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 90 researchers, across 44 institutions, totaling over $36 million.
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the care of blood cancers and there is tremendous enthusiasm for using this new treatment to help children with diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG). Ongoing clinical trials, including at City of Hope, have shown encouraging initial results. However, none of these trials has yet definitively cured a patient, and most patients unfortunately have both limited and transient responses. Improvements to this promising therapy are badly needed. Part of the challenge is that brain tumors are more complex than blood cancers and are more hostile to immune attack.
Fundamentally, successful immune therapy against DIPG/DMG must do three things. First, there must be immune cells that recognize and kill tumor cells. Second, those immune cells must be able to trigger an amplified immune response. Third, the tumor must be prevented from evading or dampening that immune response. This project addresses these challenges in several ways. First, structures called tertiary lymphoid structures (TLSes) are sometimes found in brain tumors, and their presence correlates with improved clinical outcomes. TLSes are lymph node-like structures that have been shown to optimize and amplify immune reactions, and we hypothesize that this improved immunity will lead to better responses. Thus, we propose to induce TLS formation in
DIPG/DMG to improve immune reactions. Second, we have shown that a drug called decitabine makes DIPG cells more amenable to immune attack; this drug does not penetrate the blood-brain barrier, and delivery into the cerebrospinal fluid (CSF) has only been tested in non-cancer conditions. We propose to test delivery of decitabine directly into the CSF to prevent DIPG/DMG cells from avoiding immune attack. Additionally, decitabine treatment increases the expression of a protein called IL13RA2, to which we have designed CAR T cells, currently being tested in clinical trial at City of Hope.
We hypothesize that combining TLSes with decitabine and CAR T cell therapy will further improve our ability to combat DIPG/DMG. We expect that successful completion of this project will greatly advance the field of CAR T cell therapy for pediatric brain tumors by creating advanced cellular therapies capable of sparking a potent and sustained antitumor immune response. We hope to move these promising new therapies into clinical trial within three years.
Diffuse intrinsic midline glioma (DIPG) is a rare and fast-growing brain tumor that mainly affects children. Tragically, only about 1% of children diagnosed with DIPG survive beyond five years. This is due to its location in the part of the brain that controls vital functions, making surgery impossible, and the lack of alternative effective and safe treatment options. To improve the chances of survival for children with DIPG, researchers are developing so-called precision-guided therapies (PGTs) that are customized based on the specific genetic changes in each child's tumor. However, there are significant challenges: 30% of DIPG slack genetic changes that can be targeted with available drugs, there is limited understanding of which patients will benefit from specific therapies, and
DIPGs evade the effects of single-drug treatments.
Drugs that inhibit the mitogen-activated protein kinase (MAPK) pathway are among the most frequently recommended PGTs for childhood DIPG due to the high frequency (13%) of changes in genes activating this pathway. Activation of the MAPK pathway drives the progression of DIPG. Importantly, experiments on DIPG samples from children showed that a significant subset of samples without these genetic changes were also highly sensitive to MAPK inhibitors. These included samples with changes in a gene called
phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), which activate the phosphoinositide-3-kinase (PI3K) pathway. We found that these samples also have high activity of the MAPK pathway. This suggests that the population of children with DIPG who might benefit from PGTs targeting the MAPK pathway is potentially much larger than previously recognized, offering hope to patients and families suffering from this devastating disease. In a pilot experiment, we also found that the efficacy of single MAPK inhibitors can be enhanced by combining them with an inhibitor targeting another key player in the same pathway. This approach, called vertical pathway blockade, resulted in strong synergism and improved efficacy in 70% of DIPG samples and showed superior activity over combinations targeting both the MAPK and PI3K pathways.
This collaborative project builds on this foundation to fully understand which children with DIPG will benefit from MAPK-targeting therapies and to identify the most effective and safe combinations to prevent resistance, ultimately aiming to improve survival and quality of life for children with DIPG.
Diffuse midline glioma (DMG) is a deadly childhood tumor with no effective treatments. The Histone 3–Lysine-27–Methionine (H3-K27M) mutation occurred in 60-70% of patients with DMG, leading to widespread alterations in histone modifications that drive DMG tumorigenesis. Recent advances in single-cell technologies have characterized molecular signatures in various cell states from DMGs. However, the unique signature of DMGs, genome-wide histone modification alterations, has not yet been studied in clinical samples at single-cell resolution.
