Growing up in Tanzania, I knew that fruit trees were useful. Climbing a mango tree to pick a fruit was a common thing to do when I was hungry, even though at times there were unintended consequences. My failure to resist consuming unripened fruit, for example, caused my stomach to hurt. With such incidents becoming frequent, it was helpful to learn from my mother that consuming the leaves of a particular plant helped alleviate my stomach pain.

This lesson helped me appreciate the medicinal value of plants. However, I also witnessed my family and neighboring farmers clearing the land by slashing and burning unwanted trees and shrubs, seemingly unaware of their medicinal value, to create space for food crops.

But this lack of appreciation for the medicinal value of plants extends beyond my childhood community. As fires continue to burn in the Amazon and land is cleared for agriculture, most of the concerns have focused on the drop in global oxygen production if swaths of the forests disappear. But Im also worried about the loss of potential medicines that are plentiful in forests and have not yet been discovered. Plants and humans also share many genes, so it may be possible to test various medicines in plants, providing a new strategy for drug testing.

As a plant physiologist, I am interested in plant biodiversity because of the potential to develop more resilient and nutritious crops. I am also interested in plant biodiversity because of its contribution to human health. About 80% of the world population relies on compounds derived from plants for medicines to treat various ailments, such as malaria and cancer, and to suppress pain.

Future medicines may come from plants

One of the greatest challenges in fighting diseases is the emergence of drug resistance that renders treatment ineffective. Physicians have observed drug resistance in the fight against malaria, cancer, tuberculosis and fungal infections. It is likely that drug resistance will emerge with other diseases, forcing researchers to find new medicines.

Plants are a rich source of new and diverse compounds that may prove to have medicinal properties or serve as building blocks for new drugs. And, as tropical rainforests are the largest reservoir of diverse species of plants, preserving biodiversity in tropical forests is important to ensure the supply of medicines of the future.

Plants and new cholesterol-lowering medicines

The goal of my own research is to understand how plants control the production of biochemical compounds called sterols. Humans produce one sterol, called cholesterol, which has functions including formation of testosterone and progesterone - hormones essential for normal body function. By contrast, plants produce a diverse array of sterols, including sitosterol, stigmasterol, campesterol, and cholesterol. These sterols are used for plant growth and defense against stress but also serve as precursors to medicinal compounds such as those found in the Indian Ayurvedic medicinal plant, ashwagandha.

Humans produce cholesterol through a string of genes, and some of these genes produce proteins that are the target of medicines for treating high cholesterol. Plants also use this collection of genes to make their sterols. In fact, the sterol production systems in plants and humans are so similar that medicines used to treat high cholesterol in people also block sterol production in plant cells.

I am fascinated by the similarities between how humans and plants manufacture sterols, because identifying new medicines that block sterol production in plants might lead to medicines to treat high cholesterol in humans.

New medicines for chronic and pandemic diseases

An example of a gene with medical implications that is present in both plants and humans is NPC1, which controls the transport of cholesterol. However, the protein made by the NPC1 gene is also the doorway through which the Ebola virus infects cells. Since plants contain NPC1 genes, they represent potential systems for developing and testing new medicines to block Ebola.

This will involve identifying new chemical compounds that interfere with plant NPC1. This can be done by extracting chemical compounds from plants and testing whether they can effectively prevent the Ebola virus from infecting cells.

There are many conditions that might benefit from plant research, including high cholesterol, cancer and even infectious diseases such as Ebola, all of which have significant global impact. To treat high cholesterol, medicines called statins are used. Statins may also help to fight cancer. However, not all patients tolerate statins, which means that alternative therapies must be developed.

Tropical rainforests are medicine reservoirs

The need for new medicines to combat heart disease and cancer is dire. A rich and diverse source of chemicals can be found in natural plant products. With knowledge of genes and enzymes that make medicinal compounds in native plant species, scientists can apply genetic engineering approaches to increase their production in a sustainable manner.

Tropical rainforests house vast biodiversity of plants, but this diversity faces significant threat from human activity.

To help students in my genetics and biotechnology class appreciate the value of plants in medical research, I refer to findings from my research on plant sterols. My goal is to help them recognize that many cellular processes are similar between plants and humans. My hope is that, by learning that plants and animals share similar genes and metabolic pathways with health implications, my students will value plants as a source of medicines and become advocates for preservation of plant biodiversity.

