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.
https://www.connorman.org/wp-content/uploads/sites/9/2020/04/Monje_200.png300200Jenny Mosierhttps://www.connorman.org/wp-content/uploads/sites/9/2017/08/CMDDF-Logo.pngJenny Mosier2020-04-06 10:38:332020-04-06 10:38:33Stanford’s Dr. Michelle Monje Reports on Breakthrough DIPG Research Funded by Defeat DIPG and ChadTough
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.
“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”
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.”
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).
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.”
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)
https://www.connorman.org/wp-content/uploads/sites/9/2020/01/2020_DefeatDIPG_Master_v1.jpg640640Jenny Mosierhttps://www.connorman.org/wp-content/uploads/sites/9/2017/08/CMDDF-Logo.pngJenny Mosier2020-01-29 20:29:002020-01-30 11:43:12Defeat DIPG, ChadTough Award $2.8 Million for Ten New DIPG-Specific Research Projects
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.
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.
https://www.connorman.org/wp-content/uploads/sites/9/2019/12/Untitled-design-131.jpg00Jenny Mosierhttps://www.connorman.org/wp-content/uploads/sites/9/2017/08/CMDDF-Logo.pngJenny Mosier2019-12-17 00:11:382019-12-17 00:31:38Defeat DIPG, ChadTough Announce $3.4 Million in New DIPG Research Funding
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.
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
https://www.connorman.org/wp-content/uploads/sites/9/2019/10/image0.jpeg18001200Jenny Mosierhttps://www.connorman.org/wp-content/uploads/sites/9/2017/08/CMDDF-Logo.pngJenny Mosier2019-10-31 15:45:032019-11-05 22:27:16Northwestern University’s Dr. Chen Shen Studies How ATRX Mutation Affects DIPG
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).
https://www.connorman.org/wp-content/uploads/sites/9/2019/07/skyline-over-zurich-switzerland_800.jpg533800https://www.connorman.org/wp-content/uploads/sites/9/2017/08/CMDDF-Logo.png2019-07-31 11:16:452019-11-05 22:27:26Immunotherapy Experts Gather to Tackle DIPG
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.”
https://www.connorman.org/wp-content/uploads/sites/9/2019/06/image002.jpg37355309Mark Mosierhttps://www.connorman.org/wp-content/uploads/sites/9/2017/08/CMDDF-Logo.pngMark Mosier2019-06-28 09:18:182019-06-29 10:27:31Harvard’s Dr. Anastas: Applying Epigenetics to Unlock the Mystery of DIPG Growth
https://www.connorman.org/wp-content/uploads/sites/9/2019/04/IMG_5653.jpg720535Jenny Mosierhttps://www.connorman.org/wp-content/uploads/sites/9/2017/08/CMDDF-Logo.pngJenny Mosier2019-04-11 20:30:502019-04-12 06:00:48Announcing New Kansas Chapter: Carson Hall Defeat DIPG Foundation
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.”
https://www.connorman.org/wp-content/uploads/sites/9/2019/04/David-Ashley1-235x300.jpg300235Chrissie Wywrothttps://www.connorman.org/wp-content/uploads/sites/9/2017/08/CMDDF-Logo.pngChrissie Wywrot2019-04-10 09:42:222019-04-10 15:32:08Polio as a treatment? Dr. Ashley thinks it’s possible.
https://www.connorman.org/wp-content/uploads/sites/9/2019/04/ONC201-284x300-2.png300284Jenny Mosierhttps://www.connorman.org/wp-content/uploads/sites/9/2017/08/CMDDF-Logo.pngJenny Mosier2019-03-12 15:36:372019-04-10 15:47:20xCures to Implement an Intermediate Size Expanded Access Protocol for ONC201
Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation have partnered to fund more than $3.3 million in Diffuse Intrinsic Pontine Glioma (DIPG) grants. Their first round of grants were announced in 2017 and included a fellowship awarded to Zach Reitman, MD, PhD (Harvard University, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center).
Reitman spoke with Defeat DIPG ChadTough team to provide an update on his project, “Prioritizing PPM1D mutations as a target for new DIPG therapies,” for foundation supporters:
Q: Can you provide an overview of your research project?