This project aims to generate the first comprehensive map of genome-wide histone modifications of DMGs at a refined cell type/state resolution. By utilizing well-established computational pipelines and advanced artificial intelligence models, we will gain a deeper understanding of the genetic and epigenetic dysregulation in DMGs, identify key regulatory elements, and predict the function of genetic risk mutations. This knowledge could pave the way for new targeted therapies and improve DMG outcomes.
Diffuse Midline Gliomas(DMGs) are highly aggressive and incurable pediatric brain tumors with <1-year overall survival. Radiotherapy remains the only treatment available for DMG, extending survival by only a few months. While immunotherapies like CAR-T cell therapy have shown transformative success in other cancers, they have yet to demonstrate meaningful survival benefits in DMGs. It is therefore imperative to advance new and more effective treatments against DMGs. Tumor-associated macrophages and microglia (TAMs) have come to the forefront of the cancer immunotherapy field due to their central role in regulating immune responses and eliminating tumor cells. In an anti-tumor state, TAMs engulf tumor cells, produce tumoricidal molecules and induce anti-tumor immune responses. However, in most solid tumors, TAMs remain immunosuppressive, resulting in a cold microenvironment that promotes tumor growth and inactivates the immune system; and this is particularly exacerbated in DMGs. Reprogramming TAMs from immunosuppressive into anti-tumoral represents a promising strategy to reconstitute anti-tumor immunity and drive tumor regression. PI Moles has developed an innovative approach using mRNA nanoparticles to re-educate the immune system to fight DMG. This is achieved through nanoparticle-driven expression of specialized tumor-targeting molecules in the immune cells, called Chimeric Antigen Receptors, which reprogram the immune cells to acquire anti-tumor functions and specifically attack the DMG cells. This project will explore the therapeutic value of our mRNA technology in reprogramming TAMs directly in the tumor microenvironment to combat DMG, offering a potentially more effective approach to restore anti-tumor immunity and suppress DMG growth. An additional Aim of this proposal will be to investigate the potential benefits of our approach in boosting the tumor infiltration and efficacy of CAR-T cell therapy. Our novel approach has the potential to change the treatment paradigm for DMG to ultimately improve outcomes and survival of patients. This project integrates a team of internationally recognized investigators who are experts in nanomedicine (Moles), DMG (Dun,Ziegler) and macrophage biology (Hampton, Pimanda), immunocompetent DMG models (Phoenix) and CAR-T cell therapy (Brown,Gargett). Our team provides a network of established scientific and clinical collaborative structures, being uniquely positioned to carry out this study and translate its findings.
DIPG and DMG are devastating brain tumors that tragically take the lives of children and young adults, and finding an effective treatment is an urgent challenge. At our institution, we are leading groundbreaking research to fight these tumors using the power of the immune system. Our innovative therapy, called CAR T-cell therapy, is like giving the body’s immune cells a high-tech upgrade to specifically target and attack the tumor. We’re testing a unique version “quad- CAR T cell product” that focuses on four key proteins to better combat these cancers.
In this exciting clinical trial, we’re also gathering cerebrospinal fluid (CSF)—a liquid surrounding the brain and spine—before and after the treatment. By studying these samples, we can uncover clues about how the
tumors respond to therapy and identify potential side effects. This knowledge will help us fine-tune the treatment and improve its effectiveness. This project is already underway, with samples being collected and a team of experts analyzing them. With strong progress and a clear plan, we are confident this research will yield critical insights in just three years. Most importantly, it aligns with the ChadTough Defeat DIPG Foundation’s vision of a future where no child or young adult has to face these devastating diseases. Together, we are taking a bold step toward that goal!
Radiotherapy (RT) remains the primary treatment to prolong life and alleviate symptoms for children with diffuse midline glioma. However, the effectiveness of radiotherapy varies greatly between individuals and it is currently not possible to say before the treatment how much an individual tumor will respond. Current treatment protocols rely on a "one-size-fits-all" approach, borrowed from studies in adults, which does not account for the unique biology of tumors in children which indeed are considered a different disease.