[ Expertise in your inbox. Sign up for The Conversations newsletter and get a digest of academic takes on todays news, every day. ]

Walter Suza, Adjunct Assistant Professor of Agronomy, Iowa State University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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The Medicine Plant That Could Have Changed the World. - The National Interest Online

Posted By: Staff WriterNovember 18, 2019

With artificial intelligence and genetic engineeringcontinuing to shape the future of scientific innovation and discovery,questions about the ethical implications only seem to get more complicated.

Additionally, CRISPR a tool for DNA sequencing and geneediting is bringing new technological changes and advancements in a rapidlyshifting landscape.

A panel discussion at Stanford University later thisweek, moderated by Russ Altman a professor of Bioengineering, Genetics,Medicine, Biomedical Data Science and Computer Science at the university, seeksto discuss how AI and CRISPR are influencing these ethical quandaries and howthey might influence the evolutionary process.

The two panelists for the free, sold-out event areleaders in the field. Jennifer Doudna, a professor of chemistry and molecularand cell biology at UC Berkeley, helped discover CRISPR-Cas9. Fei-Fei Li is acomputer science professor at Stanford in the universitys Institute forHuman-Centered Artificial Intelligence. She previously worked at the schoolsAI Lab and at Google.

The Institute for Human-Centered Artificial Intelligenceis hosting for forum at Stanfords CEMEX Auditorium, 655 Knight Way. It is setfor Tuesday, November 19, from 7 to 8:30 p.m.

While the event has sold out of pre-registration tickets,limited general admission will be available at the site. It will also belivestreamed.

To see more details, click here.

To watch the livestream, click here.

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Examining the ethics of scientific discovery - Cupertino Today

Mila Makovec has high pigtails in her dark hair and a cloth doll tucked under her arm as she wakes up in a hospital bed, where shes just been injected with a one-of-a-kind drug intended to save her life.

The drug works for only one person in the world this 9-year-old girl from Boulder.

In a spectacular example of what the future might hold for precision medicine, the drug was made only for her in a quest to save Mila from a neurological disease that is destroying her brain. Her DNA is in the formula. The 22-letter genome sequence in the drugs recipe matches the one in Milas cells that is broken.

It is the first time the FDA has approved a drug for a single person.

The drug appropriately called milasen might not have come soon enough to save Mila, as it can only slow the process of degeneration, not replace the brain cells that have already died.

But this story is no longer just about Mila; it never actually was.

This is not just for my daughter anymore, said Julia Vitarello, who took to social media to fundraise and find a researcher and drug manufacturer who would help her. This is for something much bigger.

Milas case catapulted specialized drug development at least a decade into the future, her doctors say, opening a new path for other children with rare genetic diseases that have no cure.

Childrens Hospital Colorado, where Mila was diagnosed three years ago and now receives her treatment, and Boston Childrens, where her drug was designed, are leading the way in creating a model in which academic researchers could help perhaps a handful of children each year by crafting one-of-a-kind medicines. Next year, Childrens Colorado will begin whole-genome sequencing with a new machine called a Novaseq, a major step in the process of finding mutations in DNA.

The whole concept raises ethical questions for sure: How safe is it to initiate a clinical trial for a single child? Who makes sure the children who could benefit most not just those whose families have money or the ability to raise money get the specialized treatment?

Vitarello, who created Milas Miracle Foundation and raised $3 million while trying to save her daughter, wants to establish funding for children who need drugs tailored to their own cellular biology. She suggests an admissions process where the researchers deciding whether to help a child do not know that childs name, face or ability to pay.

There are going to be parents who are going to do anything for their kid, Vitarello said. They are going to come with money. Thats totally fine, no judgment. I would do the same thing. But in an ideal world, there would be patients coming through a funnel with no names or faces or money attached. Whoever is at the table makes the best decision.

The path forward is likely in the academic, nonprofit space, Vitraello said. She is initiating talks with the National Institutes of Health, the largest public funder of biomedical research, as well as research institutions, the FDA and the pharmaceutical industry. An estimated 1.3 million people with rare genetic diseases could potentially benefit from a treatment like Milas, she said.

