Abstract
Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options. Among them, H3 K27-altered diffuse midline gliomas (DMG) of the brainstem stand out due to their distinct molecular features and dismal prognosis. Recent advances in molecular profiling techniques have unveiled the critical role of H3 K27 alterations, particularly a lysine-to-methionine mutation on position 27 (K27M) of the histone H3 tail, in the pathogenesis of DMG. These mutations result in epigenetic dysregulation, which leads to altered chromatin structure and gene expression patterns in DMG tumor cells, ultimately contributing to the aggressive phenotype of DMG. The exploration of targeted therapeutic avenues for DMG has gained momentum in recent years. Therapies, including epigenetic modifiers, kinase inhibitors, and immunotherapies, are under active investigation; these approaches aim to disrupt aberrant signaling cascades and overcome the various mechanisms of therapeutic resistance in DMG. Challenges, including blood-brain barrier penetration and DMG tumor heterogeneity, require innovative approaches to improve drug delivery and personalized treatment strategies. This review aims to provide a comprehensive overview of the evolving understanding of DMG, focusing on the intricate molecular mechanisms driving tumorigenesis/tumor progression and the current landscape of emerging targeted interventions.
Weisbrod LJ, Thiraviyam A, Vengoji R, Shonka N, Jain M, Ho W, Batra SK, Salehi A. Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies. Cancer Lett. 2024 May 28;590:216876. doi: 10.1016/j.canlet.2024.216876. Epub 2024 Apr 10. PMID: 38609002; PMCID: PMC11231989.
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a childhood malignancy of the brainstem with a dismal prognosis. Despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. This article aims to review the current understanding of the genetic pathophysiology of DIPG and to highlight promising therapeutic targets. Various DIPG treatment strategies have been investigated in pre-clinical studies, several of which have shown promise and have been subsequently translated into ongoing clinical trials. Ultimately, a multifaceted therapeutic approach that targets cell-intrinsic alterations, the micro-environment, and augments the immune system will likely be necessary to eradicate DIPG.
Damodharan S, Lara-Velazquez M, Williamsen BC, Helgager J, Dey M. Diffuse Intrinsic Pontine Glioma: Molecular Landscape, Evolving Treatment Strategies and Emerging Clinical Trials. J Pers Med. 2022 May 20;12(5):840. doi: 10.3390/jpm12050840. PMID: 35629262; PMCID: PMC9144327.
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a type of intrinsic brainstem glial tumor that occurs primarily in the pediatric population. DIPG is initially diagnosed based on clinical symptoms and the characteristic location on imaging. Histologically, these tumors are characterized by a heterogenous population of cells with multiple genetic mutations and high infiltrative capacity. The most common mutation seen in this group is a lysine to methionine point mutation seen at position 27 (K27M) within histone 3 (H3). Tumors with the H3 K27M mutation, are considered grade 4 and are now categorized within the H3 K27-altered diffuse midline glioma category by World Health Organization classification. Due to its critical location and aggressive nature, DIPG is resistant to the most eradicative treatment and is universally fatal; however, modern advances in the surgical techniques resulting in safe biopsy of the lesion have significantly improved our understanding of this disease at the molecular level. Genomic analysis has shown several mutations that play a role in the pathophysiology of the disease and can be targeted therapeutically. In this review, we will elaborate on DIPG from general aspects and the evolving molecular landscape. We will also review innovative therapeutic options that have been trialed along with new promising treatments on the horizon.
From the article:
Figure 1. DIPG Imaging Findings. MRI of the brain with and without gadolinium in a child with an H3 K27-altered, DIPG. The imaging demonstrates a sagittal T1 hypointense (A) and axial T2 hyperintense (B) lesion with homogeneous enhancement along with obstruction within the fourth ventricle of the brain occupying almost half of the axial diameter.
Perrone MG, Ruggiero A, Centonze A, Carrieri A, Ferorelli S, Scilimati A. Diffuse Intrinsic Pontine Glioma (DIPG): Breakthrough and Clinical Perspective. Curr Med Chem. 2021;28(17):3287-3317. doi: 10.2174/0929867327666200806110206. PMID: 32767913.
Abstract
Diffuse intrinsic pontine glioma (DIPG) mainly affects children with a median age of 6-7 years old. It accounts for 10% of all pediatric tumors. Unfortunately, DIPG has a poor prognosis, and the median survival is generally less than 16-24 months independently from the treatment received. Up to now, children with DIPG are treated with focal radiotherapy alone or in combination with antitumor agents. In the last decade, ONC201 known as dopamine receptor antagonist was uncovered, by a high throughput screening of public libraries of compounds, to be endowed with cytotoxic activity against several cancer cell lines. Efforts were made to identify the real ONC201 target, responsible for its antiproliferative effect. The hypothesized targets were the Tumor necrosis factor-Related Apoptosis-Inducing Ligand stimulation (TRAIL), two oncogenic kinases (ERK/AKT system) that target the same tumor-suppressor gene (FOXO3a), dopamine receptors (DRD2 and DRD3 subtypes) and finally the mitochondrial Caseynolitic Protease P (ClpP). ONC201 structure-activity relationship is extensively discussed in this review, together with other two classes of compounds, namely ADEPs and D9, already known for their antibiotic activity but noteworthy to be discussed and studied as potential "leads" for the development of new drugs to be used in the treatment of DIPG. In this review, a detailed and critical description of ONC201, ADEPs, and D9 pro-apoptotic activity is made, with particular attention to the specific interactions established with its targets that also are intimately described. Pubmed published patents and clinical trial reports of the last ten years were used as the bibliographic source.
