ChadTough Defeat DIPG Foundation funds the most promising childhood brain cancer research across the globe. To date, the foundation, along with their partners and donors, has funded over 80 researchers, across 42 institutions, totaling over $33.5 million.
A significant finding in DIPG research is the histone H3K27M mutation, present in over 80% of patients. This mutation, found in both H3.1 and H3.3 isoforms, plays a crucial role in tumor growth by affecting gene regulation. Targeting this mutation offers hope for more effective and less harmful treatments.
However, the H3K27M mutation is considered “undruggable” because traditional drug methods struggle with its lack of easily targetable sites.
This project aims to overcome this challenge using expertise in protein chemistry and covalent drug discovery. We will develop an innovative platform to target the H3K27M mutation, employing chemoproteomics and AI-driven drug discovery.
Preliminary research with a probe named JNSY1 shows promise. JNSY1 selectively binds to H3.1K27M in DIPG cells, restores normal gene function, and induces selective toxicity in DIPG cells.
Dr. Bertoldo’s goal is to further optimize JNSY1, discover probes targeting H3.3K27M, and evaluate their potential as new DIPG treatments, leading to the first drug specifically targeting the main cause of DIPG.
Targeting Energy Metabolism in Diffuse Intrinsic Pontine Glioma
A key feature of DIPG tumors is a mutation where lysine 27 in histone H3 is replaced by methionine (H3K27M), found in about 80% of cases. This mutation leads to distinct molecular subgroups of DIPG with specific clinical characteristics.
Unlike normal cells, cancer cells, including those in DIPG, reprogram their metabolism to use multiple energy sources for growth. A key metabolite, α-ketoglutarate (α-KG), plays an important role in tumor growth by causing changes in gene regulation. DIPG tumors have high levels of α-KG, which is involved in DNA and histone modifications that promote tumor growth. Targeting α-KG production could therefore be a valuable therapeutic approach.
This project proposes that DIPG tumors from different molecular subgroups might rely on alternative nutrient sources to produce α-KG. Dr. Pichumani aims to find ways to reduce α-KG production in DIPG cells and mouse models by using nutritional supplements (like oxaloacetate and zinc) and commercially available metabolic inhibitors.
This research aims to identify key energy sources that DIPG cells use to maintain high α-KG levels, leading to the discovery of new targets for therapy. Additionally, it will explore the feasibility of new, non-invasive diagnostic methods, such as 11C-acetate PET scans and 13C-hyperpolarized MRI, to monitor α-KG synthesis in DIPG patients.
Bioelectricity, which regulates cell structure and function, could offer a new way to treat cancers like DIPG that resist standard therapies. However, current technology cannot provide the precise electric fields needed to target the tumor without affecting surrounding brain tissue. Surface electrodes can’t reach deep brain tumors, and surgically implanted electrodes pose a risk of damaging critical brain areas. Additionally, DIPG tumors are highly infiltrative and often too small to detect with imaging, making surgical implantation difficult.
Dr. Sarkar aims to develop the first non-surgical brain implant for bioelectric therapy for DIPG. Based on her initial studies, this technology involves nanoelectronic devices that travel through the body’s blood vessels, autonomously recognizing and targeting the tumor, even those too small to detect with imaging. These devices generate controlled electric fields directly within the tumor, adjustable in intensity and frequency, to selectively destroy tumor cells without harming surrounding tissue.
This approach could dramatically improve treatment by reducing therapy time to just a few minutes per day using a portable or wearable device, eliminating the need for head shaving, and significantly enhancing the patient’s quality of life. Combining this technology with existing treatments like chemotherapy and radiation could further improve effectiveness and increase patient survival rates.
Moreover, the low cost of mass-producing these nanoelectronic devices makes this cutting-edge technology potentially accessible to many people. This innovative therapy could revolutionize DIPG treatment, offering new hope to affected children and their families.
The H3K27M mutation is known to be a key factor in the growth of DMG tumors, but we don’t yet fully understand how this mutation causes tumors to form or how best to target it with treatments.
This project aims to explore the potential of targeting an enzyme involved in DNA repair called SMARCAL1 as a new treatment strategy for DMG-H3K27M. SMARCAL1 has not yet been studied as a treatment target for these tumors. Dr. Waitkus’ initial research shows that reducing SMARCAL1 in DMG-H3K27M cells causes DNA damage, slows down tumor growth, increases the survival of mice with these tumors, and triggers inflammation within the tumor.
