Michael Mosier Defeat DIPG®Foundation, a nonprofit whose mission is finding a cure for the deadliest pediatric brain cancer, DIPG (diffuse intrinsic pontine glioma), announced today the addition of a chapter in Gresham, Oregon, to its Defeat DIPG®Network:  Levi Harden Defeat DIPG®Foundation. Today would have been Levi Harden’s fourth birthday. Levi passed away from DIPG in October 2019, at three years old, just two months after diagnosis.

The new chapter adds to Defeat DIPG Network’s existing presence across the United States, in Maryland and Washington, D.C. as Michael Mosier Defeat DIPG Foundation, in Illinois as Anthony’s Avengers Defeat DIPG®Foundation, in Texas as Connor Man Defeat DIPG®Foundation, and in Washington as Avery Huffman Defeat DIPG®Foundation and Vivian Rose Weaver Defeat DIPG®Foundation. The Defeat DIPG Network has raised over $7.4 million for DIPG research in less than 5 years.

The Oregon chapter, which will operate as Levi Harden Defeat DIPG Foundation, is founded in memory of Levi Harden, son of Jenica and Nathan Harden. Levi loved sports, and from just two years old he could play miniature golf, hit a golf ball across the yard, play baseball, shoot hoops for hours and throw football with a perfect spiral. Levi was full of laughter and love and adored his big brother Clayton and new little sister Erin who was born around three weeks before his diagnosis with DIPG. 

The Harden Family
(left to right: Jenica, Erin, Levi, Nathan, and Clayton)

“We believe the best way to honor our son’s memory is to continue his fight against the disease that took his precious life,” says Jenica Castillo-Harden, Levi’s mother who will serve as Director of Levi Harden Defeat DIPG Foundation. “We are committed to finding a cure for DIPG because we believe that every child deserves a chance to grow up.  No family should have to hear their child’s doctor say, ‘there is nothing we can do.’ We know that together with our Defeat DIPG partners, we can change the future for kids with DIPG.” 

Jenny and Mark Mosier created Michael Mosier Defeat DIPG Foundation in June 2015 to fund DIPG research and promote awareness of the disease, after the passing of their 6-year-old son, Michael. With its geographic expansion and growth of existing initiatives, the Foundation expects to continue to increase its capacity to fund essential childhood cancer research.  

The Foundation, with its chapters, has announced over $7 million in DIPG-specific research funding, in partnership with The ChadTough Foundation. Two grants are also in partnership with SoSo Strong Pediatric Brain Tumor Foundation. Michael Mosier Defeat DIPG Foundation works with a preeminent Scientific Advisory Council of brain tumor experts that advises its Board of Directors on how to maximize its resources to fund research for a cure for DIPG. 

The Mosier, Harden, Gaskin, Huffman, Olympia, and Weaver families will work to grow the already powerful base of support in each of their communities, and to honor and unite all children and families who have had to confront this disease.  

“It is an honor to stand side-by-side with other families who share such a deep passion and dedication for finding a cure for DIPG,” says Jenny Mosier, Executive Director of Michael Mosier Defeat DIPG Foundation. “The devastating experience of losing our own children inspires our work to improve the dismal prognosis of less than 1% survival for children with DIPG. By driving more resources to DIPG research, we are pushing the field forward to find treatments for these children.” 

DIPG is the deadliest form of pediatric brain cancer, with a median survival from diagnosis of 9 months and a near 0% survival overall. DIPG typically strikes children between ages four and eleven. Because of its location in the brainstem where all motor activity is controlled, DIPG is inoperable. The disease progresses by taking over a child’s motor functions one-by-one, typically starting with vision and balance problems, before moving to partial paralysis, followed by the inability to chew, speak, swallow, move and eventually breathe – all of this while the child remains mentally intact.

For decades, treatment for DIPG has remained the same and has been ineffective. The entire amount spent annually on DIPG research – approximately $3 – 5 million – is less than 0.0005% of the total funding for cancer research.  In just the past few years, due to better medical technology and increased access to tumor tissue, researchers have made real advances in their understanding of this disease.  There is finally hope for progress in finding a cure.

