen in the next three to five years.

This is a monster cancer that we’ve been dealing with for many years in children.”
Ali Shilatifard
Robert Francis Furchgott Professor of Biochemistry and Molecular Genetics and Pediatrics, Northwestern University

“I’ve been working on this translocation for more than two decades, and we’re finally at the point where in five to 10 years, we can get a drug in kids that can be effective,” Shilatifard said. “If we can bring that survival rate up to 85 percent, that’s a major accomplishment.”

Earlier work from Shilatifard’s laboratory published in Cell in 2018 identified compounds that could slow cancer growth by interrupting a gene transcription process known as “Super Elongation Complex” (SEC). It was the first compound in its class to do this.

This MLL stabilization process discovered in the most recent paper could potentially work in cancers with solid tumors, such as breast or prostate cancer, said first author Zibo Zhao, a postdoctoral research fellow in Shilatifard’s lab.

“This opens up a new therapeutic approach not only for leukemia, which is so important for the many children who are diagnosed with this terrible cancer, but also for other types of cancers that plague the population,” Zhao said.

“The publication of these four papers and the possibility of a future human clinical trial could not have happened if it weren’t for the cross-disciplinary collaboration at Northwestern,” Shilatifard said.

Learn more: Pediatric leukemia ‘super drug’ could be developed in the coming years

 

 

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Novel discovery tool is a potential game changer in the development of new technologies

Laser-induced heating of nanoparticles on micropillars for carbon nanotube growth

New megalibrary approach proves useful for the rapid discovery of new materials

Different eras of civilization are defined by the discovery of new materials, as new materials drive new capabilities. And yet, identifying the best material for a given application—catalysts, light-harvesting structures, biodiagnostic labels, pharmaceuticals and electronic devices—is traditionally a slow and daunting task. The options are nearly infinite, particularly at the nanoscale (a nanometer is one-billionth of a meter) where material properties—optical, structural, electrical, mechanical and chemical—can significantly change, even at a fixed composition.

A new study published this week in the Proceedings of the National Academy of Sciences (PNAS) supports the efficacy of a potentially revolutionary new tool developed at Northwestern University to rapidly test millions (even billions) of nanoparticles to determine the best for a specific use.

“When utilizing traditional methods to identify new materials, we have barely scratched the surface of what is possible,” said Northwestern’s Chad A. Mirkin, the study’s corresponding author and a world leader in nanotechnology research and its applications. “This research provides proof-of-concept—that this powerful approach to discovery science works.”

The novel tool utilizes a combinatorial library, or megalibrary, of nanoparticles in a very controlled way. (A combinatorial library is a collection of systematically varied structures encoded at specific sites on a surface). The libraries are created using Mirkin’s Polymer Pen Lithography (PPL) technique, which relies on arrays (sets of data elements) with hundreds of thousands of pyramidal tips to deposit individual polymer “dots” of various sizes and composition, each loaded with different metal salts of interest, onto a surface. Once heated, these dots are reduced to metal atoms forming a single nanoparticle at fixed composition and size.

“By going small, we create two advantages in high throughput materials discovery,” said Mirkin, the George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences; professor of chemical and biological engineering, biomedical engineering and materials science and engineering in the McCormick School of Engineering; and executive director of Northwestern’s International Institute for Nanotechnology (IIN). “First, we can pack millions of features into square-centimeter areas, creating a path for making the largest and most complex libraries, to date. Second, by working at the sub-100 nanometer-length scale, size can become a library parameter, and much of the action, for example, in the field of catalysis, is on this length scale.”