There are 1.3 million kids that are dying that have no other treatment, no pharma company is going to help them, there is nothing that we can do, and now suddenly, weve opened up a pathway for that, she said Tuesday at the hospital in Aurora, as Mila rested following her injection. The only way to get it is to have more academic institutions treat more kids one, two, five, 10. Open it up.

The goal is that kids with flaws in their DNA could receive precision medicine sooner, halting neurological diseases before they steal the ability to walk, talk, eat or see.

Mila was a perfectly healthy child the first three years of her life. She was learning to ski, went hiking with her parents and had a vocabulary advanced beyond her years.

Her mom noticed the subtle changes before anyone the way she pulled books close to her face because she couldnt see, how her feet turned inward, that she began bumping into things and fell for no reason, how she stuttered sometimes but it wasnt like typical stuttering.

Vitarello brought her to 100 doctors and therapists from the East Coast to the West and in Canada, many of whom told her to calm down and that her daughter seemed fine. I had doctors tell me I was pretty much crazy. Very top level doctors told me to chill out, she said. Well, I wasnt going to chill out. I just kept going.

By age 7, Mila was having trouble walking and eating and was going blind. Her body was wracked with multiple seizures each day.

I spent three years trying to figure out what was wrong with her, Vitarello said. I basically gave up and brought her to the ER at Childrens Colorado.

Mila was admitted and her case assigned to Dr. Austin Larson, a geneticist whose main job at the hospital is to figure out whats wrong with patients who have an undiagnosed disease. An MRI found that the part of Milas brain that is responsible for balance, the cerebellum, was smaller than expected. But it was a genetic test that for the first time gave Vitarello a name for Milas illness: Batten disease, and a specific type of Batten that is so rare, just 25 people in the world are known to have it.

The disease occurs when both of a childs two CNL7 genes are mutated one mutation from each parent.

Larson was able to identify the defective gene from Milas father, but could not find one from her mother. At the time, Childrens Colorado along with most places didnt have the technology to search that deeply into Milas DNA through whole-genome sequencing, and Larson warned Milas family that it was likely impossible to find a clinical lab that could. She would need a researcher.

Vitarello turned to Facebook, begging for help for Mila but also so she could find out if her son, who was 2 at the time and completely healthy, had the same devastating disease that was taking away her daughter.

I was going to get nowhere with Mila unless I just opened up my story fully, to everyone, her mom said.

Dr. Larson had given her enough information and the right words to make a plea. A Boston physician saw her message and connected her with Dr. Timothy Yu, a neurogeneticist at Boston Childrens.

At the same time, the FDA had just approved a new drug called Spinraza, the first drug to treat a separate genetic condition called spinal muscular atrophy. The drug, injected into the fluid around the spinal cord, helped babies in clinical trials improve head control, sitting and standing.

The way Spinraza was designed was a game-changer for medicine and key in helping Mila. Yu and his team in Boston wondered if they could make a similar drug for the Colorado girl.

The Boston team spent days staring at screens of Milas DNA sequences until they discovered the other piece of the genetic puzzle in addition to the gene mutation from her father, Mila had inherited extra genetic material from her mother. The combination meant that, in the most basic terms, Mila had a sequence of broken DNA in her cells.

The drug created only for Mila contains little pieces of synthetic genetic material that search for a specific 22-letter sequence and cover it up so that her cells cannot read it. We are taking a Band-Aid and sticking it onto that part, said Dr. Scott Demarest, a pediatric neurologist at Childrens Colorado and a specialist in rare genetic epilepsies. That is literally what is happening. It is sticking to that spot so that the cell skips over that and goes to the next part that is correct.

The only difference between Spinraza and milasen is the genetic sequence inside the drugs send Band-Aids to different addresses.

After discovering the genetic flaw, Yu in Boston and Larson in Colorado called Milas mom together to give her the news. Her son did not have either of the recessive genes, and her daughter had both.

It was a huge mix of extreme happiness and, within the same second, just extreme falling-to-the-floor sadness for Mila, Vitarello recalled. My daughter had gotten both of the bad mutations and my son had gotten both of the good ones.

Next, Vitarello had to persuade a drugmaker to make a drug for one, and the FDA to allow doctors to inject it in her daughters spinal fluid.

The stars aligned, she says, still in disbelief.

Milas team made it happen by emphasizing that although this drug had the potential to work only on one person, the process could become a blueprint for other patients. Only the DNA sequence in the medicine would change.

