Michelle Monje, MD, PhD, is a pediatric neuro-oncologist at Stanford University and one of the world’s top researchers in the study of high grade-gliomas.  In 2017, Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation awarded a research grant to Dr. Monje for her project titled “The Tumor Microtube Network in DIPG:  Targeting a Possible ‘Achilles Hill’ Required to Defeat DIPG.”

Through this research, Dr. Monje discovered that deadly brain tumors integrate themselves into the brain’s electrical network and then hijack signals from healthy nerve cells to fuel their own growth. Her findings were published in Nature and featured on NPR, and The Defeat DIPG ChadTough team had an opportunity to discuss this project with her:

Q: You recently had a study published in Nature.  Can you tell us about that?

MM: We have, for many years in my lab, been trying to understand the way that DIPG and other pediatric high grade gliomas interact with the normal brain, particularly the abnormal cells in the developing childhood brain. One thing that we’ve learned in the past and that we’ve published, is that neural activity, the activity of the brain itself, very robustly promotes the growth of DIPG and other childhood brain tumors. One of the important mechanisms that we discovered that is responsible for this is the brain activity dependent release of a particular kind of growth factor.

This is a growth factor that under normal circumstances helps to promote brain plasticity, and this overall process might have roles in learning and memory and brain development, but the cancer is hijacking it and taking advantage. When we looked at it, this mechanism seems to be so important. If we disrupt it, DIPG really can’t grow. So we’ve been trying to understand why that’s true, and that prompted us to look at the cellular consequences of exposure to this molecule. 

One of the cellular consequences was upregulation of genes in the tumor cells that enable them to form networks. In adult glioblastoma this network formation had been described as occurring and it was kind of shocking to people because a previous conception of cancer is that one cell goes bad and it divides in this mindless way while some of the different cells take on different functions in the tumor. It’s homogeneity but basically it’s just continuous growth. What the paper in adult glioblastoma showed was that, in fact, the tumor cells were connecting with each other and forming kind of a cooperative network. What we’ve discovered is the extent to which that same kind of network formation was happening in DIPG between the tumor cells, and how that might interface with how the tumor interacts with the normal brain. The study also tries to understand if this is indeed important for DIPG growth and might represent a therapeutic target.

Q: Have you seen research trickling down to other pediatric brain cancers yet? Have you seen it making an impact?

MM: Yes, I think actually in the work I was just describing for you, that there’s a lot of cross pollination between different kinds of high grade gliomas. I described sort of a cross pollination between adult and pediatric high grade gliomas, but some of what we’ve discovered in DIPG we have found to be equally relevant to other forms of pediatric high grade gliomas. That starts some collaborations to look for similar physiologies or pathophysiologies in ependymoma and the broad area of understanding how the normal brain cells are interacting with the cancer cells. I think this is something that all pediatric brain tumor researchers need to think about; many of them are thinking about. A lot of what we’re learning in DIPG is helping to inform that.

Q: Chad Carr and Michael Mosier were diagnosed a little over 5 years ago.  Are there differences in treatment today versus 5 years ago?

MM: In the past 5 years, a number of laboratory studies on DIPG have identified new promising treatments for DIPG, from immunotherapy to novel drugs targeting epigenetic, metabolic and microenvironmental vulnerabilities of DIPG. Several new clinical trials based on these laboratory studies are now opening. We know more about the biology of DIPG than ever before, and soon that new knowledge may lead to effective therapy.

Q: What is the importance of private funding, such as the Defeat DIPG ChadTough grant you received for this project, in moving the field of DIPG forward?

MM: Private funding enables researchers to be more nimble and pursue new ideas more rapidly.

Q:  What do you think the impact will be of this groundbreaking discovery? Will it drive changes in treatment for DIPG patients?

MM: Our new appreciation that DIPG integrates into neural circuitry opens up a whole new dimension of possible therapeutic targets that I am hopeful will make a difference in outcomes for children with this terrible brain cancer. 