By going small, we create two advantages in high throughput materials discovery.”
Chad Mirkin | nanotechnology pioneer

The new study is a partnership between Northwestern’s IIN and the Air Force Research Laboratory as part of the U.S. Air Force Center of Excellence for Advanced Bioprogrammable Nanomaterials at Northwestern. The team utilized a megalibrary and an in situ Raman spectroscopy-based screening technique called ARES™ to identify Au3Cu (a gold-copper composition) as a new catalyst for synthesizing single-walled carbon nanotubes. (ARES was developed by Benji Maruyama, leader, Flexible Materials and Processes Research Team, Materials & Manufacturing Directorate, Air Force Research Laboratory, and Rahul Rao, research scientist, Air Force Research Laboratory and UES, Inc.)

Carbon nanotubes are light, flexible and stronger-than-steel molecules used for energy storage, drug delivery and property-enhancing additives for many plastic materials. The screening process took less than one week to complete and is thousands of times faster than conventional screening methods.

“We were able to rapidly zero in on an optimal composition that produced the highest nanotube yield much faster than using conventional methods,” said Maruyama, a study co-author. “The findings suggest we may have the ultimate discovery tool—a potential game changer in materials discovery.”

Learn more: New megalibrary approach proves useful for the rapid discovery of new materials

 

 

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A new device can optimize treatment of neonatal jaundice, skin diseases, seasonal affective disorder and reduce risk of sunburns and skin cancer

via Northwestern University

Smaller than an M&M and thinner than a credit card, device can optimize treatment of neonatal jaundice, skin diseases, seasonal affective disorder and reduce risk of sunburns and skin cancer

The world’s smallest wearable, battery-free device has been developed by Northwestern Medicine and Northwestern’s McCormick School of Engineering scientists to measure exposure to light across multiple wavelengths, from the ultra violet (UV), to visible and even infrared parts of the solar spectrum. It can record up to three separate wavelengths of light at one time.

The device’s underlying physics and extensions of the platform to a broad array of clinical applications are reported in a study to be published Dec. 5 in Science Translational Medicine. These foundational concepts form the basis of consumer devices launched in November to alert consumers to their UVA exposure, enabling them to take action to protect their skin from sun damage.

When the solar-powered, virtually indestructible device was mounted on human study participants, it recorded multiple forms of light exposure during outdoor activities, even in the water. The device monitored therapeutic UV light in clinical phototherapy booths for psoriasis and atopic dermatitis as well as blue light phototherapy for newborns with jaundice in the neonatal intensive care unit. It also demonstrated the ability to measure white light exposure for seasonal affective disorder.

As such, it enables precision phototherapy for these health conditions, and it can monitor, separately and accurately, UVB and UVA exposure for people at high risk for melanoma, a deadly form of skin cancer. For recreational users, the sensor can help warn of impending sunburn.

The device was designed by a team of researchers in the group of John Rogers, the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering in the McCormick School of Engineering and a professor of neurological surgery at Northwestern University Feinberg School of Medicine.

“From the standpoint of the user, it couldn’t be easier to use – it’s always on yet never needs to be recharged,” Rogers said. “It weighs as much as a raindrop, has a diameter smaller than that of an M&M and the thickness of a credit card. You can mount it on your hat or glue it to your sunglasses or watch.”

It’s also rugged, waterproof and doesn’t need a battery. “There are no switches or interfaces to wear out, and it is completely sealed in a thin layer of transparent plastic,” Rogers said. “It interacts wirelessly with your phone. We think it will last forever.”

Rogers tried to break it. His students dunked devices in boiling water and in a simulated washing machine. They still worked.

Northwestern scientists are particularly excited about the device’s use for measuring the entire UV spectrum and accumulating total daily exposure.

“There is a critical need for technologies that can accurately measure and promote safe UV exposure at a personalized level in natural environments,” said co-senior author Dr. Steve Xu, instructor in dermatology at Feinberg and a Northwestern Medicine dermatologist.

“We hope people with information about their UV exposure will develop healthier habits when out in the sun,” Xu said. “UV light is ubiquitous and carcinogenic. Skin cancer is the most common type of cancer worldwide. Right now, people don’t know how much UV light they are actually getting. This device helps you maintain an awareness and for skin cancer survivors, could also keep their dermatologists informed.”