A: “Happy to do so. In both the lab I’m working in and around the world, much has recently been learned about the biology of DIPGs through genomic sequencing. This work has revealed what we think drives these tumors to grow inappropriately. I’m focusing on one of the findings of this research, which is that one particular gene called PPM1D is likely to be a key driver of DIPG.
“My project is to find out more about how and why this PPM1D gene drives DIPG tumor growth. We’re growing DIPG tumor cells in a petri dish, and in mice, as laboratory models of DIPG. We’re then using genetic techniques to experiment with the PPM1D gene to find out how PPM1D is driving these model DIPG tumors to grow.
“This is really important because it will give us some clues as to why these deadly brain tumors are forming. I think it will also give us some important information on what the best way is to treat these tumors. For instance, we are finding out whether treatments that affect what the PPM1D gene is doing are likely to be effective treatments for DIPG.”
Q: How did you come across this idea?
A: “It’s really an amazing story. A lot of researchers became interested in looking at the genetics of DIPGs over the past 10 years. One of the reasons this was done is because the technology to sequence the genome and look at the genetics of tumors has dramatically improved over the past several years .
“This inspired several groups to carefully collect tumor tissue from patients with DIPG, and then to apply some of these new genomics technologies to uncover what really makes these DIPGs tick. At the time, I was working in a lab at Duke University. We carried out some genomic analyses of DIPGs, and we found this fascinating change in the PPM1D gene that I’m studying now.
“So this idea all dates back to that finding. One of the neat parts of the story is that several other groups were also looking at the genomics of DIPG patients and found that this same PPM1D gene is mutated in up to a quarter of DIPG patients worldwide. That really built up our confidence that this is really an important piece of the biology of DIPG, and not just something that was unique to the handful of DIPG tumors we had studied. It’s really a remarkable story where new technology came around, led researchers around the world to conduct some bold investigations with the permission of the patients and their families, and it led to paradigm-shifting discoveries.
“I’m now following up one of those discoveries and I’m hopeful this will help identify effective treatments for this deadly tumor.”
Q: One important thing you mentioned is collaboration across different labs and different researchers. Chad Carr’s tumor was sequenced at Michigan and they found PTEN as a key driver. What are your thoughts are around the different mutations of DIPG and the different people studying DIPG across a number of institutions?
A: “It’s so important for different researchers to study DIPG for a few reasons:
“First, I think studying diverse key drivers in DIPG is really important. This is because what we’ve found is that genetically, each DIPG is a little bit different – each patient’s tumor can have a different key driver or drivers. Some tumors, like Chad’s tumor, have PTEN as a key driver. Other tumors might have PPM1D, the gene I’m working on, as a key driver. Some tumors might have both. Others might have neither, or something else. This is why we need different groups to study the different key drivers in DIPG. We need to identify treatments that could work on tumors that have PTEN as a key driver. And we need to identify treatments that could work on patients with PPM1D as a key driver. The same goes for a number of other important drivers in DIPG. That way, when a child is diagnosed with a DIPG, there is going to be a high likelihood that research is being done that could be important for that child’s tumor.
“Second, I think having multiple researchers focusing on DIPG gives us more “shots on goal.” In cancer research, it’s very hard predict which research projects are going to ultimately result in an improvement in the standard of care for patients. In fact, most lines of research don’t ultimately lead to an improvement in how patients do. I think this speaks to the magnitude of the challenge we are up against. But there have been some amazing success stories in other types of cancer. Some types of cancer that were incurable in the past are now curable due to successful research efforts. I think by supporting many diverse ideas on how to improve care for DIPG patients, you maximize the chances that at least one of them will result in a success story for DIPG.
“Third, DIPG is a rare tumor. If only one institution studied it, you’d only have a few patients to glean information from, and you wouldn’t get a very complete picture of the biology of the disease or what treatments are going to work on the majority of DIPG patients. It’s so important to have many different institutions working together on this problem so we can combine our knowledge.”
Q: Can you go over your method and what you’re looking to produce out of your project? The answers you’re hoping to generate?
A: “One of the key methods we’re using is called CRISPR. This is a technique that’s emerged in the past few years in the molecular biology community that lets us edit the genome. A little bit of background: every cell in our body — or every cell in a DIPG tumor — contains approximately three billion pieces of DNA, or letters of DNA. CRISPR lets us very precisely edit a specific letter of that DNA. It’s a game changer.
