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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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 Michael Mosier Defeat DIPG Foundation, The ChadTough Foundation, and SoSo Strong Pediatric Brain Tumor Foundation.

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.

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.