All Grants

Post-Doc Fellowship for CAR-T Study, University of Michigan
Mentor: Carl Koschmann
3 yr, $300,000 Total
Study correlate biofluids (CSF/plasma) from patients with DIPG/DMG treated with the IL13Ra2 CAR-T Trial (NCT04510051) to understand patterns of response/resistance

DMG-ACT
1 yr, $400,000 Total
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.

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.

Featured investigators: Javad Nazarian, Mariella Filbin, Nick Vitanza, Jason Cain, Eric H Raabe, Sabine Mueller, Carl Koschmann, and Matt Dun

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The work established in Dr. Krenciute’s lab has demonstrated that additional genetic modifications are needed to improve CAR-T cell therapies. She has developed a new method which targets a molecule called B7-H3, present in many types of cancer cells.

In this project, Dr. Krenciute will use unique cell engineering tools to investigate basic CAR-T cell biology. This study will allow for the development of more effective ways to manipulate the cells therapeutically and successfully eliminate hard to treat cancers, such as DIPG.

In recent years, researchers have discovered that the majority of DIPG cells contain a genetic mutation called H3K27M. However, due to the lack of useful models, the mechanisms by which H3K27M promotes DIPG is still poorly understood.

In this project, Dr. Blackburn has developed zebrafish models of H3K27M-driven DIPG to better understand how this genetic mutation promotes critical aspects of DIPG progression. Because zebrafish and human H3K27M are identical, this study will allow Dr. Blackburn to examine the living brain of zebrafish from the earliest stages of DIPG growth to the development of treatment resistance.

Through work in his lab, Dr. Yadav has determined that the knockdown of the DNA binding protein ID1, associated with aggressive tumor cells, reduces DIPG cell invasion while significantly improving the survival of DIPG tumor bearing mice.

Dr. Yadav and his team have found that cannabidiol (CBD), a clinically available, non-toxic and non-psychotropic cannabinoid, is effective in reducing ID1 levels and making cultured DIPG cells easier to kill. This approach, which has been largely unstudied, will investigate the role ID1 plays in DIPG invasiveness and the efficacy of CBD in its reduction.

Although DIPG cells respond to initial radiation therapy, the tumor inevitably comes back, making it a universally fatal diagnosis. Dr. Koldobskiy and his team aim to understand the molecular mechanisms underlying resistance of DIPG to treatment.

This project will examine how variability in epigenetic marks allow DIPG cells flexibility to turn on and off, driving their resistance to treatment. This knowledge will allow Dr. Koldobskiy and his team to identify and exploit vulnerabilities in order to develop effective treatments.

Prior research has shown that the H3K27M histone mutation impairs PRC2 function and results in global loss of H3K27 trimethylation and a global increase of H3K27 acetylation. Dr. Mack has discovered a novel mechanism of H3K27 acetylation associated transcription of repetitive DNA elements, namely Type-H human endogenous retroviral (HERV) sequences. Transcription factors (TF) found to be highly active in these Diffuse Midline Gliomas (DMG) tumors were POU3F2/3, among other POU TF family members.

In this project, Dr. Mack will determine the Role of POU Transcription Factors in Mediating ERV Transcription in DMG, and delineate the Requirement of POU Transcription Factors for DMG-genesis.

Prior research has shown that drug ONC201 is well tolerated and may have some clinical impact in discrete DIPG patient populations with current clinical trials ongoing. But the vulnerability which ONC201 targets in DIPG has remained elusive as have other critical insights required for fully elucidating the potential of ONC201.

In this project, Dr. Stafford aims to fill that void by illuminating a novel vulnerability in DIPG, by identifying tractable ways to enhance its targeting, and by gaining a better understanding of the long-term preclinical consequences of targeting that vulnerability. In doing so, he hopes to reveal strategies to improve diagnosis and treatment of DIPG.

Prior research has shown that inhibition of the DNA damage sensing kinase ATM selectively increases the efficacy of radiation therapy in tumors that have mutations in genes that regulate the DNA damage response. Since DIPG tumors frequently contain mutations in key components of the DNA damage response pathway, an intriguing open question is whether DIPG might be susceptible to radiosensitization by ATM inhibition.

In this project, Dr. Reitman will test whether DIPG is susceptible to radiosensitization by ATM inhibition in genetically engineered mouse models of the most frequent genetic subtypes of DIPG. He will determine the molecular mechanism by which specific genetic subtypes of DIPG can be radiosensitized in this manner.