Based on these findings, he will further investigate whether inhibiting SMARCAL1 could be a new and effective treatment for DMG-H3K27M tumors. The results from this study will help justify the development of drugs targeting SMARCAL1 and provide important data to guide future clinical studies aimed at addressing DNA replication stress in these tumors.
The origins and progression of DIPG, from normal brain cells to cancerous ones, have been poorly understood for decades, hindering the development of new treatments. By the time DIPG is diagnosed, tumors are advanced and genetically diverse, making treatment difficult. But Drs. Dirks and Hawkins believe that, with earlier intervention, treatments could be significantly more effective.
To achieve this, Drs. Cynthia Hawkins and Peter Dirks aim to identify key characteristics of early-stage and pre-malignant DIPG cells, as well as noncancerous cells within the tumor. Using genetically engineered mouse models of DIPG, they will track the disease from its inception with MRI and “lineage tracing”, allowing their team to mark and follow cells with DIPG mutations over time, mapping their development from initial changes to advanced tumors.
This research aims to reveal how normal brain stem cells are altered by DIPG mutations and develop into malignant tumors. By testing methods to block the progression of early-stage cells, Drs. Dirks and Hawkins hope to provide new insights into the origins, growth, diagnosis, preventions and treatments of DIPG.
Every cell in the human body has the same genetic code, but different types of cells, like blood and nerve cells, look and function differently. This is because cell types are influenced not just by DNA, but also by epigenetic regulation, which involves changes to DNA and histone proteins. These changes, along with environmental signals, affect how cells read their DNA, turning some genes on and others off. Through this project, Dr. Filbin aims to understand DMG tumor growth and develop treatments to make tumor cells mature and stop dividing.
In diffuse midline glioma (DMG), a mutation in a histone protein disrupts this regulation, causing tumor cells to multiply uncontrollably instead of maturing properly. Researchers have tried to change the epigenetic regulation in DMG to make the tumor cells mature, which would stop their growth. However, traditional methods only allowed separate studies of epigenetic regulation and gene expression.
New technologies now allow both to be studied at the same time in the same cell. Using these, along with genetic tools to remove the histone mutation, allow for a better understanding of how this mutation changes cell fate and drives tumor growth in DMG. Along with genetic barcoding, to track individual tumor cells and see why they don’t mature properly Dr. Filbin hopes to gain a better understanding of the growth of DMG tumors and develop treatments for patients.
Multimodal Systems for Molecular Profiling and Therapeutic Tracking of DIPG
The current best way to track how a DIPG/DMG tumor responds to treatment is using MRI scans to outline the tumor. If the tumor gets worse, doctors can switch to a different treatment. However, MRI scans can be hard to read because inflammation from treatments can look like tumor growth, causing confusion and delays in treatment.
Recent research, including work from Dr. Koschmann’s lab has found that measuring tumor DNA in the cerebrospinal fluid (CSF) and blood using a technique called droplet digital PCR (ddPCR) can provide important information about the tumor’s response to treatment, often before changes show up on an MRI. Dr. Koschmann and his team have also developed new biomarkers that might offer more accurate monitoring.
The goal of this project is to create and test methods for detecting other disease biomarkers, such as specific tumor proteins (H3K27M and TP53), mutant mitochondrial DNA, and unique DNA mutations from biopsy samples. Dr. Koschmann will also test how well combining all this information with advanced machine learning can improve disease measurement and classification.
By using these new biomarkers alongside traditional imaging, Dr. Koschmann and his team hope to give doctors more precise information to better manage DIPG/DMG patient care.
Immunometabolic Modulation of Diffuse Midline Glioma Response to Therapy
Immunotherapy using CAR T cells to target complex, acidic glycolipids (GD2) has shown promise in the treatment of DMG tumors. However, certain immune cells called glioma-associated macrophages and microglia (GAMMs) invade the tumor and weaken the CAR T cells’ ability to kill the cancer. Dr. Viswanath’s research has shown that DMG cells increase a metabolic enzyme called enolase 2 (ENO2) in GAMMs, which then blocks the CAR T cells’ effectiveness.