This project aims to provide a much better informed estimation of the individual efficacy of RT for each child. This will also allow to investigate if we could improve the RT response by changing its delivery. We will harness tools from the realm of artificial intelligence (AI) and mathematical modeling to achieve three specific goals:
Predicting RT Effectiveness: The first goal is to develop tools to predict how each child’s tumor will respond to standard RT before treatment begins. By identifying children who may benefit from different RT schedules, clinicians can make more informed decisions tailored to each patient’s needs.
Customizing Treatment Timing: The second goal isto explore how changing the timing and dose of RT sessions could improve its effectiveness. Using patient data, the team will model how tumors grow and respond to different treatment schedules, helping to design personalized RT protocols that maximize benefits.
Tailoring radiation dose distribution: The final goal focuses on optimizing where the RT dose is delivered.
By analyzing imaging data, the project aims to identify areas within the tumor that are most likely to grow back after treatment. This will enable precise delivery of RT to these high-risk areas while sparing healthy tissue.
This research is groundbreaking because it uses cutting-edge techniques to analyze rare and complex data sets from children with DMG, overcoming challenges of limited patient numbers. By building on noninvasive imaging the project seeks to transform RT from a generalized treatment into a precise, personalized therapy. This could improve survival, reduce treatment side effects, and enhance quality of life for children with DMG.
Diffuse intrinsic pontine glioma (DIPG) is a devastating tumor that primarily affects children 5 - 7 years of age and is universally fatal. The location of these tumors within the brainstem prevents surgical removal, as this region controls essential functions like breathing and heart rate. Additionally, due to the significance of this area, a blood-brain barrier (BBB) acts as a cellular shield, protecting the brain from toxins, pathogens and drugs in the circulation. Consequently, chemotherapies fail because many drugs cannot effectively cross the BBB to reach the tumor. Previously, we successfully demonstrated the safety of using MR-guided focused ultrasound (MRgFUS) to temporarily open the BBB, creating a window of opportunity for administering cancer treatment.
Excitingly, Health Canada approved our Phase I clinical trial testing MRgFUS-enhanced delivery of the BBB-excluded chemotherapy drug doxorubicin in patients with DIPG, which is currently in progress. Furthermore, our clinical team now routinely performs robot-assisted brainstem biopsies of DIPG tumors in children, enabling us to characterize genetic and molecular pathway alterations and to design tumor biology-based precision therapy regimens in real-time. While we are investigating the use of doxorubicin to treat human DIPG using MRgFUS in our clinical trial, we wish to extend our preliminary experience using single, non-targeted chemotherapy to combinatorial strategies. This can only be achieved by testing novel treatment approaches in preclinical mouse models. In the first part of our proposal, we will use our genetically engineered DIPG mouse model, which closely mirrors the tumor’s key mutations and maintains an intact immune system, thereby providing a more accurate representation of the human disease. We will refine the MRgFUS procedure in this model to ensure it both increases drug delivery and helps stimulate the body’s immune defenses within the tumor. Next, we will develop a proof-of-principle combination strategy that precisely targets DIPG tumors by integrating molecular insights from individual patient biopsies with MRgFUS-enhanced delivery of both targeted agents and immunotherapies. This will allow us to identify the most effective combinations to achieve the most durable anti-cancer response and to inform future clinical trials. Our studies will ultimately advance a precision medicine approach that offers better outcomes for children with this aggressive brain tumor.
Pediatric high-grade gliomas are aggressive brain tumors that are extremely difficult to treat. These tumors often contain a mutation in proteins known as histones. This mutation (H3K27M) disrupts how cells turn genes on and off, and prevents brain cells from maturing properly, leaving them stuck in an immature, fast-growing state - fueling cancer growth. Previous studies have investigated how this mutation changes the linear 2D genome landscape. However, the human genome is organized into a 3D structure that controls the expression of genes, and we still don’t fully understand how H3K27M mutation affects the 3D structure of DNA inside the nucleus.