Already a cancer researcher, Dr. Dun began studying DIPG in 2018 when his daughter Josie was diagnosed with DIPG. Based on the positive results of rigorous pre-clinical testing in Dr. Dun’s laboratory, Josie was treated with a combination of two experimental drugs, ONC201 and GDC-084 (now known as Paxalisib).

In this project, Dr. Dun will identify the signaling pathways responsible for sensitivity and resistance to the combination treatment of ONC201 and GDC-084 and will test the treatment using DIPG cell lines and patient samples. This research may help reveal ways to improve patient response to these drugs and thus extend DIPG patient survival.

Recent research has shown that long non-coding RNAs (lncRNAs) can participate in tumor formation and progression, thus representing a novel target for cancer therapy.

Dr. Bandopadhayay has performed whole-genome DNA sequencing of DIPG tumors and discovered that almost 10% of tumors carry a rearrangement involving a specific lncRNA that was previously implicated in cancers. In this project, Dr. Bandopadhayay is examining the role this lncRNA plays to control DIPG growth, and she will use genome-editing technology to identify other lncRNAs that are required for DIPG cells to grow.

Dr. Agnihotri’s research has identified that DIPG cells have an altered metabolism compared to normal cells, and he has determined that DIPG cells are addicted to specific amino acids, which are the building blocks of protein and required for cells to rapidly grow.

In this project, Dr. Agnihotri is testing the effects of restricting a particular amino acid, methionine, in his DIPG models, and he will test novel emerging therapies targeting key proteins overexpressed in DIPG in search of novel and innovative ways of targeting DIPG.

Most DIPG patients have mutations in histone genes. Dr. Venkataraman’s research has shown that the histone mutations upregulate the MIC2 gene, which codes for a cell surface protein called CD99.

In this project, Dr. Venkataraman is comprehensively evaluating the action of CD99 in DIPG and will establish preclinical data to support the rationale for targeting MIC2 for DIPG therapy.

Developing effective treatments for DIPG requires good preclinical models that will allow researchers to test potential treatments in the laboratory. Most of the existing preclinical models were developed from DIPG cells that had already been exposed to radiation and chemotherapy, and therefore are not an ideal model of the disease.

In this project, Dr. Vitanza is using DIPG cells obtained through biopsies to establish “treatment-naïve” DIPG models. He will also use these models to test the effectiveness of a new drug before, during, and after radiation to identify the most effective possible combination sequence of the drug and radiation.

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.

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.

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.

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.

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.

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.

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.

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.

Dr. Venneti’s research has discovered that the frequently found histone H3K27M mutation in DIPG changes how the tumor cells metabolize nutrients and use metabolic pathways to modify genetic material.

In this study, Dr. Venneti and his team will target metabolic process as a potential therapy that simultaneously tackles two dysfunctional pathways in DIPGs, thus improving chances of therapeutic success.

CAR-T cell therapy has proven to be a promising new approach to kill DIPG cells. However, a major obstacle in this therapy is the risk of toxicity to health cells. Through her research, Dr. Venkataraman and her team have successfully generated and tested the functionality of new “logic gated” CAR-T cells that target two distinct toxins, CD56 and CD99, that kill DIPG cells while sparing the normal, healthy cells.

In this project, Dr. Venkataraman will investigate the safety and the preclinical efficacy of the novel logic gated CAR-T cells against DIPG and evaluate its translational relevance to DIPG patients.

Through their research, Drs. Bandopadhayay and Phoenix have discovered that the activation of the cancer-causing gene MYC (MYC Proto-Oncogene, BHLH Transcription Factor) may play a much more significant role in DIPG tumor formation and growth than previously understood.

This project will explore MYC activation when exposed to the genetic mutation H3K27M. Learning more about how the genes cooperate together could provide further understanding of DIPG tumors and possible new therapeutic strategies to treat them.

This project explores the use of oncolytic viruses (a type of virus that breaks down cancer cells, leaving normal cells intact) in combination with radiotherapy to attack the tumor in newly diagnosed DIPG patients.

DIPG cells respond well to stress, making them difficult to kill with radiation alone. In this study, Dr. Alonso will use the non-toxic, oncolytic virus, Delta-24-RGD to remove their natural defense mechanism. Combined with radiotherapy, Dr. Alonso’s study will explore the underlying immune mechanisms of DIPG cells, while uncovering new therapies for children with DIPG.

Through their research, Drs. Bandopadhayay and Phoenix have discovered that the activation of the cancer-causing gene MYC (MYC Proto-Oncogene, BHLH Transcription Factor) may play a much more significant role in DIPG tumor formation and growth than previously understood.