Light wavelengths interact with the skin and body in different ways, the scientists said.

“Being able to split out and separately measure exposure to different wavelengths of light is really important,” Rogers said. “UVB is the shortest wavelength and the most dangerous in terms of developing cancer. A single photon of UVB light is 1,000 times more erythrogenic, or redness inducing, compared to a single photon of UVA.”

In addition, the intensity of the biological effect of light changes constantly depending on weather patterns, time and space.

“If you’re out in the sun at noon in the Caribbean, that sunlight energy is very different than noon on the same day in Chicago.” – dermatologist Steve Xu

Skin cancer is reaching epidemic proportions in the U.S. Basal cell carcinoma and squamous cell carcinoma of the skin account for more than 5.4 million cases per year at a cost of $8.1 billion dollars yearly. In 2018, there will be an estimated 178,000 new cases of melanoma, causing 9,000 deaths. Every hour, one person dies of melanoma.

First accurate dosing of phototherapy

Currently, the amount of light patients actually receive from phototherapy is not measured. “We know that the lamps for phototherapy are not uniform in their output — a sensor like this can help target problem areas of the skin that aren’t getting better,” said Xu. Doctors don’t know how much blue light a jaundiced newborn is actually absorbing or how much white light a patient with seasonal affective disorder gets from a light box. The new device will measure this for the first time and allow doctors to optimize the therapy by adjusting the position of the patient or the light source.

Because the device operates in an “always on” mode, its measurements are more precise and accurate than any other light dosimeter now available, the scientists said.  Current dosimeters only sample light intensity briefly at set time intervals and assume that the light intensity at times between those measurements is constant, which is not necessarily the case, especially in active, outdoor use scenarios. They are also clunky, heavy and expensive.

How the tiny sensor works

Light passes through a window in the sensor and strikes a millimeter-scale semiconductor photodetector. This device produces a minute electrical current with a magnitude proportional to the intensity of the light. This current passes to an electronic component called a capacitor where the associated charge is captured and stored. A communication chip embedded in the sensor reads the voltage across this capacitor and passes the result digitally and wirelessly to the user’s smartphone. At the same time, it discharges the capacitor, thereby resetting the device.

Multiple detectors and capacitors allow measurements of UVB and UVA exposure separately. The device communicates with the users’ phone to access weather and global UV index information (the amount of light coming through the clouds). By combining this information, the user can infer how much time they have been in the direct sun and out of shade. The user’s phone can then send an alert if they have been in the sun too long and need to duck into the shade.

Commercially available in collaboration with L’Oreal

Called “My Skin Track UV”, the UVA version of the platform is now commercially available.

Learn more: World’s smallest wearable device warns of UV exposure, enables precision phototherapy

 

 

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Improving life for a million hydrocephalus patients

Top left: A shunt protruding from the brain during surgery. Top right: A researcher solders a new wearable shunt monitor. Bottom: A woman wears a new wearable shunt monitor on her neck.

Most people simply take ibuprofen when they get a headache. But for someone with hydrocephalus – a potentially life-threatening condition in which excess fluid builds up in the brain — a headache can indicate a serious problem that can result in a hospital visit, thousands of dollars in scans, radiation and sometimes surgery.

A new wireless, Band-Aid-like sensor developed at Northwestern University could revolutionize the way patients manage hydrocephalus and potentially save the U.S. health care system millions of dollars.

A Northwestern Medicine clinical study successfully tested the device, known as a wearable shunt monitor, on five adult patients with hydrocephalus. The findings were published in Science Translational Medicine.

Hydrocephalus can affect adults and children. Often the child is born with the condition, whereas in adults, it can be acquired from some trauma-related injury, such as bleeding inside the brain or a brain tumor.

The current standard of care involves the surgical implantation of a straw-like catheter known as a ‘shunt,’ which drains the excess fluid out of the brain and into another part of the body.