July 3, 2014 – March 6, 2020

Vivian Rose was born on July 3, 2014 to her parents, Simon and Katie Weaver.  Her family joyfully celebrated her birth, the fulfillment of prayers and excited anticipation. Her parents led her on a life of fun and adventure, heading to the Oregon coast the day after her birth to celebrate the 4th of July with family.  She was always up for experiences, whether simple visits to the park, scouring the library for good books, enjoying overnights with family and friends at a young age, staying in hotels or flying on planes. Her favorite destinations included Disney World (her Make-A-Wish destination) and Hawaii.  Near the end of her life Vivian continued to take joy in even short outings, anything that got her outside and on the move. In her final weeks she enjoyed browsing downtown Hood River, shopping at the grocery store, stopping for treats at the bakery and a quick trip to the zoo one week before she passed.   

Vivian developed into a joyful, bright, effervescent personality that never ceased to warm the hearts of those around her. Countless people commented on this, describing her as a bright light and a magical presence.  Vivian loved ballet, horses, school, books, princesses, her friends, organizing, and the color pink. 

Vivian was a hard worker who took instruction well. As a willing pupil her parents loved teaching her new things, and her curiosity enabled her to take interest in just about everything. Over the years Vivian worked on engines in their shop, cooked extensively with her mother, learned to ski, hunted deer and elk, helped build her treehouse, crafted just about everything and she loved stomping barefoot in the garden. She was easily entertained. Vivian’s imagination flourished with her father’s storytelling and drives in the car were never complete without a storytelling. Her appetite for reading books was inexhaustible. 

After two-and-a-half years at Little Oak Montessori, Vivian enrolled in Kindergarten at Whitson Elementary School in September of 2019. She loved her classmates, her teacher and the hustle and bustle of the classroom.  Even as her illness progressed Vivian participated in school. Simon and Katie remain appreciative for the resources and help the school and staff provided to make Vivian feel included and to accommodate her needs. Vivian visited her classroom for the last time 4 days before her passing, her classmates surrounding her wheelchair, showing her their artwork and tenderly touching Vivian as they greeted her.  

Vivian was an old soul. She particularly loved her extended family and her close girlfriends, especially her best friend Violet and her cousins.  Her relationships showed maturity beyond her years.  However, nothing illustrated her maturity, fortitude and character more than her response to her diagnosis of DIPG (diffuse intrinsic pontine glioma) on February 1, 2018.  DIPG is an inoperable and incurable brain tumor with an average survival of 9 months. Despite the progressive nature of this disease, Vivian never complained. Vivian insisted upon climbing onto the radiation table independently before treatments.  When she began to fall for lack of balance, she would struggle back to her feet declaring, “I’m ok!”  She endured IV placements, surgeries, long days of chemotherapy and repeated hospital visits, but she cherished spending the day with Mama or Papa on these many occasions. Before painful procedures Vivian and her parents would hold each other, say a quick prayer, and Vivian would then comply with the task at hand. She never created a scene, never screamed or yelled or refused despite her dislike of the process.  

Vivian defied the odds and for more than two years her parents cared for Vivian, investigating all available treatment options and seeking out promising therapies and cutting-edge interventions at home and abroad.  Following Vivian’s diagnosis they enlisted an army of people to pray for Vivian and the other children affected by this disease. The Weavers became keenly aware of the other families and children suffering from this disease and they established the Vivian Rose Weaver Defeat DIPG Foundation. This Foundation seeks to raise money for DIPG research with the hopes that, some day, a cure will be found. DIPG remains the deadliest of ALL childhood cancers and nearly every day one child in the United States is diagnosed with DIPG and another child dies from it.  Vivian understood her parents’ efforts, she wanted to help and she expressed a hope that other children with DIPG would not have to visit the hospital as much as she had. 

Simon and Katie remain deeply thankful to God for the gift and blessing of Vivian’s life, her love for Jesus, and His presence and faithfulness throughout.  