They persuaded a drug manufacturer in California, TriLink Biotechnologies, to make Milas drug. And the FDA agreed to speed up the clinical trial process by allowing Yu to test the drug on rats at the same time Mila was receiving her first dose. The doctor had first tested it on Milas skin cells.

Milasen is technically now in clinical trial a trial of one patient involving two childrens hospitals.

The night before Milas first injection in January 2018, as Vitarello went for a run in subzero Boston, she told herself she was OK with whatever happened. Mila was out of time. Vitarello had seen the descriptions online and knew where Mila was headed.

My daughters trajectory of not treating her was so black and white, Vitarello said. Everyone always wonders what is going to happen to your life. When you have a rare disease, you can see exactly what is going to happen to your child ahead of time and its not a good thing.

I figured the worst-case scenario was not her dying, it was her being in pain, Vitarello said, recalling that she asked Yu to tell the FDA that she thought the drugs potential benefits outweighed the risk. I said, If my daughter dies on the spot, Im OK with that.

Instead, the injections that first year seemed to stop the diseases progression. Mila quit eating through a g-tube and started eating her moms pureed food again. She could hold up her head and her upper body, and her walking improved. Her seizures decreased from 30 a day to two or three.

Quality of life, those are huge, Vitarello said.

Now in the second year of treatment, some of Milas symptoms have declined, but not as steeply as other children with her disease. Milas team has upped her doses and started injecting them every two months instead of every three, but they have no precedent to follow.

They could find out years from now that they were giving Mila 1,000 times too little, her mother said.

I honestly dont know if it was in time for Mila, Vitarello said. She was really progressed when she received her treatment. There is still hope.

The key to saving more children from rare genetic diseases is diagnosing them earlier ideally at birth.

What if we found this three years sooner? Larson asked. I think about that a lot. What would it have taken to have found this the first time that (Vitarello) took Mila to a physician and said, I am concerned about the subtle difference in the way she walks?

The answer is it takes having a very broad test and being very good at interpreting that very broad swath of information.

Science is a ways off from being able to detect diseases as rare as Milas in newborns. But breakthroughs are coming for other genetic diseases.

Starting in January, spinal muscular atrophy will become one of 38 genetic diseases newborn babies are screened for via blood tests, said Raphe Schwartz, chief strategy officer for Childrens.

Childrens intends to take what it has learned through Milas case, partner with other institutions and use it to help more children, Schwartz said. What we learn reveals the roadmap for the future, he said. The future ones we do are more effective and less expensive over time.

There is a sense of urgency, but also caution.

We want to make sure we are doing it right, we are doing it safely, we are doing it for kids who are going to benefit the most, Demarest said. There are ethical challenges around it. We need to be very thoughtful and careful that we are doing this the right way, but were also doing it in a way that allows this to be a reality for kids as soon as possible and for as many as possible.

For now, Vitarello is grateful that Mila can receive her treatments in Colorado. Until September, they were traveling to Boston every other month for 10 days, but now they can leave home after breakfast on treatment days and return by dinner.

On Tuesday, Vitarello recited Goldilocks and the Three Bears and sang camp songs while Mila, bundled in blankets, received the 10-minute injection in her lower back, which Vitarello said doesnt seem to hurt Mila. They celebrated Milas 9th birthday last week, and her little brother, now 5, picked out a squishy toy and a sequined mermaid for her birthday presents.

Im faced with a huge amount of sadness around this, but at the same time, its making such a huge difference that it gives a lot of purpose to her life and it gives a lot of purpose to my life, Vitarello said. We are still fighting hard for Mila. But I can see this making a much bigger impact.

This reporting is made possible by our members. You can directly support independent watchdog journalism in Colorado for as little as $5 a month. Start here: coloradosun.com/join

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This miracle drug was designed and manufactured for just one person a 9-year-old Boulder girl - The Colorado Sun

Autoimmune diseases are immune system disorders where the bodys immune system attacks its own tissues. Examples of common autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, multiple sclerosis (MS) and others.

A peculiarity of autoimmune diseases is that they have many genes in common, but they develop differently. For example, why does a patient with an autoimmune disease become a type 1 diabetic rather than have rheumatoid arthritis?

