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.
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.
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.
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.
Pediatric brain cancers affect nearly 4,000 children each year. Recent research emphasizes the vital role of neuron-cancer communication in their development. Neurons stimulate cancer growth, and cancer cells, in turn, boost neuron activity, creating a harmful cycle that leads to seizures and fast tumor growth. However, many aspects of this communication remain unclear due to the diverse nature of brain cancers. Studying these cancers is challenging due to the brain's functional and biochemical diversity. Understanding them requires an in-depth analysis spanning various components and levels, from protein chemistry to tumor spread. Holistic characterization of the biochemical interplay between neurons and cancer cells is critical to understanding brain cancer pathophysiology and represents a promising direction for therapy development. While basic neuron-cancer interactions are well-described, key components and mechanisms of communication and cancer pathogenesis remain unexplored.
In Michelle Monje's lab, my research aims to uncover the molecular aspects of key cell surface signaling in pediatric gliomas, mainly Diffusive Intrinsic Pontine Glioma and Diffusive Midline Glioma (DIPG/DMG). Initially, I will identify crucial proteins involved in neuron-glioma interactions using advanced mapping techniques, providing a detailed blueprint of the cell surface in DIPG/DMG and other pediatric gliomas. Subsequently, I will delve into the roles of these proteins using molecular and cellular approaches. Finally, I will develop and assess new therapies in mouse models. These findings have the potential to revolutionize our understanding of glioma cell surface signaling and inspire innovative treatment strategies.
It is hard to imagine a worse tumor than diffuse intrinsic pontine gliomas (DIPGs). These are aggressive brain tumors that grow in the most sensitive part of children’s brains, and are always fatal–usually within
months of diagnosis. One major reason that DIPGs are difficult to treat is that they vary from patient to patient, and even from cell to cell within a tumor. To effectively treat DIPG or any other tumor, the goal is to get rid of all the cancer cells inside it. One strategy that scientists are exploring is to focus on genetic changes that are common across all DIPG tumors. These are like the “early events” that happen in cancer development and are found in all the tumor cells. If we can target these changes, we will have a chance at removing the tumor completely. However, with DIPGs it has been hard to find these early events that could be targeted with drugs.
In DIPGs, one of the early events is changes in the number of chromosomes they harbor. Normally, healthy cells have 23 pairs of chromosomes, each with a short and long arm. But DIPGs, like most aggressive tumors, lose or gain entire chromosome arms. These changes help the tumor grow. Each of these chromosome arms can contain hundreds to over a thousand genes, and it is extremely difficult to understand the overall effects of changing them all simultaneously. We have a hypothesis: these whole-arm changes in chromosomes may create unique vulnerabilities in the tumor cells that can be targeted with new and unconventional treatments. By focusing on these shared changes, our hope is to find novel therapies that are effective against DIPGs and offer new hope to children and families affected by this devastating disease.
Current treatment options for DMG, such as radiation therapy, only extend survival by a few months. In a recent clinical trial, our group treated pediatric DMG patients with Delta-24-RGD (DNX-2401), a modified virus with tumor-selective and destroying ability which improved survival in the majority of our patients. To further enhance the anti-tumor effects of DNX-2401, we generated Delta-24-RGDOX (DNX-2440), that now incorporates a protein (OX40L) to activate the patient's resident immune T cells towards killing cancer cells. Recent work from another clinical trial has reported the role of engineering a separate protein (chimeric antigen receptor (CAR) on immune T cells in enhanced killing of the DMG cells. In this project, we will combine DNX-2440 with engineered CAR T cells and assess the role of this combination therapy in improving survival outcomes for DMG patients. The proposed study will potentially open new horizons for novel combination therapies for children with DMG.
H3K27M Diffuse Midline Gliomas (DMGs) including Diffuse intrinsic pontine gliomas (DIPGs) are lethal brain tumors with a universally poor prognosis1,2. Current treatments are not effective, leading to emergence of resistance and uniform lethality. Hence, there is an immediate and unmet need to develop effective therapies. Our previous research has shown that H3K27M-DIPGs profoundly rewire their metabolic needs to sustain growth and survival5. Our current proposal aims to investigate one such important metabolic pathway that is hijacked by the H3K27M DIPGs to maintain a favorable epigenetic state and mediate radiation
resistance. Our proposed research will a) unravel key tumor promoting roles of this pathway and, crucially, b) facilitate the development of targeted therapies in the future.