Our sweet Vivian Rose Weaver went to be with her loving Heavenly Father on March 6, 2020, at her home in Husum, Washington, while snuggled between her Mama and Papa. She is now resting in the arms of her Lord & Savior, Jesus Christ.  Vivian is survived by her parents, Simon and Katie (McKinney) Weaver and her sister, Lucie Beatrice Weaver, affectionately nicknamed, Lulu Bea, by Vivian.  She is also survived by her paternal grandparents, Bob & Karen Weaver, her maternal grandparents, Peter & Bea Plath, Rus & Barb McKinney, her aunts and uncles, Marc & Nicolai (Weaver) Stromvig,  Jonah & Grace Weaver, David & Amanda McKinney, Mike & Amy McKinney, Ryan & Sarah McKinney, James & Alex McKinney, Megan McKinney, Dan & Bri Plath, Jacob & Leslie (Plath) Johnson, and Katy Plath.  She was loved by all her many cousins, Caitlin, Duke, Joey, Lauren, Hudson, Helen, Oliver & Gavin McKinney & Brady, Kristen & Landon Peterson, Davis, Bennet & Graham Plath, Charlie & Grady Johnson, Cameron (Adeline), Alexandria (Remy), Riley & Micah Stromvig, Tayo Weaver.  She was preceded in death by her cousin, Chase Thomas McKinney, and Aunt Sarah Louise McKinney.

In lieu of flowers or gifts, the Weaver family asks that you consider a tax deductible donation in her honor, to fund a cure for DIPG, to Vivian Rose Weaver Defeat DIPG Foundation. Checks can be mailed to P.O. Box 239, Husum, WA 98623. 100% goes to DIPG research.

Vivian’s memorial scheduled for March 14 had to be postponed due to concerns with the coronavirus and will be rescheduled, hopefully before the summer.       

Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation, and their chapters and partner families, are thrilled to announce the funding of 11 new DIPG-specific research projects totaling $3.4 million over the next 3 years. This brings the total research dollars committed through the Defeat DIPG ChadTough partnership to more than $6.7 million in the past 3 years. Two of the new grants will be made in partnership with SoSo Strong Pediatric Brain Tumor Foundation.

The foundations will share more details on these new projects in the upcoming weeks. This round of funding includes $2.8 million through the Defeat DIPG ChadTough research program to fund: two research grants ($600,000 over three years), four new investigator grants ($250,000 over two years), and four fellowships ($150,000 over two years). All projects are reviewed by the Defeat DIPG Scientific Advisory Council, a preeminent group of experts in the field.

Defeat DIPG and ChadTough are also providing over $600,000 for an innovative new collaboration through PNOC (Pacific Pediatric Neuro-Oncology Consortium) and the DIPG Centre of Expertise in Zurich, to support preclinical and clinical work across multiple institutions to move combination therapies for DIPG into the clinic. 

We are pleased to make this announcement on behalf of all of our valued Defeat DIPG Network chapters: Anthony’s Avengers Defeat DIPG Foundation (IL), Avery Huffman Defeat DIPG Foundation (WA), Carson Hall Defeat DIPG Foundation (KS), Connor Man Defeat DIPG Foundation (TX), and Vivian Rose Weaver Defeat DIPG Foundation (WA).  We are also very grateful to work with the ChadTough partner families, Team Tommy (the Ruddy family), Team Juliam (the Boivin family), Team Colt (the DelVerne family) and Team Carter (the Jones family). 

We thank all of our supporters who make this important researching funding possible. It is because of your generous contributions that we are making progress towards finding a cure.

Dr. Chen Shen

Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation, with our chapters and partner families, have partnered to fund more than $3.3 million in Diffuse Intrinsic Pontine Glioma (DIPG) research grants. The first round of grants was announced in 2017 and included a fellowship grant awarded to Dr. Chen Shen, a research fellow at Northwestern University.  Her study is entitled “Dissection of ATRX in Diffuse Intrinsic Pontine Glioma.”

Defeat DIPG ChadTough Fellowship grants are designed to encourage outstanding scientists to choose a career involving DIPG research.

“This fellowship provides me an opportunity to work on an area that few people focus on, and the passion of the families like the Carrs and Mosiers keeps me motivated every day to try to find a cure,” shares Dr. Shen.

Members of the Defeat DIPG team visit Dr. Shen in the Northwestern lab.

Under the direction of Dr. Oren Becher at Northwestern University Feinberg School of Medicine, Dr. Shen’s project focuses on the ATRX protein and its role in driving DIPG tumor growth.  Dr. Becher’s laboratory is unique because they study DIPG exclusively and do so through genetically engineered mouse models.  Because DIPG is a heterogeneous disease, they can develop mouse models to control for specific mutations to understand how each mutation may contribute to DIPG.  