For this proposal, we aim to understand how childhood glioma carrying H3K27M mutation hijacks 3D DNA
structures to grow. Our preliminary findings suggest that these mutations may cause abnormal DNA folding patterns that resemble those seen in stem cells. Our research will investigate how this mutation creates abnormal DNA loops and clusters that keep anti-cancer genes turned off and prevent normal brain cell maturation. Specifically, we aim to discover:
(1) How does the mutation change the way DNA folds? We will use advanced imaging techniques to visualize these DNA loops and structures in brain tumor cells compared to normal cells.
(2) Does this 3D folding help cancer cells stay aggressive? We will test whether re-creating these
DNA loops in non-cancerous cells makes them behave more like tumor cells.
(3) Can we disrupt these abnormal loops to stop tumor growth? We will genetically modify tumor cells to remove or change a key protein (CBX2) that may be responsible for keeping these cancer-fueling loops in place. Then, we will test whether this change helps brain cells mature normally again or slows tumor progression in mice.
Ultimately, the goal is to identify new treatment strategies for these aggressive cancers by targeting the way
these mutated histones affect DNA organization. If we confirm that these DNA loops are essential for tumor growth, we could develop new drugs to break them apart—potentially offering a more precise and effective treatment for children with these deadly brain tumors.
DIPG represents a highly aggressive and lethal brain tumor, primarily occurring in children, characterized by a grim outlook for affected patients. The treatment is highly challenging because the tumor is located in the brainstem, which is vital for fundamental bodily functions. We focus on creating reliable treatment options for DIPG patients.
Hypothesis: Our novel polymer platform facilitates the precise delivery of effective biologics to the brain for DIPGs while concealing their effects in the bloodstream, leading to better safety and treatment outcomes.
Strategy: Numerous biologics aimed at fighting cancer have undergone significant testing, but their effectiveness in treating DIPG is greatly restricted. This limitation primarily results from an intact blood-brain barrier, which prohibits access to various molecules in the brain, including chemicals, cytokines, antibodies, and genetic materials. To address this challenge, we have engineered an advanced nanodelivery platform aimed at these molecules, ensuring the safe and effective treatment for metastasized tumors, including those in the brain. Our approach utilizes a super-hydrophilic polymer incorporating phosphorylcholine, enhancing the
brain's antitumor agent uptake. This proposal focuses on the polymer-based engineering of biologics that demonstrate enhanced cytostatic effects against DIPG, achieving
1) increased systemic circulation duration and
2) improved permeability across the blood- brain barrier, allowing for effective delivery of biologics to tumors while managing cytotoxic activity at targeted tumor sites.
Additionally, we aim to design an immuno PET probe utilizing the same platform to achieve superior detection of DIPG tumors compared to currently available methods. This integrated strategy advances therapeutic efficacy and diagnostic precision in managing DIPG.
About 50% of all brain tumors in children are gliomas. Pediatric gliomas especially diffuse intrinsic pontine gliomas (DIPG) are aggressive cancers that are difficult to treat because of the molecular heterogeneity, inability of small molecular compounds to penetrate the brain to control the tumor and more importantly the inability to achieve surgical resection. Pediatric gliomas including DIPG are heavily infiltrated with innate immune cells called macrophages, which are generally thought as tumor promoting cells. However, recent evidence, including data from our lab, shows that these cells can be exploited to control tumor growth through activating receptors that engulf cancer cells. We have discovered that a molecule called Triggering receptor expressed on myeloid cells-2 (TREM2) is an important regulator of cancer cell engulfment in adult glioblastoma (GBM). TREM2 is
frequently degraded by enzymes and therefore cannot function effectively when expressed in macrophages. To this end, recent studies have shown that TREM2 can be artificially stabilized using antibodies that bind to TREM2 and prevent its degradation and improve its activity. We currently have access to a brain penetrating version of the antibody (thus addressing concerns about blood brain barrier penetration) that can stabilize TREM2 and increase in tumor engulfment leading to inhibition of tumor growth, but this has not been tested in pre-clinical models of DIPG. TREM2 based antibodies have reached human clinical trials offering an unprecedented opportunity to target DIPG using similar approaches. With funding from the ChadTough Defeat DIPG Foundation, we hope to accelerate this novel mode of immunotherapy treatment into clinical trials for DIPG patients.
Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), is a lethal pediatric brain tumor responsible for 20–25% of pediatric cancer deaths. Median survival is just 9–11 months, and the 5-year survival rate is below 1%. Current treatment is limited to palliative radiation. Drugs such as ONC201 and paxalisib have shown promise in animal models of DIPG and, when administered in combination as a
consolidation strategy post re-irradiation therapy in the recent PNOC022 trial, extended survival of DIPG patients by an additional 8.8 months. However, this survival benefit was only seen when the drugs were administered at cancer progression, and not when the same treatment strategy was used at initial diagnosis. The reasons for this disparity remain unclear but may involve immune-related factors, metabolomic changes, or challenges with drug distribution.
In this project, we will analyze tumor tissues from DIPG patients (including those in the PNOC022 trial) using our advanced “spatial multiomics” platform. These spatial analyses will assess drug distribution, quantifying concentrations in specific types of brain and tumor cells in the biopsy. They will also assess immune activity and metabolomic impacts of the drugs, allow identification of responsive cell populations and resistance mechanisms, and provide deeper insights into treatment response. Additionally, we will use cutting-edge spatial protein assays to confirm new drug targets and the brain cells most affected by treatment and to identify potential novel non-invasive protein biomarkers of response and failure. This research will establish a robust pipeline for evaluating drug penetration and drug-induced metabolomic and gene expression changes in DIPG patient biopsies. By informing trial design, optimizing sequential strategies, and refining therapy dosing, this pipeline creates a foundation for future trials and brain cancer research, with the ultimate aims of extending survival and improving
quality of life for DIPG patients. The project will help us learn from the past to improve the future for other DIPG patients.
Post-Doc Fellowship for CAR-T Study, University of Michigan
Mentor: Carl Koschmann
Chad Tough Defeat DIPG Post-Doctoral Fellowship for IL13Ra2 CAR-T Study: A post-doctoral
fellow will study correlate biofluids (CSF/plasma) from patients with DIPG/DMG treated with
the IL13Ra2 CAR-T Trial (NCT04510051) to understand patterns of response/resistance, under
the supervision of Dr. Carl Koschmann. This is an exciting project that combines one of the
most promising active cellular therapies for DMG/DIPG with DIPG/DMG correlate CSF/plasma
analysis expertise.
The Fellow will be responsible for leading the correlate analysis (CSF / plasma cell-free tumor
DNA, metabalomics and immune cell/cytokine analysis) and comparison with
radiographic/clinical outcomes, as well as mechanistic explorations into tumor biology and
genetics underpinning response/resistance to IL13Ra2 CAR-T therapy. Hundreds of specimens
have already been collected/banked under the supervision of Dr. Leo Wang from patients
enrolled thus far at City of Hope for analysis. Continued enrollment/collection will occur at City
of Hope and the other two cites opening this trial (U of M and CHLA).
Focus: Find effective combination therapies for children diagnosed with DIPG and DMG.
An an international and multidisciplinary team of experts across multiple institutions, with the combined aims of:
Elucidating drug mechanisms of action.
Creating robust in vitro and in vivo data on drug efficacy as single and combination therapy.
Creating rapid and efficient pipelines for mapping drug targets and identify clinically relevant predictive biomarkers.
H3K27M altered tumors are a common type of diffuse midline glioma(DMG)/diffuse intrinsic
pontine glioma (DIPG). These tumors are lethal and form as a result of abnormal mutated brain
cells that grow out of control and expand through the brain and brainstem. Despite aggressive
treatment with radiation, these tumors continue to grow and relapse very quickly. In our laboratory,
we have identified a gene that is turned on in these tumors that is likely responsible for this poor
response to therapy and its quick relapse. Now that Dr. Syed and his team have identified
this gene, they aim to study it further and identify its vulnerabilities. If Dr. Syed can
understand how this gene protects the cancer cells, he can then create new treatments that will
attack the cancer and hopefully improve outcomes for patients.
Developing immunotherapy for DIPG/DMG brain tumors has been especially challenging due to the unique nature of these tumors, including their limited interaction with the body’s immune system. To create better treatments, we need to understand how and where the body triggers an immune response to fight these tumors.