To donate to support DIPG research in honor of Levi, please visit levidefeatdipg.org/donation.

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. 

Families, researchers, government regulators, and advocates gathered in Washington, DC, on February 13, 2020, for a multi-part event for the DIPG community, organized by the DIPG Advocacy Group.  There was an excellent turnout from throughout the country, a powerful example of collaboration and persistence of families who will not stop pushing to do better for the children facing DIPG (diffuse intrinsic pontine glioma). 

Jenny Mosier, Dr. Sabine Mueller, Dr. Eugene Hwang, and Dr. Carl Koschmann

In the morning, a Congressional Briefing was held to educate Congressional offices and advocate for passage of H. Res. 114, a resolution to support establishing May 17 as DIPG Awareness Day and encouraging greater consideration for pediatric and high mortality-rate cancers in the research grant process with public and private funding sources.  We thank Congresswoman Jackie Speier for her support for this important event.  There are nearly 100 co-sponsors for the bill to date, but additional support is needed.  Following the briefing, attendees gathered for a State of DIPG Summit that involved discussion of hot topics in the community, such as research initiatives, challenges facing patients and families, development of ONC201, the FDA regulatory framework, data-sharing, and advocacy opportunities.  A listing of speakers is below.

A highlight of the day was hearing from three patients:  young adults who are currently fighting DIPG and DMG (diffuse midline glioma).  Jace Ward, Anjalie Bartee, and Katie Bedingfield spoke with strength and passion about the reality for young adults and children fighting this difficult disease.  They emphasized the urgency of driving research forward and drawing more attention to the needs of this vulnerable population.

Jace Ward, Katie Bedingfield, and Anjalie Bartee

“I can’t promise I’ll be back here next year.  Which is exactly why I respectfully ask you to co-sponsor H. Res. 114 before you leave for the weekend. DIPG won’t wait until this is convenient. DIPG won’t wait until we are ready. While we have been ‘waiting’ to take a solid stand, DIPG has been taking the sight, the hearing, the speech, the ability to swallow and eventually the breath of thousands of kids across this country.” — Jace Ward, 21 years old, fighting DIPG since May 17, 2019.

Katie Gaskin, Stacey Sands, and Antonio Halek

A number of other families in the midst of the fight with their child made an incredible effort to take part in the event, including the Basha family from New York (with Elita in attendance), Halek family from Illinois (with Noah in attendance), and Stacey Sands from Kansas (in honor of Hudson).  And there were countless families who carry the heartbreak of losing a child who took part in memory of their precious children.  The power of standing together as a united community was palpable.  

Michael Mosier Defeat DIPG Foundation was proud to sponsor this event alongside other organizations:  The ChadTough Foundation, Dragon Master Foundation, Jack’s Angels Foundation, Julia Barbara Foundation, Smashing Walnuts Foundation, and Team Cozzi Foundation.  We thank Covington & Burling LLP for generously hosting the State of DIPG Summit and Akin Gump LLP for supporting the Congressional Briefing effort.  We appreciate the hospitality and great food from We, The Pizza, a restaurant owned by The Mendelsohn Family who are steadfast supporters of the fight to Defeat DIPG.

YOU CAN TAKE ACTION

There are two immediate action items where all can contribute to the coordinated efforts to establish May 17 as DIPG Awareness Day, as a catalyst for increased attention to this tragic disease.

Support H. Res. 114 – Federal Recognition

The DIPG Advocacy Group has detailed information on how you can engage with your Congressional representative to urge their participation as a co-sponsor for H. Res. 114.  Please visit the DIPG Advocacy Group website for instructions on how to contact the legislator who represents your district, either to request their support or to thank them for signing on to the resolution. 

Support “DIPG Across the Map” – State Level Recognition  

We call on everyone to use their stories and voice to help get all 50 states to recognize May 17 as DIPG Awareness Day.  To sign up for this project, please visit www.defeatdipg.org/dipgacrossthemap.  Michael Mosier Defeat DIPG Foundation organizes this project – a collaboration of foundations and individuals throughout the country – as a companion effort to our federal efforts.  We will provide step-by-step instructions and materials to assist in advocating within your state.  In 2019, 32 states recognized May 17 as DIPG Awareness Day.  We hope to increase that number in 2020, with the collective effort of the DIPG Community.