The first step of Dr. Shen’s project was to develop a new mouse model that also deleted ATRX in addition to the histone mutation to study how ATRX contributes to DIPG formation.  While the histone mutation is commonly seen in human DIPG tumors, ATRX has been found to be deleted in a subset of only 10-30% of human DIPG tumors.   When ATRX deletions do occur in human DIPG tumors, they co-occur with the more commonly seen histone mutations.  This model will be used to look at what happens when you add the deletion of ATRX on top of the histone mutation.  

Dr. Becher reports that the new mouse model has been developed and work is ongoing to evaluate how ATRX deletion changes genes that are turned on in tumor cells.  Final results are expected at the end of this year.  

Interestingly, they were also able to obtain additional information on some other genes that appear to be regulated by ATRX loss with this model, and are currently validating these genes that are differentially expressed between the tumors with and without ATRX.  “Once we validate these genes that appear to be regulated by ATRX, this will be important knowledge for the field because it has not been well described what genes are regulated by ATRX in DIPG cells specifically with the histone mutation,” said Dr. Becher.  

Additionally, Dr. Shen will test some of the ATRX mutant mouse cell lines with and without ATRX loss to see how ATRX affects response to radiation. Radiation is the current standard of treatment for DIPG used to temporarily improve clinical symptoms, and can increase survival by about 3-6 months.  Dr. Becher notes that not all children with DIPG respond to radiation in the same way.  “There are some kids that we treat with radiation and they don’t benefit at all and some that have a dramatic response,” said Dr. Becher.  Because of these differences in response, they would like to explore if this response can be linked to ATRX loss.    

Dr. Becher’s lab will continue this project after the fellowship grant work ends as they have some new angles to explore once the target genes that appear to be regulated by ATRX have been validated.  This work is planned to begin soon.   

Written by Ellen Klepack, a ChadTough Volunteer Writer

Immunotherapy researchers from across the globe are gathering in Zurich, Switzerland, on August 7-8, 2019, for a first-of-its-kind meeting on the role of immunotherapy in treating DIPG and DMG. The working meeting, sponsored by Michael Mosier Defeat DIPG Foundation and organized by the DIPG Center of Expertise Zurich (DCEz), is a gathering of researchers working together to explore and develop a path forward to apply immunotherapy treatments to DIPG and DMG.

“The invited team represents physicians, scientists, and clinical trialists. We need all three areas of expertise to experiment, validate, and translate the knowledge,” explains Javad Nazarian, PhD, MSC, head of the DIPG Research Institute of DCEz and member of the Defeat DIPG Scientific Advisory Council, “We are hoping that this meeting will be the first of such focused meetings and hope that more like-minded colleagues would join to help in making a difference.” 

Over the past two years, Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation, with their chapters and partner families, have made immunotherapy research initiatives a priority and have awarded $500,000 in Defeat DIPG ChadTough Grants to support promising immunotherapy studies.

“Immune-therapeutic approaches have achieved significant breakthroughs for specific adults cancers as well as leukemia; however, successful implementation of immunotherapy for patients with brain tumors – specifically for children with one of the deadliest tumors referred to as DIPG – remains under active investigation,” says Sabine Mueller, MD, PhD, Head of the Clinical Programme of the DCEz and pediatric neuro-oncologist at University of California – San Francisco, “Leading experts will be gathered in this Think Tank to outline a roadmap how to best move immunotherapy approaches forward in children with brain tumors.”

Dr. Nazarian adds, “The meeting would not have happened without the support of Michael Mosier Defeat DIPG Foundation.  The idea of having such a meeting was born just this Spring and the foundation immediately volunteered to support the meeting.  This is a classic example of foundations helping to push the science forward, because they know how little time these children have.”

DCEz, which is a part of the University Children’s Hospital of Zurich, focuses on finding novel ways of treating of DIPG and DMG by researching different drug delivery pathways, combining multiple drugs into a combined therapy, and marrying the best of medical and scientific knowledge bases. The center is hoping to offer new treatments and treatment options to those suffering from DIPG and DMG.

Keep up with what’s going on at the DIPG/DMG Immunotherapy Meeting on Defeat DIPG’s social media accounts (@DefeatDIPG).

