These are some of the notable projects funded by The ChadTough Foundation and Michael Mosier Defeat DIPG Foundation in prior grant cycles.
Game Changer Grants
Marta M Alonso
University Hospital of Navarra
“Oncolytic Immunotherapy for Diffuse Intrinsic Pontine Gliomas”
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.
David Ashley
Duke University
“Recombinant Attenuated Poliovirus Immunization Vectors Targeting H3.3(K27M) in DIPG.”
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.
Pratiti Bandopadhayay and Tim Phoenix
Dana-Farber Cancer Institute and University of Cincinnati
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 grant is being funded jointly by the ChadTough Defeat DIPG Foundation and SoSo Strong Pediatric Brain Tumor Foundation.
Catherine Flores
University of Florida
“Enhancing efficacy of adoptive immunotherapy against DIPG using hematopoietic cells.”
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.
Stephanie Galban
University of Michigan
“Targeting Cancer Stem Cells in DIPG.”
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.
Nalin Gupta and Daniel Lim
University of California San Francisco
“Use of a Long Non-coding RNA (lncRNA) as a Therapeutic Target in DIPG.”
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.
Daphne Haas-Kogan and Brendan Price
Dana-Farber Cancer Institute
“Dependence of DIPGs on DNA polymerase for DNA repair defines a new therapeutic
target.”
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.
Michelle Monje
Stanford University
“The Tumor Microtube Network in DIPG: Targeting a Possible ‘Achilles Heel’ Required to Defeat DIPG.”
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.
Hideho Okada
University of California San Francisco
“Next-generation CAR T cell therapies for treatment of DIPG, utilizing sequential ‘prime-and-kill’ circuits to achieve safe and effective tumor targeting”
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.
Sujatha Venkataraman
University of Colorado
“Targeting DIPG using novel CAR-T cell therapy”
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.
Sriram Venneti
Michigan Medicine
“Metabolic therapies for DIPGs
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.
NEW INVESTIGATOR GRANTS
Sameer Agnihotri
University of Pittsburgh School of Medicine
“Therapeutic Targeting of Metabolic Vulnerabilities in DIPG”
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.
Pratiti Bandopadhayay
Dana-Farber Cancer Institute
“Characterizing long non-coding RNAs as therapeutic targets in diffuse intrinsic pontine glioma”
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.
Jessica Blackburn
University of Kentucky
“Use of H3(K27M) – Driven Zebrafish Models to Identify Targetable Vulnerabilities in 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.
Matthew Dun
Hunter Medical Research Institute at the University of Newcastle
“Unlocking oncogene addition to identify synergistic treatment targets for the treatment of DIPG”
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.
Michael Koldobskiy
Johns Hopkins University
“Epigenetic regulation of phenotypic plasticity in DIPG”
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.
Giedre Krenciute
St. Jude Children’s Research Hospital
“Targeting T-cell intrinsic and extrinsic regulators to improve T cell therapies in DIPGs”
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.
Stephen Mack
Baylor College
“Interrogating the role of POU Transcription Factor Driven ERV Activation in H3K27M Diffuse Midline Glioma”
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.
Zach Reitman
Duke University
“Enhancing the efficacy of radiation therapy for 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.
This grant is being funded jointly by the ChadTough Defeat DIPG Foundation and SoSo Strong Pediatric Brain Tumor Foundation.
James Stafford
University of Vermont
“ONC201 in DIPG; establishing mechanism, enhancing efficacy and determining long-term phenotypic consequences”
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.
Sujatha Venkataraman
University of Colorado Denver
“MIC2 inhibition mediated apoptosis in 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.
Nicholas Vitanza
Fred Hutchinson Cancer Research Center
“Optimal combinatorial targeting of HDAC inhibition and radiation in DIPG”
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.
Vivekanand Yadav
Children's Mercy Hospital
“Epigenetically activated ID1 is a key transcriptional regulator of DIPG Invasion and is targetable with cannabidiol”
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.
FELLOWSHIP GRANTS
Jamie Anastas
Harvard University/Boston Children’s Hospital
“Targeting chromatin regulation to treat 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.
Dr. Anastas’s mentor for this project is Yang Shi.
Chan Chung
University of Michigan
“Targeting DIPGs by interrupting metabolic pathways”
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. Chung’s mentor for this project is Dr. Sriram Venneti.
Andrew Groves
Dana-Farber Cancer Institute
Targeted Protein Degradation of LSD1 as a Therapeutic Strategy in DIPG
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.
Under the mentorship of Dr. Mariella Filbin, 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.
Alan Jiao
Boston Children’s Hospital
“Dissecting mechanisms of H3K27M oncohistone function in DIPG”
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. Jiao’s mentor for this project is Dr. Yang Shi.
Nneka Mbah
University of Michigan
“Therapeutic Targeting of the Disrupted Metabolic State in DIPG to Induce Ferroptotic Cell Death”
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. Mbah’s mentors for this project are Costas Lyssiotis and Sriram Venneti.
Mateus Mota
Michigan Medicine
Therapeutic Targeting of the PBAF Chromatin Remodeling Complex in diffuse intrinsic pontine gliomas
Conducted under the mentorship of Dr. Sriram Venneti, 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.
Eshini Panditharatna
Dana-Farber Cancer Institute
“Targeting epigenetically induced vulnerabilities in DIPG”
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. Panditharatna’s mentor for this project is Dr. Mariella Filbin.
This grant is being funded jointly by the ChadTough Defeat DIPG Foundation and SoSo Strong Pediatric Brain Tumor Foundation.
Zach Reitman
Harvard University/Dana-Farber Cancer Institute
“Prioritizing PPM1D mutations as a target for new DIPG therapies”
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. Reitman’s mentors for this project are Rameen Beroukhim and Pratiti Bandopadhayay.
Chen Shen
Northwestern University
“Dissection of ATRX in Diffuse Intrinsic Pontine Glioma”
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. Shen’s mentor for this project is Oren Becher.
Xu Zhang
Columbia University
“Mechanistic studies on the WNT5A signal pathway in DIPG tumor”
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. Zhang’s mentor for this project is Dr. Zhiguo Zhang.