Traditionally, lymph nodes were thought to be the main areas where immune responses begin. However, Dr. Park's research has revealed that the bone marrow in the skull, specifically near the back of the head (the occipital bone), plays a key role in recognizing brain diseases. This area may act like a lymph node, producing immune cells that help fight the tumor. He believe the skull bone marrow could be central to the body’s immune response against DIPG/DMG by creating antibodies that target the tumor. This project aims to explore this, using advanced techniques, including high-tech imaging, genetic testing, and computer analysis, to study DIPG/DMG in detail.
CAR-T cell therapy, a promising treatment for DMG (Diffuse Midline Gliomas), faces challenges in working effectively. These specially engineered immune cells often lose energy and stop working too soon because the tumor environment isn’t supportive enough for them. The lack of inflammation in the tumor area makes it hard for the CAR-T cells to do their job.
Additionally, when CAR-T cells are active for too long, they start producing proteins like PD-1 and TIM-3, which slow them down and cause them to wear out. This project aims to solve these problems by combining CAR-T cells with a TIM-3-blocking antibody. Early studies show that blocking TIM-3 can make the tumor environment more supportive and help CAR-T cells stay effective for longer.
The goal is to create a safer, more effective therapy for DMG, especially since current CAR-T treatments can sometimes affect brain functions like movement and thinking. The research will test how well the CAR-T/TIM-3 combination works to shrink tumors while monitoring for side effects like brain inflammation or cognitive issues. If problems arise, the team will explore ways to protect the brain, including previously developed treatments. This approach aims to improve CAR-T cell therapy for DMG, making it both more powerful and safer for young patients.
Diffuse Intrinsic Pontine Gliomas (DIPG) are aggressive brain tumors with unique traits linked to the type of cells they come from and genetic mutations, particularly the H3K27M mutation, which starts the disease. However, scientists don’t fully understand how DIPG tumors process nutrients to fuel their growth.
Recent research has found that DIPG tumors use more branched-chain amino acids (BCAAs)—nutrients like leucine, isoleucine, and valine—than normal cells. These tumors rely on an enzyme called BCAT1 to break down these amino acids, and studies suggest that DIPG cells can’t grow without BCAT1. This is similar to other cancers that also depend on BCAT1.
The research has two main goals: first, to figure out why DIPG tumors need BCAAs by studying how the nutrients are used and what happens when BCAT1 is blocked. Second, researchers will explore whether reducing BCAAs in a patient’s diet could help slow tumor growth. Special diets that lower BCAAs have already been safely used in children with metabolic disorders and have shown promise in affecting cancer cells in other studies.
This work aims to uncover how DIPG cells rely on specific nutrients and could lead to a new treatment approach to stop tumor growth and extend the lives of patients.
Diffuse Intrinsic Pontine Glioma (DIPG) and Diffuse Midline Glioma (DMG) are among the most aggressive pediatric brain tumors, with most children surviving less than a year after diagnosis. A common feature of these tumors is the H3K27M mutation, which disrupts normal gene activity by altering the proteins that help organize DNA. Another challenge is that these tumors lack immune cells, like T cells, making it difficult to use immune-based treatments effectively.
This research focuses on viroimmunotherapy, a promising approach that uses engineered viruses to kill cancer cells and stimulate the immune system to fight the tumor. A recent clinical trial using the oncolytic virus Delta-24-RGD in children with DIPG showed it could improve survival without causing significant side effects.
This project aims to explore how the virus interacts with the tumor’s altered histone proteins and how this affects the immune system's ability to respond. Early studies combining Delta-24-RGD with a drug that modifies histones have shown promising results in reducing tumor cell survival. The goal is to understand how these changes suppress the immune response and eventually test this combination therapy in clinical trials for children with DIPG and DMG.
Diffuse midline glioma (DMG) is highly resistant to chemotherapy and radiation, which contributes to its poor outcomes. However, a recent breakthrough with the drug ONC201 highlights a potential weakness in DMG: its reliance on controlling reactive oxygen species (ROS), harmful molecules that build up in cells. Most ROS are managed by an enzyme called PRX3, which protects tumor cells from damage.