We feared for many months that Vivian would never make it to this day. We even thought about doing the party early, just in case. We thought it about more on the days she seemed to be doing worse. Today, though, we can celebrate a small victory – on July 3rd, Vivian turned five.

We couldn’t have made it this far without your prayers and support. We’re thankful every day for the support we get from you, our DIPG community. Without you this journey would be far more difficult. In addition to your prayers and emotional support, there’s something more you can do: Please watch this video and help to find a cure for DIPG by donating. All donations (after credit card processing fees) go directly to funding DIPG research.

To donate click here.

Dr. Anastas, Photo by Robyn Guo.

Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation, with our chapters and partner families, have partnered to fund more than $3.3 million in Diffuse Intrinsic Pontine Glioma (DIPG) research grants. Their first round of grants was announced in 2017 and included a fellowship grant awarded to Dr. Jamie Anastas, a research fellow at Harvard University and Boston Children’s Hospital.

Dr. Anastas was awarded a Defeat DIPG ChadTough fellowship grant for her study, “Targeting chromatin regulation to treat DIPG.” The study looks at how the histone mutation commonly found in DIPG affects how the tumor cells function. 

Dr. Anastas spoke with the Defeat DIPG ChadTough team to provide an update:

Q: Can you provide an overview of your project?

Dr. Jamie Anastas: “Sure! I’m currently working as a postdoc in Yang Shi’s lab at Boston Children’s Hospital where we study epigenetics, which is essentially a field where we look for factors that can lead to changes in cellular behaviors and gene expression but don’t involve changes in the DNA sequence. So one of the main things that we’re focused on are proteins called histones, which help to control which genes are turned on and off in both normal cells and tumor cells. Histones are really interesting in the context of DIPG because the majority of DIPG tumors produce a mutant version of one of these histone proteins which can then go on to disrupt gene regulation. I’m studying various pathways that regulate the ability of histones and other factors to control cell behaviors to try to figure out if any of those pathways might be targeted in DIPG. Hopefully we can develop new therapies for DIPG and understand a little bit more about the basic biology of this disease.”

Q: Your project says you screened 1,300 regulators in an effort to narrow it down to see which aided in DIPG survival. Are there any results you can share?

Dr. Jamie Anastas: “We don’t have the final answer yet, but I can speak more generally about the method we’re using to try and narrow down pathways. Like you said, we did a screen for around 1,300 different chromatin factors. To do this, we grew up a bunch of DIPG cells and used a relatively new technology called CRISPR Cas9 where we use a bacterial enzyme to induce cuts or disruptions in the sequence of these genes to block their function. Instead of inhibiting one factor at a time, we used a pooled approach where we were able to look at conditions that disrupt the function of all these genes at once in one big experiment. After getting a list of potential hits from the screen, there have been a lot of validation steps. Although we only did the screen initially in two cell lines, we’ve now expanded to many more patient cell lines through collaboration with Mariella Filbin’s and Todd Golub’s groups. 

“The first thing we were able to do was look for hits that were coming across in a majority of the cell lines. We then had to validate the hits in individual cell lines, ensuring that the tools we were using to disrupt these genes really led to the changes we expected. The gene-targeting libraries we used to do the screen were based on a bioinformatic approach, but we still had to actually look at the cells and make sure that the genes were mutated or that the protein encoded by them was lost. We’ve been able to do that for a subset of the screen hits. Another important thing was to see whether disrupting these genes can also affect the growth of normal cells. While it’s not completely essential that disrupting these genes only kills DIPG cells, it’s of course nice if they’re at least more sensitive. When thinking about eventually developing a drug to one of these pathways, we wouldn’t want it to hurt normal tissues.”

Q: What is the next step in the process after completing a project like this, in the grand scope of DIPG?

Dr. Jamie Anastas: “Ideally, once you’re really confident that a certain pathway is important for DIPG growth — including in mouse models, which is something we’re still working on — we would want to then identify a drug or some other therapeutic intervention that can either directly or indirectly affect that pathway. This might involve repurposing already existing drugs, or, in some cases, it might involve trying to generate entirely new compounds or strategies. I think in the context of DIPG, a lot of the pre-existing drugs just haven’t been effective, so I think we need to be open minded about identifying new targets and hopefully continue to work on ways to activate or inhibit them.”