In mouse models, using a safe drug that inhibits ENO2 reduces the presence of GAMMs, restores the CAR T cells’ ability to kill the tumor, and leads to tumor shrinkage. Additionally, we have developed an imaging agent that can non-invasively monitor ENO2 activity and show how well the tumor is responding to treatment.
We believe that our studies will pave the way for new treatments and imaging techniques for children with DMGs.
CAR T-cell therapy has shown success in treating certain types of cancer in children. This therapy trains the immune system’s T cells to locate and eliminate cancer cells. However, until recently, CAR T-cell therapy was not available for children with brain tumors like DIPG. In 2021, Stanford doctors, including Dr. Ramakrishna, initiated a clinical trial to use CAR T-cells for treating DIPG in children and young adults. Encouragingly, 10 out of 12 patients who received these CAR T-cells experienced tumor shrinkage and improvement in symptoms. This project aims to gain insights from patients to understand why CAR T-cell therapy succeeded or failed, with the aim of enhancing and optimizing the treatment.
In all cancers, certain genes become overactive to fuel their growth and aggressiveness. To function properly, genes need to convert their DNA code into a temporary form called RNA, which serves as a template for producing proteins that carry out cellular functions. In DIPG, many of the genes responsible for cell growth disrupt the normal process of RNA translation, leading to the production of unintended protein products. Through this project, Dr. Prensner proposes that targeting this abnormal RNA processing could be a vulnerability in DIPG that can be exploited for treatment. This research will be the first systematic exploration of this abnormal RNA translation in DIPG and will link it to different known genes involved in driving the disease.
This project aims to develop a powerful and innovative immunotherapy using induced pluripotent stem cell (iPSC)-derived NK cells. These engineered NK cells aim to eliminate DIPG and enhance the activity of other immune cells against the tumor. Dr. Matosevic intends to demonstrate that combining iPSC-engineered NK cells with strategies to disrupt the DIPG TME will challenge current treatment approaches and revolutionize the way we treat DIPG.
Dr. Ligon and his team have developed a new treatment called RNA nanoparticle vaccines (RNA-NPs) to combat DIPG and other cancers. These personalized vaccines stimulate the body’s immune system to recognize and eliminate cancer cells. The treatment has shown promise in clinical trials for adult brain cancer patients, and now they plan to extend the trials to children with a different type of brain cancer, as well as patients with melanoma (skin cancer) and osteosarcoma (bone cancer). Encouraging initial results suggest that RNA-NPs could also be effective against DIPG. This project aims to further investigate the potential of RNA-NPs for treating children with DIPG and gain a better understanding of their effectiveness across various cancer types.
DMG is characterized by a specific mutation called H3K27M. This mutation affects a group of proteins known as polycomb repressive complexes 2 (PRC2), which play a vital role in determining cell development. The goal of this project is to gain a deeper understanding of PRC2’s role in the normal development of the pons, a critical part of the brain. Specifically, Dr. Keane will study cells with increased PRC2 activity and examine their DNA to identify any changes that occur when PRC2 activity is heightened. Additionally, she will investigate the presence and role of immune cells in the pons during this crucial time, examining how they contribute to the growth and expansion of this vulnerable region.
DMGs are brain tumors that often spread diffusely, making it challenging to track their progression. Current methods rely heavily on MRI scans, which do not always provide accurate information about treatment response. Dr. Viswanath and Dr. Mueller have discovered that changes in deuterated glucose metabolism can be observed within five days of radiotherapy in mice with DMGs, even when MRI scans show no visible alterations. In this study, they aim to investigate whether deuterated glucose can be used to visualize active tumor tissue and serve as an early indicator of therapy response in DMG-bearing mice.
New research has shown that 80% of DMG cases exhibit high levels of a protein called GD2. To target GD2, scientists are utilizing immunotherapy to destroy cancer cells. Dr. Omer and his team have improved the effectiveness of the GD2-targeting CAR T-cells by incorporating an additional gene, C7R, which enhances their anti-tumor capabilities and extends their lifespan. So far, they have treated 12 patients, with two experiencing tumor reduction exceeding 50%. To further enhance the therapy’s effectiveness, they plan to attack the tumor from multiple angles by administering CAR T-cells intravenously and directly into the spinal fluid surrounding the brain and spine.