This project will explore MYC activation when exposed to the genetic mutation H3K27M. Learning more about how the genes cooperate together could provide further understanding of DIPG tumors and possible new therapeutic strategies to treat them.

In collaboration with Dr. Wendell Lim at UCSF, Dr. Okada has developed innovative CAR T cell circuits that recognize tumor cells based on sequential antigen combinations. These circuits use a “prime-and-kill” strategy, in which the first antigen, which is uniquely expressed on cells in the brain or brain tumor, primes the T lymphocytes to express a CAR to kill nearby tumor cells expressing antigens only found on tumor cells but not normal cells in the brain.

In this project, Dr. Okada will evaluate his “prime-and-kill” strategy using preclinical models of DIPG. His goal is to identify and establish antigen combinations that could be used to safely treat DIPG.

Recent research by the Haas-Kogan and Price team has shown that, unlike most cancers, DIPGs have high levels of basal damage to their DNA. DIPG tumors have learned to tolerate this DNA damage, allowing them to escape cell death, and resist treatment with chemotherapy or radiation.

In this project, Dr. Haas-Kogan and Dr. Price will target the alternate-end joining (alt-EJ) DNA repair pathway that helps DIPG to tolerate DNA damage thus providing a new approach to directly kill DIPG and increase their sensitivity to radiation. The team will also use POLQ inhibitors to target the hyper-active alt-EJ repair pathway in DIPGs, and study how POLQ inhibition alters therapeutic responses to radiation in both cell and animal models.

Dr. Galban’s research has identified a small sub-population of DIPG cancer cells known as stem cells, which contain specific genes to protect them from radiation treatment, which permits them to grow and cause tumor recurrence. These cells exhibit high levels of AKT and are especially sensitive to a drug which targets AKT and MAPK, a pathway often upregulated in resistant tumor cells.

In this project, Dr. Galban is targeting the signaling axes in cancer stem cells responsible for protecting them from radiation treatment as a new therapeutic strategy for DIPG. She will use a combination of drugs to inhibit these key targets to sensitize them to radiation therapy and to improve patient time to progression.

Recent research has shown that targeting a new class of molecules called long noncoding RNAs (lncRNAs) may provide a unique opportunity to develop effective treatments for DIPG. Drs. Gupta and Lim have identified several lncRNAs that can be targeted to kill DIPG cells without causing harm to normal brain cells, and that can enhance the efficacy of radiation.

In this project, Drs. Gupta and Lim are studying these lncRNAs and expect to obtain the data necessary to advance lncRNA therapy to clinical trials in children with DIPG. They also expect that their results will provide new, fundamental insights into why cancer forms and how we might cure this disease.

A recent study of adult brain tumors showed that the cancer cells connect to each other through thin extensions called “tumor microtubes,” and that these connections help the tumor cells survive and resist treatment.

Dr. Monje believes she has uncovered similar microtubes within DIPG tumors. She is investigating the microtubes to determine whether targeting them will make DIPG tumor cells more susceptible to treatment.

This immunotherapy project uses adoptive cell therapy, which involves removing cancer cells from the patient, creating a large number of T cells that can identify and attack the cancer cells, and then infusing those cells back into the body.

Dr. Flores is developing an adoptive cell therapy treatment for DIPG that uses both the DIPG cells obtained from a biopsy and also cells from the patient’s bone marrow. She will also administer the blood stem cells with the T cells, which can enhance the T cells’ ability to infiltrate the tumor.

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.

The Duke team recently 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, Dr. Ashley is modifying the poliovirus vaccine so that it can be used to treat DIPG 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.

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.

Dr. Groves project will investigate combination strategies that work by fighting DIPG from multiple angles. In recent work, Dr. Groves found that the combination of two drugs, an HDAC inhibitor and an LSD1 degrader, is highly effective in killing DIPG cells.

Dr. Groves will thoroughly investigate the mechanism by which these two drugs synergize, and determine whether this strategy could feasibly translate into clinical trials. In order to do this, Dr. Groves will use a multi disciplinary approach to fully dissect the relationship between HDAC and LSD1 in cell culture models of DIPG, then determine how well the drugs penetrate through the blood-brain barrier and whether the combination decreases tumor growth and survival in mouse models.

Dr. Mota’s research project will investigate the association of a very frequent mutation in DIPG tumor cells with proteins that help to establish the structure of DNA.