Q: Can you talk about your professional background and how you got to be here doing the study?

Dr. Jamie Anastas: “I went to graduate school at the University of Washington where I was also working on cancer but not working in epigenetics. I was working on secreted molecules called WNTs that can activate various signaling pathways. Somewhere during that process I got really interested in epigenetics and gene regulation, so I went on to contact various labs so that during my postdoc work I would learn about chromatin and epigenetics and genomics and all of these sort of things. I ended up joining the Shi lab, and, at the time I was interviewing in the lab for the postdoc position, papers finding mutations in histone proteins in DIPG and other tumors had just come out. 

“I remember talking to Yang saying that this was really cool, that we should study this, and we should find a way to understand the epigenetic drivers of this disease. It’s been challenging in some ways because the lab I’m in really focuses on the basic molecular biology of chromatin. It’s not a brain tumor lab. So I’ve been really fortunate to have had lots of support from other researchers, Mariella Filbin in particular who’s a neuro oncologist is closely collaborating with us on various projects, other DIPG groups, like Michelle Monje’s, Nada Jabado’s, Keith Ligon’s and Suzanne Baker’s labs have generously given us cell lines and protocols. I think it’s pretty exciting to have a chance to take this knowledge of molecular biology and biochemistry and do our best to apply it to a really terrible disease and a really challenging problem.”

Q: Do you plan to continue focusing on DIPG once this study is complete?

Dr. Jamie Anastas:  “Long term, I’m certainly interested in exploring other mechanisms driving DIPG tumorigenesis. I have a previous background in signaling, so the obvious next steps now that I’ve screened through these different chromatin factors would be to expand to look at how different systems might regulate DIPG growth – signaling or otherwise. It’s definitely something that I’m interested in, it’s just a matter of having the time and personnel to go through those experiments. From a practical point of view — since I’m doing my postdoc in an epigenetics lab where we’ve got all of the tools and expertise in that area — it makes sense for me to focus on the lab’s strengths for now. 

It is also pretty clear that one drug or one intervention like radiation is probably not going to work in DIPG, so being able to understand how different pathways and processes might interact to drive tumorigenesis might be really key to eventually finding treatments that work. Beyond that, these tumors are, of course, not identical even though the majority of them have mutant histones. There’s a lot of heterogeneity, in terms of differences in genetic mutations and potentially in epigenetic regulation. So we may need to look at a variety of targets or pathways to find treatments that may be tailored to individual patients.”

Q: How will this fellowship allow you to advance your career?

Dr. Jamie Anastas: “This fellowship will help my career by giving me the opportunity to pursue more mechanistic lines of research to determine how chromatin regulators might drive DIPG tumorigenesis, which will allow me to learn and develop methods for studying brain tumors more generally. Hopefully, the skills and knowledge gained while supported by the ChadTough and Defeat DIPG foundations will help me prepare to lead a research group focused on understanding the molecular biology of pediatric brain tumors.”

Dr. David Ashley

Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation have partnered to fund more than $3.3 million in Diffuse Intrinsic Pontine Glioma (DIPG) research grants. Their first round of grants was announced in 2017 and included a research grant awarded to Dr. David Ashley, the Director of the Preston Robert Tisch Brain Tumor Center at Duke University.

In recent years, the Duke University team has developed an immunotherapy treatment that uses a modified form of the poliovirus to treat brain tumors. This treatment has received significant attention, including two segments on 60 Minutes. In 2017, the Duke team began a clinical trial using the poliovirus vaccine in children with high-grade gliomas, but DIPG patients were excluded due to a risk of inflammation. In this study, “Recombinant Attenuated Poliovirus Immunization Vectors Targeting H3.3 K27M in DIPG,” Dr. Ashley works to modify the poliovirus to effectively target the H3.3 K27M mutation in DIPG. This mutation occurs in approximately 80-percent of DIPG tumors.

“The Duke team has been doing groundbreaking work in developing the polio virus for treatment of brain tumors in adults,” said Defeat DIPG co-founder, Mark Mosier. “When we saw the stories on 60 Minutes, we knew that we needed to bring this treatment to DIPG. We are very encouraged by the initial work on this project, and we are excited about the possibility that DIPG patients will receive the polio virus treatment in the future.”