*****

Congressional Briefing Speakers

Janet Demeter (Jack’s Angels Foundation), Sabine Mueller (University of California San Francisco and [zurich]), Adam Resnick (Children’s Hospital of Philadelphia and Children’s Brain Tumor Tissue Consortium), Charles Keller (FILL IN), Malcolm Smith, David Arons (National Brain Tumor Society), Jace Ward (DIPG patient), Jenny Mosier (Michael Mosier Defeat DIPG Foundation), Elizabeth and William Psar (Julia Barbara Foundation, and Jill, Cam, and Phebe Morin (Luke’s Posse). Video available at this link.

State of DIPG Summit Speakers

Mark Mosier (Michael Mosier Defeat DIPG Foundation), Janet Demeter (Jack’s Angels Foundation), Elizabeth Psar (Julia Barbara Foundation), Paul Miller (advocate), Jenny Mosier (Michael Mosier Defeat DIPG Foundation), Sabine Mueller, MD, PhD (University of California San Francisco and [zurich]), Eugene Hwang, MD (Children’s National Hospital), Carl Koschmann, MD (University of Michigan), Paul Cozzi (Team Cozzi Foundation), Katie Gaskin (Anthony’s Avengers Defeat DIPG Foundation), Anjalie Bartee (patient), Katie Bedingfield (patient), Wolfgang Oster, MD, PhD (Oncoceutics), Amanda Haddock (Dragon Master Foundation), Adam Resnick (Children’s Hospital of Philadelphia and Children’s Brain Tumor Tissue Consortium), Gregory Reaman, MD (U.S. Food and Drug Administration), Jonathan Agin (Max Cure Foundation, Oncoheroes Biosciences), Danielle Leach (National Brain Tumor Society), and Jace Ward (patient). Video available at this link.

Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation are funding ten new Diffuse Intrinsic Pontine Glioma (DIPG)-specific research projects totaling more than $2.8 million over the next three years (2020-22).  Two of the new grants will be made in partnership with SoSo Strong Pediatric Brain Tumor Foundation.

To date, the Defeat DIPG ChadTough grant program has committed $6.1 million to 23 DIPG research projects.  In addition, Defeat DIPG and ChadTough have committed $600,000 to help fund an innovative collaboration between PNOC (Pacific Pediatric Neuro-Oncology Consortium) and the DIPG Centre of Expertise in Zurich, supporting preclinical and clinical work across multiple institutions.

“By working together, we are amplifying our capacity to make significant investments in DIPG-specific research,” says Defeat DIPG Executive Director Jenny Mosier. “It is the generosity, passion, and commitment of the Defeat DIPG and ChadTough supporter networks that propel our shared mission of finding a cure for this devastating disease.”  

The ten projects to be funded (listed below) include:  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).

Jason Carr, President of The ChadTough Foundation, explains, “Our grant program is designed to push the field forward by investing in research that is likely to fuel progress and add to our understanding of this disease, while also ensuring we empower the next generation of researchers to bring this over the finish line for our children.  We hope for a cure in the near term, but we realize we need a pipeline of researchers who have the expertise and drive to follow through with this work as long as needed”

Defeat DIPG ChadTough Fellow Eshini Panditharatna,
Dana-Farber Cancer Institute
Photo by: Dana-Farber

All projects for the Defeat DIPG ChadTough grant program are reviewed by the Defeat DIPG Scientific Advisory Council, an unparalleled group of experts in pediatric brain cancer who evaluate each application for scientific merit.  “Our Scientific Advisory Council brings a breadth of experience and expertise that sets our grant program apart,” says Mark Mosier, Chair of the Defeat DIPG Board of Directors. “Their rigorous review of the many applications we receive ensures we are using donor funds as efficiently and effectively as possible.”