This project will build on Dr. Majzner’s experience treating children with DIPG with CAR T-cells. Several patients have developed significant responses, however, some showed only temporary improvement or did not respond at all. Through this project, Dr. Majzner and his team aim to test and validate a new type of GD2 CAR T cell that is capable of enhanced persistence and anti-tumor efficacy, providing a more effective strategy for treating patients with DIPG/DMG.
This grant enables the purchase a Beckman-Coulter Optima MAX-XP Tabletop Ultracentrifuge. It is required for the optimized protocol for ribosome profiling for DIPG samples.
Most DIPGs are triggered by a specific genetic event that impacts the way brain cells regulate DNA activity. In effect, DIPG cells begin to awaken parts of the genome that are generally kept quiescent. Some of these genomic regions may produce retroviral elements. Under normal circumstances, these retroviral elements can be toxic when highly active, but DIPG cells appear to utilize, or at least tolerate, the presence of retroviral elements. Understanding which of these genomic elements are specifically activated in DIPG, and which produce proteins, may provide unique insights into how DIPG cells function, leading to opportunities for novel therapeutic approaches in this deadly childhood brain cancer.
Dr. Lu discovered that chaetocin, a substance produced naturally by a fungus, when combined with radiation, has an impressive killing effect on DMG/DIPG cells. This project will test this combination in conjunction with the oral drug ONC201 to discover why they work so well together and what may be needed to make them even more effective in the future.
The objective of Dr. Souweidane’s project is to develop more effective drug delivery methods for DIPG/DMG patients. To accomplish this, he will test various drug combinations and drug delivery techniques to more effectively target DIPG/DMG tumors, while avoiding the toxicities associated with the conventional administration of drug therapies. Dr. Souweidane expects the establishment of this drug-delivery platform will support many cutting-edge therapies and early-stage trials in the fight against DIPG/DMG tumors.
Delivering therapeutics directly to brain tumors safely and effectively has been one of the main limitations for the treatment of DIPG/DMG tumors. Drs. Raju and Becher have recently developed an innovative drug delivery technology that crosses the blood-brain barrier, delivering the drug safely to the site of the tumor. In this study, they will optimize the use of this technology in an effort to improve outcomes for DIPG/DMG patients.
A potential new treatment approach in the fight against DIPG/DMG tumors is to combine radiation therapy with targeted treatments against a specific molecule found in the tumor. However, some subtypes of DIPG appear to be resistant to this method. In this project, Dr. Reitman will carry out experiments to determine why that is so and identify combinations of treatments that could be used to overcome this resistance.
While the nature of mutations in DIPG/DIPG progression is still not fully understood, nerve cell activity is emerging as a critical cause of tumor growth. In this study, Dr. Venkatesh will use molecular biology and neuroscience techniques to better understand the dynamics between neurons and DIPG cells, along with combination treatment strategies to potentially change the way DIPG/DMG tumors are treated.
The objective of this study will be to evaluate the use of drugs that target signaling molecules called CDK. These findings will establish a basis for future clinical trials using these inhibitors as therapies for DIPG/DMG tumors in combination with other drugs. The approach of combining multiple drugs under investigation in clinical trials for DIPG treatment will challenge existing paradigms and provide a basis for the development of drug combinations aimed at achieving complete tumor control.
Dr. Vittorio works with copper chelating agents, which already have wide use in other cancers, to demonstrate the effectiveness of treating brain tumors. This grant will allow his research team to exhibit their expertise in copper biology as they uncover effective drug combinations to reduce copper in DIPG/DMG cancer cells, killing them and improving the survival rate in DIPG/DMG patients.
In addition to the grants made through the structured program, the foundation is excited to continue to support the promising Car T-cell trial led by Dr. Michelle Monje of Stanford University with our new co-funders, Storm the Heavens Fund, the SoSo Strong Pediatric Brain Tumor Foundation and the Elle’s Angels Foundation. The trial has shown great promise and, after decades, could finally offer patients with DIPG/DMG a new treatment option for a disease that has historically proven resistant to other therapies.
ChadTough Defeat DIPG Foundation is a 501(c)(3) nonprofit organization.
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