Dr. Ashley spoke with the Defeat DIPG ChadTough team to provide an update on this project:

Q: Can you provide an overview of your research project, specifically the excitement around the polio vaccine and the adjustments you’re working on to make this a possible treatment for DIPG?

Dr. Ashley: “The polio virus, in its original form, is a rapidly replicating virus. It causes a lot of inflammation it is an entero-virus, entering patients through the gastrointestinal tract. Matthias Gromier and his colleagues changed that part of the original virus that caused brain toxicity through taking part of the virus out and exchanging it for part of the common cold virus. So, we were able to maintain the inflammatory parts of it, but take away the parts of it that cause the injury to the brain and spinal cord cells.”

“The other interesting part is that the modified polio virus is able to attack cancer cells almost exclusively. Almost every human cancer cell has the entry receptor on it. This means the virus can get into the cancer cell very easily, replicates like crazy and causes inflammation, causes an immune response, and that’s the basis of the use of the polio virus. With use in adults, and with three children we’ve treated now in a pediatric study, we inject the modified virus directly into the brain tumors of the patients. That does seem to be successful in approximately a quarter to a third of patients in causing long-term responses of disease stability in glioblastoma.

“In thinking about DIPG, there’s a couple of issues. One is the delivery of something into the brain that can cause a lot of inflammation. That’s why we haven’t gone immediately to introducing this modified virus directly into the brain. The other is, DIPG does have this target that we’re hoping to exploit: the H3.3 K27M mutation. So, what we hope we are able to do is exploit the inflammation that’s caused by polio virus and add that bit of the H3.3 K27M mutation into the viral vector — into the virus itself — and use it as an immunization, not unlike the way we give original polio vaccine.

“The reason that we think this might be more effective than just using peptides, that under investigation for this illness, is that the virus is much more inflammatory than peptides by getting into the immune cells and it activating the immune cells. We think it’s really a clever way of administering a vaccine against the H3.3 K27M target in DIPG. That is the basis of this study.”

Q: Will you be injecting this vaccine directly into the tumor?

Dr. Ashley: Rather than using the polio virus for a direct injection into the brain tumor, we’re going to be using the polio virus construct in a vaccination schedule. Ultimately, the patient would get a vaccine just like they would get a polio vaccine — just an injection into the muscle. Then we think there will be immune responses to the virus and in turn to the mutant H3.3 K27M.”

Q: Is this particular mutation present in all DIPGs or only certain mutations of DIPG?

Dr. Ashley: “This is a mutation that’s in the vast majority of DIPG – approximately 80 percent. In fact, outside DIPG, this particular mutation is carried in other high grade tumors in childhood as well. So we would hope that this could be something that could be helpful for the majority of patients with DIPG. So, where to from here? The next step will be to go to the FDA to understand what other evidence or studies they’d like to see before we move toward clinical trial.”

Q: You recently submitted your manuscript for publication – what does that paper include?

Dr. Ashley: “We’ve created the construct, done the work rebuilding the virus, and then we’ve been able to do parallel experiments in mice and in human cells. We used a model system with a protein that we know works to immunize mice against tumors, so we showed that we could use the virus in that situation and get immune effects. Then, in addition to that, we’re able to take human cells and infect them with the human virus and show that we’re able to derive a very robust immune response in human cells … in a dish, if you like. So, we have two levels of evidence that this is going to work. One is in animals and the other is in a dish with human cells.”

Q: Can you articulate how important foundation funding is for research of this type of disease?

Dr. Ashley: “The answer is twofold. One, it’s a very rare disease. Although it’s horrible for families and the patients, obviously, it’s difficult to get funding for these sort of rare diseases, because public health institutions and large organizations tend to focus on the ‘big-ticket items,’ the big public health scourges. Second, it’s really hard to get initial startup funding to do this type of research, because it is pretty innovative and high risk. We didn’t know that this would work. We thought it would, we had hypothesised it would, but before you’ve got preliminary data to support your hypotheses, it’s really hard to get national peer-reviewed funding for this type of work. The funds that the Defeat DIPG and ChadTough Foundations provide allows us to do early, innovative work like this in rare diseases that otherwise would never get done.”