Shunts have a nearly 100 percent failure rate over 10 years, and diagnosing shunt failure is notoriously difficult. More than a million Americans live with shunts and the constant threat of failure.

The groundbreaking new sensor, developed by the Rogers Research Group at Northwestern, could create immense savings and improve the quality of life for nearly a million people in the U.S. alone.

Impact

  • 1 in 1,000 people affected by hydrocephalus
  • 100% failure rate of shunts over 10 years
  • $50,000 treatment costs per patient per year

 

When a shunt fails, the patient can experience headaches, nausea and low energy. A patient experiencing any of these symptoms must visit a hospital because if their symptoms are caused by a malfunctioning shunt, it could be life threatening. Once at the hospital, the patient must get a CT scan or an MRI and sometimes must undergo surgery to see if the shunt is working properly.

The new sensor allowed patients in the study to determine within five minutes of placing it on their skin if fluid was flowing through their shunt. The soft and flexible sensor uses measurements of temperature and heat transfer to non-invasively tell if and how much fluid is flowing through.

“We envision you could do this while you’re sitting in the waiting room waiting to see the doctor,” said co-lead author Siddharth Krishnan, a fifth-year Ph.D. student in the Rogers Research Group. “A nurse could come and place it on you and five minutes later, you have a measurement.”

I’m trying to live a normal life, and I really can’t because of the headaches.”

Willie Meyer
Hydrocephalus patient

A device like this would be life changing for Willie Meyer, 26, who has undergone 190 surgeries, spent virtually every holiday in the emergency room and almost missed his high school graduation because of emergency brain surgeries.

Meyer’s mother, Beth,  said she learned Willie had hydrocephalus when he was two years old after complaining that “his hair hurt.”

Symptoms of a malfunctioning shunt, such as headaches and fatigue, are similar to symptoms of other illnesses, which causes confusion and stress for caregivers.

“Every time your kid says they have a headache or feels a little sleepy, you automatically think, ‘Is this the shunt?’” said co-senior author Dr. Matthew Potts, assistant professor of neurological surgery at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician. “We believe that this device can spare patients a lot of the danger and costs of this process.”

Co-lead author Dr. Amit Ayer, who has treated Willie’s hydrocephalus for the last four years, said his patients are a driving force behind his motivation to get the device to market.

“Our patients want to know when they can actually use the device and be part of the trial,” said Ayer, who is a neurosurgery resident at Northwestern Medicine and a student at Kellogg School of Management at Northwestern. “I want to get it out there, so we can help make their lives better.”

How it works

Top left: A shunt protruding from the brain during surgery. Top right: A researcher solders a new wearable shunt monitor. Bottom: A woman wears a new wearable shunt monitor on her neck.

It looks like a Band-Aid that’s talking to a cellphone. There’s nothing like this out there today.”

John A. Rogers

A very small rechargeable battery is built into the sensor. The device is Bluetooth enabled so it can talk to a smartphone and deliver the readings via an Android app. The sensor advances concepts in skin-like “epidermal electronics,” which the Rogers Research Group has been working on for nearly a decade.

It uses a thermal transport measurement, which means the sensor uses tiny amounts of thermal power to minimally increase the temperature of the skin.

If the shunt is working and the excess cerebral spinal fluid is draining properly, the sensor will measure a characteristic heat signature. Similarly, if there is no flow because the shunt has malfunctioned, the sensor will be able to quickly indicate that through heat flow measurements.

The team tested the device in the laboratory before heading to the clinic to perform a pilot study on five patients at Northwestern Memorial Hospital. The team could detect clear differences in cases between measurements over working shunts and on adjacent confusing control locations with no flow.

“This means if someone wants to check if their shunt is working, say, when they have a headache, they can quickly do what we call a ‘spot measurement,’” said co-lead author Tyler Ray, a postdoctoral research fellow in the Rogers Research Group. “This device can also measure flow throughout the day enabling, for the first time, the possibility of continuously monitoring shunt performance. This can lead to important insights into the dynamics of cerebral spinal fluid flow previously inaccessible with current diagnostic tools and flow measurement techniques.”