The Defeat DIPG Scientific Advisory Council is chaired by Suzanne Baker (St. Jude Children’s Research Hospital) and includes David Ashley (Duke University School of Medicine), Oren Becher (Northwestern University’s Feinberg School of Medicine), Cynthia Hawkins (Hospital for Sick Children), Duane Mitchell (University of Florida College of Medicine), Michelle Monje (Stanford University), and Javad Nazarian (University Children’s Hospital Zurich, Children’s National Medical Center).

The Defeat DIPG ChadTough grant program was structured with guidance from the Defeat DIPG Scientific Advisory Council to ensure the grant amount, duration, and criteria were shaped to achieve the most meaningful results to push the field forward.  All of the Defeat DIPG ChadTough grants are multi-year grants, allowing researchers to spend more of their time in the lab and less seeking additional funding for future years.  Researchers submit progress reports to ensure the studies are proceeding as anticipated.

Defeat DIPG and ChadTough bring together 11 families with children who have fought or are fighting DIPG that are actively raising research dollars.  

“We are grateful for the opportunity to work together with this incredible set of families who contribute so much,” says Tammi Carr, Co-Founder and Board Member of The ChadTough Foundation, “They have all been through such a difficult experience with their own child’s battle, yet they harness their grief and passion to make a difference for families who will face DIPG in the future.”

Michael Mosier Defeat DIPG Foundation is led by co-founders Mark and Jenny Mosier, and includes their Defeat DIPG Network chapters:  Katie Gaskin and Ruben Cardoza (Anthony’s Avengers Defeat DIPG Foundation (IL)), Amanda and Brandon Huffman (Avery Huffman Defeat DIPG Foundation (WA)), Alexisand Peter Olympia (Connor Man Defeat DIPG Foundation (TX)), and Katie and Simon Weaver (Vivian Rose Weaver Defeat DIPG Foundation (WA)).

The ChadTough Foundation is led by co-founders Jason and Tammi Carr, and includes partner families Gina Hatzivasilis and Sam Reinhold (Team Benjamin) Connie and James Jones (Team Carter), Jeff and Shannon DelVerne (Team Colt), Brad and Nettie Boivin (Team Julian), and Tom and Amanda Ruddy (Team Tommy).

SoSo Strong Pediatric Brain Tumor Foundation is a nonprofit established in honor of Sophia Ann Myers and is co-funding two of the ten grants awarded in this grant cycle.

Learn more about The ChadTough Foundation at chadtough.org and Michael Mosier Defeat DIPG Foundation at defeatdipg.org.

RESEARCH GRANTS

  • Hideho Okada, University of California San Francisco, “Next-generation CAR T cell therapies for treatment of DIPG, utilizing sequential “prime-and-kill” circuits to achieve safe and effective tumor targeting”
  • Daphne Haas-Kogan, Dana-Farber Cancer Institute, “Dependence of DIPGs on DNA polymerase q for DNA repair defines a new therapeutic target”

NEW INVESTIGATOR GRANTS

  • James Stafford, University of Vermont, “Onc201 in DIPG; establishing mechanism, enhancing efficacy and determining long-term phenotypic consequences.”
  • Zachary Reitman, Duke University, “Enhancing the efficacy of radiation therapy for DIPG”
  • Stephen Mack, Baylor College of Medicine, “Interrogating the Role of HERV Activation in H3K27M Pediatric Glioma.”
  • Matthew Dun, University of Newcastle (Australia), “Unlocking oncogene addition to identify synergistic treatment targets for the treatment of DIPG.”

FELLOWSHIPS

  • Eshini Panditharatna, Dana-Farber Cancer Institute, “Targeting epigenetically induced vulnerabilities in DIPG.”  (Mentor:  Mariella Filbin)
  • Chan Chung, University of Michigan, “Targeting DIPGs by interrupting metabolic pathways.”  (Mentor: Sriram Venneti)
  • Alan Jiao, Boston Children’s Hospital, “Dissecting mechanisms of H3K27M oncohistone function in DIPG)  (Mentor: Yang Shi)
  • Xu Zhang, Columbia University, “Mechanistic studies on the WNT5A signal pathway in DIPG tumor.”  (Mentor: Zhiguo Zhang)

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).

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.”