Brain function involves the firing of neurons to deliver information. Unfortunately, neuronal activity also promotes diffuse intrinsic pontine glioma (DIPG) growth and disease progression. We have found that like normal glial cell types, DIPG cells can become integrated into neural circuits. Some DIPG cells form synapses with neurons, similar to a normal glial precursor cell that receives synaptic inputs from neurons. This synaptic communication between neurons and DIPG cells results in electrical currents that promote DIPG growth. Membrane depolarization alone is sufficient to drive DIPG proliferation1, but we don’t yet know
which voltage-sensitive mechanisms promote tumor progression. I used CRISPR/Cas9-based genetic screening to identify key genes for DIPG cells to interact with neurons and grow in the tumor microenvironment. My screening results suggest that voltage-gated calcium channels may play crucial roles in converting electrical activity to promote DIPG growth. Therefore, I propose to study voltage-sensitive calcium channel signaling in DIPG, and compare it with neural stem and progenitor cells in the developing brain. The proposed research on voltage-dependent regulation of DIPG may elucidate novel therapeutic targets for DIPG.
Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric tumor occurring in the pons accounting for ~80% of brainstem gliomas. Each year, DIPG affects over 300 children in the U.S., with a median survival of only 11 months. Due to the tumor location, surgical resection is impossible, while resistance to current treatments makes the prognosis dismal. Chimeric antigen receptor (CAR) T cells are a new, targeted immunotherapy that has had remarkable success in curing children with hematological malignancies. This technology must now be translated to children with DIPG. B7-H3 is a protein expressed on nearly all DIPG but not on normal brain, enabling CAR T cells to selectively target tumor cells. Our Seattle Children’s team just completed BrainChild-03 (NCT04185038), a first-in-human phase 1 clinical trial for children with DIPG and found the planned highest dose, 100 million cells, to be safe. Some patients have also had remarkable clinical benefit, including two patients still on trial 2.5 years from their diagnosis without progression. Unfortunately, these encouraging results have not been universal, but a new era of combinatorial clinical trials is now possible.
ONC206 is a small molecule derived from ONC201, an allosteric agonist of the protease ClpP, that has shown even greater benefit in initial laboratory studies. ONC201 has had promising clinical efficacy against DIPG, but - as with CAR T cells - the positive outcome is not universal. While there is hope that ONC206 is more effective for children than ONC201, these agents will need to be combined with other therapies to reach a cure. Based on clinical success of B7-H3 CAR T cells, along with the advancement of ONC206 to clinical trials, in this project we will evaluate the combinatorial benefit of these agents together, determining their best time sequence for a future clinical trial for children with DIPG.
DIPG tumor cells feed on vast quantities of glucose to support their uncontrolled growth. Increase reliance on glucose leads to the increase production of a metabolite called lactate. Although long considered as a waste product, it has been discovered in recent years that lactate is used by the cancer cells to aid their growth and division. Yet, the precise mechanisms by which DIPG tumor cells utilize lactate for abnormal cell growth remains to be elucidated. Our research project is impactful, because it will investigate the dual functions of lactate serving as both (1) a fuel for energy producing pathways and (2) a substrate for a recently discovered DNA-associated modification. Our goal is to target this critical dependency on lactate, thereby, killing DIPG cells using an integrated epigenetic and metabolic approach.
It is widely recognized that the tumor cells’ (“the seed”) surrounding ecosystem, known as the tumor microenvironment (“the soil”), plays an active role in supporting tumor survival and promotion, immune evasion, and chemoresistance. The tumor microenvironment (TME) is comprised of tumor cells, a myriad of normal and immune cells, extracellular matrix, blood vessels and many other factors, which are all constantly cross-talking and influencing each other. Within the TME, tumor cells secrete an array of chemical signals that hijack normal tissue support systems and avoid destruction from the immune system.