This research focuses on whether blocking PRX3 could be an effective way to kill DMG cells, either on its own or alongside existing treatments. Early studies show that a PRX3-blocking drug, already being tested for another cancer, is highly effective at destroying DMG cells by disrupting their ability to manage ROS. Additionally, combining PRX3 blockers with ONC201 may improve outcomes by overwhelming tumor cells with ROS, especially in cases where patients don’t respond well to ONC201 or develop resistance over time.
The goal is to understand how PRX3 blockers work against DMG and how they can enhance other therapies. Since the PRX3-blocking drug is already in clinical trials, this research has the potential to quickly lead to new treatments for DMG patients.
This research is focused on creating a groundbreaking treatment for diffuse intrinsic pontine glioma (DIPG), a devastating brain cancer that mainly affects children. The approach uses advanced immune cell therapy and gene editing to develop powerful tools to fight the disease.
The key players in this strategy are gamma delta (γδ) T cells—specialized immune cells that can survive tough conditions and naturally target cancer. To enhance their ability to fight DIPG, these T cells will be equipped with chimeric antigen receptors (CARs), which act like a GPS to guide them to the tumor and a metal detector to pinpoint and attack cancer cells. Two types of CARs will be created, one targeting a protein called B7H3 and another targeting HER2, both commonly found on DIPG tumors.
To make these γδ T cells even stronger, gene editing technology like CRISPR will be used to remove genes that weaken the cells and add genes to help them overcome the tumor’s defenses. A “dual-CAR” system will also be tested, splitting the detection job between two CARs on the same T cell, making it harder for the tumor to hide and improving the T cells’ durability.
The enhanced T cells will first be tested in the lab on DIPG cells to identify the best performers. Then, the top candidates will be tested in mouse models, including those developed from real patient tumors. If successful, this project could pave the way for a highly effective and safer immunotherapy for DIPG, with potential applications for other brain tumors and pediatric cancers. The ultimate goal is to generate the data needed to move this treatment into clinical trials, offering new hope for children facing DIPG and similar challenging diagnoses.
Patients with H3K27M-mutant diffuse midline glioma (DMG) currently have no effective treatments beyond radiation. A drug called ONC201 has shown promise for some patients, but not everyone responds to it, and many who do eventually see their tumors return. This research aims to understand why ONC201 doesn’t work for all patients and to find ways to improve its effectiveness.
Preliminary findings suggest that a protein called EGFR might play a role in making tumors resistant to ONC201. Lab studies show that DMG cells with high levels of EGFR grow faster and are less likely to die when treated with ONC201. These findings suggest that EGFR helps tumors resist the drug and that targeting EGFR could be key to overcoming this resistance.
ONC201 works by disrupting the tumor’s metabolism and changing its gene activity to slow down growth and promote tumor cell death. However, tumors with high EGFR seem to create a different metabolic environment that counters these effects. This study will explore how EGFR affects the tumor’s metabolism and gene activity, helping it resist ONC201.
By understanding the role of EGFR in this process, researchers hope to develop new treatments that block EGFR, making ONC201 more effective and providing better options for patients with H3K27M-DMG.
Diffuse midline gliomas (DMGs) are deadly brain tumors that form from immature "stem-like" cells, which normally would develop into specialized brain cells. This process, called differentiation, is controlled by changes in how DNA is packaged around proteins called histones. In DMG, mutations in these histones disrupt this process, preventing cells from maturing and allowing the stem-like tumor cells to keep growing unchecked.
Recent research has found that certain lipids (fat-like molecules) can encourage these stem-like tumor cells to differentiate, slowing down the tumor’s growth. In fact, diet-based approaches that increase these lipids in the brain have shown promise in slowing DMG growth in lab models. Scientists have also identified a key protein that plays a role in this process by helping regulate gene activity during differentiation.
This research will explore how these lipids and the key protein work together to promote differentiation and stop tumor growth. First, the study will investigate how the identified protein interacts with DNA and responds to these lipids to switch on genes that encourage differentiation. Next, researchers will use chemical tools that mimic these lipids to identify other proteins in DMG cells that interact with them. By studying how these lipid-binding proteins and the key regulator protein work together, the goal is to uncover new ways to push DMG cells to mature, reducing the growth of these aggressive tumors. This approach could lead to innovative therapies that target DMG at its roots.
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.
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.
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.
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.
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.
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.
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.
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