Decio L. Eizirik, a researcher at Universit Libre de Bruxelles Centre for Diabetes Research in Belgium, who is also a senior research fellow at the Indiana Biosciences Research Institute, recently published research in the journal Nature Genetics that found significant insight into this question. Eizirik took time to speak with BioSpace about the research and how a researcher in Belgium came to collaborate with researchers in Indiana, Spain, the UK and the U.S. National Institutes of Health.

Several autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, etc., have as much as 30 to 50% of their candidates genes in common, said Eizirik, raising the question on why in some individuals the immune system attacks, for instance, the insulin-producing beta cells, causing type 1 diabetes, while in others it targets joint tissues, leading to rheumatoid arthritis. Most of the research in the field has focused on the role for these candidate genes on the immune system, but our work indicated that many of these candidates genes affect the function and survival of pancreatic beta cells, leading to a misguided dialogue between them and the immune system that culminates in diabetes.

The early stages of type 1 diabetes, for example, show local autoimmune inflammation and progressive loss of the pancreatic beta cells that produce insulin. How these genetic transcription factors, or cytokines, interact with the beta-cell regulatory environment, and the changes that occur, suggest a key role in how the immune system gets triggered to attack the beta cells.

The research was conducted by Eizirik, Lorenzo Pasquali from the Institucio Catalana de Recerca I Estudis Avancats (ICREA) in Barcelona, Spain, and colleagues from Oxford, UK; Pisa, Italy, and the NIH. For about 20 years, Eizirik has run a diabetes-focused laboratory in Brussels. In August 2019, he launched a new laboratory at the IBRI, where, he said, three top scientists and assistants, Donalyn Scheuner, senior staff scientist at IBRI, Bill Carter, research analyst at IBRI, and Annie Rocio Pineros Alvarez, postdoctoral fellow in medicine at Indiana University, are already working. These two laboratories are working closely togetherfor instance, we have weekly meetings by videoconference, and besides my regular visits to the IBRI, scientists are moving between our European and USA labs on a temporary or permanent basis.

The IBIR was created by the State of Indiana and the states leading life science companies, academic research universities and medical school, as well as philanthropic organizations. The focus is on metabolic disease, including diabetes, cardiovascular disease obesity and poor nutrition. Its laboratories and offices are housed in about 20,000 square feet of space in Indian University School of Medicines Biotechnology Research and Training Center in Indianapolis. It expects to move into a new 68,000-square-feet site in mid-2020.

Eizirik said, The IBRI offers a unique opportunity to translate our basic research findings to the clinic, and we are working closely together with colleagues at Indiana University, particularly Carmella Evans-Molina, director of the Indiana Diabetes Research Center (IDRC) and the IDRC Islet and Physiology Core, to confirm our basic research findings in patients samples, and to eventually bring them to the clinic.

The specific research study looked at the binding of tissue-specific transcription factors. Transcription factors are basically proteins whose job it is to turn genes on or off by binding to DNA. So, for example, there are specific transcription factors whose job it is to regulate insulin production in pancreatic beta cells. In the case of this research, Eizirik and his team studied tissue-specific transcription factors that open the chromatin. Chromatin is a complex of DNA and protein found in the nucleus of the cell. It allows long DNA molecules to be packaged, typically in the form of chromosomes.

For gene transcription to occur, Eizirik said, chromatin must open and provide access to transcription factors. This allows binding of pro-inflammatory transcription factors induced in the beta cells by local inflammation.

For certain people who are genetically predisposed to type 1 diabetes, this leads to the generation of signals by the beta cells, Eizirik said, that contribute to attract and activate immune cells, rendering beta cells a potential target to the immune system.

Eizirik said, These observations have clarified the role for pancreatic beta cells in type 1 diabetes and provided an explanation for the reasons behind the immune system targeting beta cells.

The amplifying loop mechanism observed potentially explains other autoimmune diseases. Eizirik notes, Binding of tissue-specific transcription factors, within an inflammatory context and in genetically predisposed individuals, could generate signals that would attract and activate immune cells against specific target tissues.

Testing the theory in other autoimmune diseases will be required to verify it, but potentially could open up new therapies or preventive treatments for type 1 diabetes and other autoimmune diseases.

Type 1 diabetes has a strong genetic component, Eizirik said. At least 50% of the disease risk is due to genetic causesand understanding the role for candidate genes in the disease may point to novel therapies. For instance, up to now, nearly all therapeutic approaches to prevent type 1 diabetes have targeted the immune system, with little success. Our findings suggest that we must also take steps to directly boost beta cell survival.