Within the DMG-H3K27a (formerly known as DIPG) tumor mass, the dominant non-tumor cell population are glioma-associated microglia and macrophages. In healthy brain and spinal cord tissue, specialized immune cells known as microglia and macrophages play a key role in innate immunity by fighting infections, clearing cellular debris, and eliminating tumor cells. However, in the DMG-H3K27a TME, tumor cells co-opt microglia and macrophages into secreting growth factors that promote tumor growth and progression instead. The identity of the microglial-derived growth factors and their effect on tumor biology is not well characterized. In our preliminary studies, we have discovered and identified microglial-derived growth factors that DMG-H3K27a tumor cells are dependent on, which represents new avenues for developing targeted therapies.
The primary objectives of this research are to 1) investigate the biological consequences of microglial secretion of growth factors and its effect on DMG-H3K27a tumor growth and progression in vitro and 2) evaluate the therapeutic potential of targeting the cell-cell communication between microglial cells and tumor cells by using blood brain barrier penetrant, clinically relevant drugs, and a neutralizing antibody we have developed in vivo. Ultimately, these findings provide further insights on DMG-H3K27a biology and inform future therapy paradigms.
After decades of intense research it has become clear that DIPGs are highly treatment resistant tumors that unlikely will be cured by monotherapy. To effectively eliminate DIPG cells, a combination of different treatment modalities, such as radio-, chemo- and immunotherapy, is likely needed to reach clinical effect. In this project we propose to study a combination therapy in which we incorporate both radiotherapy and two drugs, Paxalisib and Givinostat, which are currently in clinical trials for DIPG (Paxalisib) or for children with Duchenne muscle dystrophy (Givinostat). We recently identified that very low doses of Givinostat can kill DIPG cells growing in a dish and that this drug can enhance the tumor-killing effect of radiotherapy and Paxalisib. Furthermore, preliminary data suggest that Givinostat treatment results in local inflammation in DIPG-bearing mice, a sign that the immune system is fighting the tumor cells, and reprogramming of immune cells that support DIPG growth. However, although promising, Givinostat by itself was insufficiently potent to cure mice from DIPG, suggesting that it should be used in combination with other treatment modalities. It is the aim of this project to test different treatment regimens incorporating Givinostat, Paxalisib and radiotherapy in DIPG mouse models to identify the most optimal combination therapy and dosing scheme. Besides looking at survival benefit of these treatments, we will study the impact on the immune cells within the tumor and its surrounding healthy brain tissue. By obtaining a better understanding of the biological effect of this drug combination we can prepare for the inclusion of Givinostat on a backbone of Paxalisib in future clinical trials, either as a radio/chemotherapy combination or as a backbone for immunotherapy. As such, the results from this study open the door for therapeutic combinations that ultimately may lead to an increased progression free- and overall survival of DIPG patients.
The immune system plays a crucial role in the anti-tumor response. Despite the encouraging clinical results obtained in other types of tumors, the particular immunological environment of the diffuse intrinsic pontine glioma (DIPG) has hindered the use of this approach as an efficacious alternative to the current treatment of DIPG. Even so, our group has demonstrated the feasibility of using oncolytic viruses, a type of bioimmunotherapy, at different levels of this disease.
As we have shown, the preclinical administration of the oncolytic adenovirus Delta-24-ACT (with the capacity to awake the patients’ immune system) in DIPG is safe, but its efficacy can be further enhanced. Incorporating additional transgenes to Delta-24-ACT can be a feasible strategy to achieve a sustained in situ delivery of additional molecules, potentiating the effect of oncolytic virotherapy while overcoming the risk of exacerbating systemic toxicity. On the other hand, preliminary data from our lab indicates that the expression of TIM-3 in the tumor microenvironment (TME), specifically in the myeloid compartment, could pose a resistant mechanism to anti-DIPG therapies. Moreover, we have demonstrated that TIM-3 is a potential therapeutic target in DIPG and that its blockade mediates potent anti-tumor responses in DIPG mouse models.
Here we propose to develop the Delta-24-ACT virus encoding a TIM-3 inhibitory molecule as a comprehensive approach against DIPG, invigorating innate and adaptive arms of the anti-tumor immune response in a single treatment. The dual anti-tumor effect of this virus (oncolysis and immunostimulation) will be assessed in relevant murine and humanized DIPG models. If successful at the end of this project, we will be in the position to propel a phase I/II clinical trial with this new oncolytic virus: Delta-24-DMG-ACT.
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