Elevated expression of these proteins seems to affect the normal function of DNA and may result in abnormal cell growth. Dr. Mota’s aim is to inhibit these DNA proteins to specifically target the potential cause contributing to the maintenance of DIPG cells. He expects that elimination of these DNA proteins will result in a greater effect in terms of reducing aberrant DIPG cell growth and tumor progression. This knowledge will then be used to develop a drug that reduces these DNA proteins, then test the drug in animal models to learn if DIPG cells have effectively been killed.

Dr. Jiao studies the epigenetic effects of the histone mutation commonly found in DIPG. He is testing how these effects can be reversed so that the normal epigenetic landscape is restored in DIPG cells. This testing will hopefully lead to the development of new treatments for DIPG.

Dr. Chung studies how the histone mutation alters how DIPG cells metabolize nutrients. He will target this metabolic pathway as a potential therapy that simultaneously tackles two dysfunctional pathways in DIPGs, thus improving chances of therapeutic success by overcoming the ability of cancer cells to resist treatment via redundant biological pathways.

Dr. Panditharatna studies the epigenetic dysregulation in DIPG cells caused by the histone mutation. She has identified genes that are part of five major epigenetic classes, which are essential for the survival of DIPG cancer cells. She will study these epigenetic classes to understand the role of these specific epigenetic vulnerabilities in advancing DIPG biology, and to identify a novel combination of epigenetic targeted therapy to treat children with DIPG.

Dr. Zhang studies how oncogenic mutations reprogram the epigenome in DIPG. He has discovered that DIPG tumor cells rely on the non-canonical WNT signaling pathways for the proliferation and survival. In this project, he will further characterize this pathway in DIPG and identify additional druggable targets for this deadly disease.

Dr. Mbah studies how DIPG cells are sensitive to ferroptosis, an iron-dependent form of cell death. Dr. Mbah is testing whether the disrupted metabolic/redox state sensitizes DIPG to ferroptosis, and she is evaluating the anti-tumor activity of ferroptosis in human patient-derived DIPG tumor models.

Dr. Shen is focusing on the ATRX protein and its role in driving DIPG tumor growth. Her hypothesis is that the loss of ATRX works with the histone mutation to promote DIPG growth. She is investigating whether the loss of ATRX impacts the DIPG tumor’s response to radiation.

Dr. Reitman studies the role the PPM1D mutation plays in helping DIPG tumors grow. In this project, he is testing whether targeting the PPM1D gene slows DIPG cell growth to determine whether a PPM1D inhibitor should be developed as a potential treatment for DIPG.

Dr. Anastas studies how the histone mutation commonly found in DIPG affects how the tumor cells function. After screening 1,300 chromatin regulators, she has identified multiple proteins that are necessary for DIPG cells to proliferate and survive, but are dispensable for normal cell growth. Her research is determining the roles of these proteins in DIPG development.

Diffuse midline glioma (DMG) characteristically has an “immunologically cold” tumor microenvironment (TME)
leading to poor clinical responses and resistance to immunotherapy. To overcome scarce lymphocyte infiltration
and limited immune checkpoint (IC) expression in cold TMEs, our team and others have established novel viral
mimicry activating therapies that leverage the accumulation of immunogenic double-stranded RNAs and anti-
viral innate immune response to change the TME and sensitize tumors to immunotherapies. Traditionally, drugs
that modulate the epigenome have been used to activate the viral mimicry response in tumors. Unfortunately,
these drugs have lacked efficacy in DMG clinical trials amid dosing limitations secondary to systemic toxicities
and poor neuro-penetrance. Thus, novel targets to activate viral mimicry and potentiate the immune response
against DMG are critically needed. We propose a paradigm shift to focus on targeting epi-transcriptomic (RNA
modifications) regulators, which promise to be more effective with less off-target effects in DMG. Via an unbiased
screen, we have found that the RNA editor ADAR is significantly upregulated in DMG. Interestingly, ADAR-
mediated RNA editing has been shown to help some cancer cells escape antitumor immune responses. In
patient-derived DMG cell lines, our preliminary results show that ADAR knockdown (KD) increases immunogenic
RNA species, activates an interferon response, reduces cell proliferation, and increases MHC-I and IC ligand
levels on the tumor cell surface. The objective of this proposal will be to determine the mechanism for the
observed ADAR-dependency in DMG cell lines, and to assess if this promising epitranscriptomic target activates
viral mimicry to synergize with immunotherapies against DMG in vivo. This project will expand our immunologic
understanding of upregulated epitranscriptomic regulators in DMG, and the results of these studies will open the
doors to novel multi-modal regimens involving epitranscriptomic reprogramming and inform potential clinical trials
for immune modulation in 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.

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.

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.