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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.

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.

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 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.

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 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.

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.

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.

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.

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.

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.

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.