He compared targeting the immune system only in type 1 diabetes to trying to fly a plane with only one wing. Our present and previous data suggest that we need two wings: first, to re-educate the immune system to stop its attack on the beta cells, and second, to increase the beta cell resistance to the immune attack, and to find means to restore the lost beta cell mass. Unfortunately, to achieve these goals in both type 1 diabetes and other autoimmune diseases is not easy, and we must redouble our efforts.

The next stages of the research will be to study the function of two novel candidate genes for type 1 diabetes that were discovered in the research. They both act at the beta cell level. He expects to conduct that research with Pasquali. The second stage is to evaluate the impact of other immune mediators that act earlier in the disease course at the beta cell level. And the third stage is to test their hypothesis regarding the role for the target tissue in other autoimmune diseases.

In addition to that ambitious agenda, Eizirik and his group are establishing an Inducible Pluripotential Cell Core at the IBRI.

Eizirik said, This will allow us to de-differentiate, for instance, skin cells from patients into pluripotential cells, and then to differentiate them into pancreatic beta cells. This will allow us to study the impact of the novel candidate genes we are discovering on beta cell function and survival, again in collaboration with Lorenzo Pasquali and Carmella Evans-Molina. This will also provide an excellent model to test new drugs to protect the beta cells in early type 1 diabetes.

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Researchers Working to Understand Why Some Patients with Autoimmune Diseases Develop Diabetes Instead of Arthritis - BioSpace

News Release

Wednesday, November 20, 2019

Studies in cell and animal models reveal insights into cancer cells vulnerability that could lead to new strategies against brain cancers.

Researchers have devised a new plan of attack against a group of deadly childhood brain cancers collectively called diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), thalamic glioma and spinal cord glioma. Scientists at the National Institutes of Health, Stanford University, California, and Dana-Farber Cancer Institute, Boston, identified a drug pair that worked together to both kill cancer cells and counter the effects of a genetic mutation that causes the diseases.

The researchers showed that combining the two drugs panobinostat and marizomib was more effective than either drug by itself in killing DMG patient cells grown in the laboratory and in animal models. Their studies also uncovered a previously unrecognized vulnerability in the cancer cells that scientists may be able to exploit to develop new strategies against the cancer and related diseases. The results were published Nov. 20 in Science Translational Medicine.

DMGs are aggressive, hard-to-treat tumors that represent the leading cause of brain cancer-related death among U.S. children. DMGs typically affect a few hundred children a year between ages 4 to 12; most children die within a year of diagnosis. Most cases of DMG are caused by a specific mutation in histone genes. Histones are protein complexes in the cell nucleus. DNA wraps around histones to form chromatin, which packages DNA in the nucleus. How DNA winds and unwinds around histones is influenced by enzymes, including histone deacetylases. These enzymes add or remove chemical tags, which indirectly controls if genes are turned on or off.

In an earlier study, Stanford neuro-oncologist Michelle Monje. M.D., Ph.D., and her colleagues showed that panobinostat, which blocks key histone deacetylase enzymes, could restore the DIPG histone function to a more normal state. While panobinostat is already in early clinical testing in DIPG patients, its usefulness may be limited because cancer cells can learn to evade its effects. So Monjes team wanted to identify other possible drugs and combinations of them that could affect the cancer.

Very few cancers can be treated by a single drug, said Monje, a senior author of the study who treats children with DIPG and other diffuse midline gliomas. Weve known for a long time that we would need more than one treatment option for DIPG. The challenge is prioritizing the right ones when there are thousands of potential options. Were hopeful that this combination will help these children.

Monje and the National Cancer Institutes Katherine Warren, M.D., now at Dana-Farber Cancer Institute and Boston Childrens Hospital, collaborated with Craig Thomas, Ph.D., and his colleagues at the NIHs National Center for Advancing Translational Sciences (NCATS). Thomas and his team used NCATS drug screening expertise and matrix screening technology to examine drugs and drug combinations to see which ones were toxic to DIPG patient cells.

NCATS robotics-enabled, high-throughput screening technologies enable scientists to rapidly test thousands of different drugs and drug combinations in a variety of ways. Scientists can examine the most promising single drugs and combinations, determine the most effective doses of each drug and learn more about the possible mechanisms by which these drugs act.