“The CRISPR technology lets us ask some therapeutically imporatant questions. For instance, it lets us ask if a particular letter of DNA is important for DIPG cells to grow. One of the central aims of my work is to test whether a few important letters in the PPM1D gene are important for the growth of DIPG tumors using CRISPR. We’re using CRISPR to edit this gene and see if that causes the tumor to stop growing. Our hope is to produce a publication describing this, describing what we see, and we think that this will be valuable to determine whether treatments that affect this particular gene are worth pursuing.”
Q: Can you explain what happens after you publish a paper? How does that work in the grand scheme of DIPG?
A: “While our ultimate goal is to identify new treatments for DIPG, publications are an important milestone because they allow us to disseminate new research findings. This benefits the DIPG research community, because it gives other scientists a chance to build on our results. This also gives other groups a chance to validate our work and make sure its reproducible. An important part of the publication process is that the research is peer reviewed by other scientists, who make sure the work is rigorous and provide some feedback that can be very helpful to future work. And we continue to get feedback from the research community after the publication, which can be helpful for ongoing work and could even result in fruitful research collaborations.
“In some cases, publications can provide information for folks in the pharmaceutical industry in order to help them develop the best new cancer therapies. An important piece of background for this project is that pharmaceutical companies have already been developing chemicals that specifically target PPM1D, which is the gene we’re studying. This could eventually lead the way to a drug that targets PPM1D in the clinic. But there’s still a long way to go to get a drug that’s ready for clinical trials in kids. Developing a drug to that point is costly and takes years. A pharmaceutical company has to have a information that indicates that their drug likely to be helpful in order to make the investment to continue to pursue drug development.
“With our project, we hope that we can figure out if a drug that targets PPM1D is likely to be useful in kids with DIPG. If it is, it will provide a rationale that it might be worth the investment to develop a drug further. If we find out this isn’t likely to be a good strategy, it might help guide resources to be allocated towards more promising projects.
“Another interesting finding is that PPM1D also seems to be important in other types of cancers like breast cancer and some gynecologic cancers. So if we can show in our lab that it’s also important in DIPG, we can say, ‘Hey, look, this is a really important drug target. If a drug is developed that hits this target, it might be helpful for kids with DIPG in addition to these other tumor types. We’re hoping to provide a really fundamental biological insight that could prioritize whether this way of treating these tumors should be pursued further.”
Q: How will the Defeat DIPG ChadTough Fellowship impact your career?
A: “As I carry out this research project, the Defeat DIPG ChadTough Fellowship is providing me with research training that will help me in my career goal of establishing a laboratory aimed at identifying new treatment strategies for tumors like DIPG. As I mentioned above, I think work by multiple independent research groups is critical for the overall success of DIPG research. Training the next generation of research leaders is important to maintain this research community, and make sure that the very best people are going into DIPG research.
“A diverse set of skills is needed to lead a team that can tackle a terrible disease like DIPG. These skills do include a deep understanding of experimental laboratory techniques. But they also include skills to manage a team of researchers, to plan out long-term research projects, to understand how findings in the laboratory are translated to the clinic, and to effectively communicate results. And one needs experience in managing a budget to make sure funds are spent appropriately and effectively.
“Mastering these skills doesn’t happen overnight. For me, it started with my MD and PhD degrees at Duke University, which I followed with clinical residency training in the Harvard Radiation Oncology Program. The Defeat DIPG ChadTough fellowship is now giving me a chance to further master laboratory skills, to supervise a small group of researchers, and to start managing research funds. This is all being done under the supervision of my research mentors, Dr. Pratiti Bandopadhayay and Dr. Rameen Beroukhim, who both have a successful track record of leading research teams at the Dana-Farber Cancer Institute. By enabling me to gain this experience and to successfully complete meaningful projects, the fellowship is helping me towards my goal of one day leading a research group and identifying new treatment strategies for DIPG.”
Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation are excited to have Zach Reitman engaged in this research project, uncovering important data for DIPG research. Both foundations look forward to what he will do in the field in the future.