A larger pediatric clinical trial will be starting soon at Ann & Robert H. Lurie Children’s Hospital of Chicago with the goal of targeting this very vulnerable population. The study authors are also working on outsourced production on the scale of a few hundred sensors to support this study and further develop the technology. Rogers and Ayer are co-founders of Rhaeos, Inc., a company that is commercializing the technology described here.

Learn more: Skin sensor could improve life for a million hydrocephalus patients

 

 

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Discovery: A new kill code embedded in each cell to extinguish cancer

A kill code is embedded in every cell in the body.

Cancer’s most deadly assassin exists in every cell

A kill code is embedded in every cell in the body whose function may be to cause the self-destruction of cells that become cancerous, reports a new Northwestern Medicine study. As soon as the cell’s inner bodyguards sense it is mutating into cancer, they punch in the kill code to extinguish the mutating cell.

The code is embedded in large protein-coding ribonucleic acids (RNAs) and in small RNAs, called microRNAs, which scientists estimate evolved more than 800 million years ago in part to protect the body from cancer. The toxic small RNA molecules also are triggered by chemotherapy, Northwestern scientists report.

‘Now that we know the kill code’

Cancer can’t adapt or become resistant to the toxic RNAs, making it a potentially bulletproof treatment if the kill code can be synthetically duplicated. The inability of cancer cells to develop resistance to the molecules is a first, the scientists said.

“Now that we know the kill code, we can trigger the mechanism without having to use chemotherapy and without messing with the genome. We can use these small RNAs directly, introduce them into cells and trigger the kill switch,” said lead author Marcus E. Peter, the Tomas D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine.

Chemotherapy has numerous side effects, some of which cause secondary cancers, because it attacks and alters the genome, Peter said.

“We found weapons that are downstream of chemotherapy,“ noted Peter, also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The paper describing the kill code and identifying how the cancer-fighting microRNAs use the code to kill tumor cells was published Oct. 29 in Nature Communications. The paper describing that protein-coding large RNAs can be converted into toxic small RNAs was published Oct. 16 in eLife.

Following nature’s lead

“My goal was not to come up with a new artificial toxic substance,” Peter said. “I wanted to follow nature’s lead. I want to utilize a mechanism that nature developed.”

In published research in 2017, Peter showed cancer cells die when he introduced certain small RNA molecules. He also discovered cancer cells treated with the RNA molecules never become resistant because the molecules simultaneously eliminate multiple genes cancer cells need for survival.

At the time, Peter said, “It’s like committing suicide by stabbing yourself, shooting yourself and jumping off a building all at the same time. You cannot survive.”

But he didn’t know what mechanism caused the cells to self-destruct. What he knew was a sequence of just six nucleotides (6mers) present in small RNAs made them toxic to cancer cells. Nucleotides are organic molecules that are the building blocks of DNA and RNA. They are G, C, A or T (in DNA), or U (in RNA).

In the first of the new studies, Peter then tested all 4,096 different combinations of nucleotide bases in the 6mers until he found the most toxic combination, which happens to be G-rich, and discovered microRNAs expressed in the body to fight cancer use this 6mer to kill cancer cells.

In the second new study, Peter showed the cells chop a gene (Fas ligand) involved in cancer cell growth into small pieces that then act like microRNAs and are highly toxic to cancer. Peter’s group found about three percent of all protein-coding large RNAs in the genome can be processed in this way.

“Based on what we have learned in these two studies, we can now design artificial microRNAs that are much more powerful in killing cancer cells than even the ones developed by nature,” Peter said.

The next step? “We absolutely need to turn this into a novel form of therapy,” Peter said. He is exploring multiple ways to trigger the embedded kill code to kill cancer cells, but stressed a potential therapy is many years off.

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