The NCATS researchers first studied the effects of single approved drugs and investigative compounds on DIPG cell models grown in the laboratory from patient cells. They focused on agents that could both kill DIPG cells and cross the brains protective blood-brain barrier, a necessity for a drug to be effective against DIPG in patients. The team then tested the most effective single agents in various combinations.

Such large, complex drug screens take a tremendous collaborative effort, said Thomas, also a senior study author. NCATS was designed to bring together biologists, chemists, engineers and data scientists in a way that enables these technically challenging studies.

While there were multiple, promising outcomes from these screens, the team focused on the combination of histone deacetylase inhibitors (like panobinostat) with drugs called proteasome inhibitors (such as marizomib). Proteasome inhibitors block cells normal protein recycling processes. The panobinostat-marizomib combination was highly toxic to DIPG cells in several models, including DIPG tumor cell cultures that represented the main genetic subtypes of the disease and mice with cells transplanted from patient tumors. The combination also reduced tumor size in mice and increased their survival. A similar response was found in spinal cord and thalamic DMG models developed from cells grown in culture from patient cells.

The screening studies also provided important clues to the ways the drugs were working. Building on these data, the collaborative team subsequently conducted a series of experiments that showed the DIPG cells responded to these drugs by turning off a biochemical process in the cells mitochondria that is partly responsible for creating ATP, which provides energy to cells. The drug combination essentially shuts down tumor cell ATP production.

The panobinostat-marizomib drug combination exposed an unknown metabolic vulnerability in DIPG cells, said first author Grant Lin, Ph.D., at Stanford University School of Medicine. We didnt expect to find this, and it represents an exciting new avenue to explore in the development of future treatment strategies for diffuse midline gliomas.

Plans are underway for clinical trials of the drug combination and of marizomib alone.

Many drugs that we test have multiple effects on DIPG cells, said Warren, a senior study author. Panobinostat, for example, inhibits a specific enzyme, but it has other mechanisms working in tumor cells that may contribute to its effectiveness. Were still trying to understand the various Achilles heels in these cancer cells. This work is an important step in translating our preclinical data into patients.

Monje stressed the panobinostat-marizomib combination might be an important component of a multitherapy strategy, including approaches that harness the immune system and those that disrupt factors in the tumor microenvironment that the glioma cells depend on to grow. Like Warren, Monje emphasized the need to better understand how drugs target and impact the DIPG cells vulnerabilities.

Our work with NCATS showed the need to gather more preclinical data in a systematic, high-throughput way to understand and prioritize the strategies and agents to combine, Monje said. Otherwise were testing things one or two drugs at a time and designing clinical trials without preclinical data based on hypothesized mechanisms of action. We want to move past this guesswork and provide preclinical evidence to guide clinical decisions and research directions.

Lin added, The idea is to get as many effective tools as possible to work with that can have an impact on patients.

The research was funded by Alexs Lemonade Stand Foundation, Izzys Infantry Foundation, McKenna Claire Foundation, Unravel Pediatric Cancer, Defeat DIPG Foundation, ChadTough Foundation, N8 Foundation, Kortney Rose Foundation, Cure Starts Now Foundation and the DIPG Collaborative, Sam Jeffers Foundation, Lyla Nsouli Foundation, Abbies Army Foundation, Waxman Family Research Fund, Virginia and D.K. Ludwig Fund for Cancer Research, National Institute for Neurological Disorders and Stroke (R01NS092597) and NIH Directors Common Fund (DP1NS111132), Maternal and Child Health Research Institute at Stanford, the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases, The DIPG All-In Initiative and the NCATS and NCI intramural programs.

Reference:GL Lin et al. Therapeutic Strategies for Diffuse Midline Glioma from High-Throughput Combination Drug Screening. Science Translational Medicine. DOI: 10.1126/scitranslmed.aaw0064

About the National Center for Advancing Translational Sciences (NCATS):NCATS conducts and supports research on the science and operation of translation the process by which interventions to improve health are developed and implemented to allow more treatments to get to more patients more quickly. For more information about how NCATS is improving health through smarter science, visithttps://ncats.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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Scientists find promising drug combination against lethal childhood brain cancers - National Institutes of Health