________________________________________________________________________
If you search Facebook https://www.facebook.com/search/top/?q=H3K27%20%20Diffuse%20Intrinsic%20Pontine%20Glioma you will find heart-breaking story after story like the one below.
It is with a heavy heart that Lynn and I write this post.
Mackenzie Lynn Barron, our beautiful 3 year old daughter was just diagnosed with a super rare brain cancer.
Diffuse Intrinsic Pontine Glioma.
She fell about 8 weeks ago and hit her head hard enough that we had to take her to the emergency room. During a routine CT scan, they saw a bright spot on her brain. At the time they didn't know if it was something or just static. They ordered up and MRI that was finally performed on June 15th, 2018.
Lynn and I learned of the diagnoses Yesterday at the MRI reading with the doctor.
The Doctor was visibly shaken while trying to give us the news. As of now, there is no chemo therapy available, no cure, no treatments outside of radiation. Radiation therapy may reduce the tumor, thus prolonging the inevitable.
There are less then 300 children diagnosed with this cancer every year. We were informed that the average expected time is 18 mos.
We go see her Oncologist and radiologist this coming Monday to discuss all options available. We are requesting a second opinion be performed through St. Jude's Hospital.
Our hearts are broken and we need all the prayer and love our family and friends can give. We are so far away and feel so alone, it is unbearable.
Please ask God to look over our Mackenzie and move those mountains.
At this time we request that no phone calls or text messages until Monday evening. Allow us this weekend with our baby girl to make some memories and process this news.
Thank you everyone for your thoughts and prayers
Thomas, Lynn, Noah, Kayla and Mackenzie
_________________________________________________________________________
A 13-year-old named Lucas from Belgium has become the world's first known child cured of diffuse intrinsic pontine glioma (DIPG), a rare and aggressive brain cancer.
After a seven-year journey through treatments, there is no trace of the tumour remaining, according to Dr Jacques Grill, head of the brain tumour program at the Gustave Roussy Cancer Center in Paris.
DIPG, aka diffuse intrinsic pontine glioma, is known for its aggressive nature and lack of effective treatment options, with only around 300 children in the United States and 100 in France diagnosed each year.
This type of childhood cancer forms in the brainstem. It is very rare and almost always occurs in the paediatric population.
However, the outlook for DIPG remains bleak, with most children not surviving beyond a year post-diagnosis, and only 10 percent alive two years later, according to recent studies.
Lucas and his family participated in the BIOMEDE trial in France, testing potential new drugs for DIPG. Remarkably, Lucas responded positively to the cancer drug Everolimus, which he was randomly assigned, leading to the complete disappearance of the tumour.
Dr Grill, as per news agency AFP, noted that Lucas's case is unique globally. But the exact reasons for his full recovery and its potential implications for other children are yet to be fully understood.
While seven other children in the trial survived for years after diagnosis, Lucas's case is exceptional as his tumour vanished entirely.
Dr Grill suggested that the unique response could be linked to the "biological particularities" of each child's tumour, with Lucas having an extremely rare mutation that made his tumour cells highly sensitive to the drug.
https://www.indiatoday.in/health/story/13-year-old-becomes-worlds-first-child-to-beat-rare-brain-cancer-in-drug-trial-2502682-2024-02-15?fbclid=IwY2xjawLlWS5leHRuA2FlbQIxMQABHiytoD0GQ-rfRYL4nCcDi6ry2F2CE7toOqIOkRUJZRiRe_Ci0sEMfkQrfy9z_aem_F8rAkgaCw8LthjewUFYfHw
25 years. A quarter century. 25 years ago I was diagnosed with terminal brain cancer called Diffuse Intrinsic Pontine Glioma (DIPG). Like so many other parents, mine were told there was almost no hope and that they should go home and make memories while they could, because I probably wouldnt make it a year. 25 years of hospital visits, MRIs, PET scans, blood tests, and meeting with doctors from around the world. 25 years of worrying about what my next check up would show. 25 years of meeting new kids who have the same diagnosis, none of whom deserved it. I think the most frustrating thing is that 25 years later, the treatment options and survival rate have not changed.
Its pretty fitting that September, the month I celebrate making it another year, is childhood cancer awareness month. Childhood cancers are the leading cause of death by disease for children under the age of 19 yet only 4 percent of government cancer funding is devoted to researching childhood cancers. This is unacceptable. We need to do better. These kids deserve better. Even if kids survive their cancer, they are usually left with health problems down the line. I havent had any treatment since I was 12, but im still dealing with the effects of that treatment. I’m a lucky one though because im still able to live a normal life, many kids don’t get that chance. The first step in helping is awareness. Awareness is power. Awareness leads to funding. Funding leads to research, and research leads to a cure. As I’ve grown older, I've realized just how lucky I am. No one can explain why I've remained stable for so long. I was given a second chance and I will not stop using my voice to raise awareness and to help these families.
https://www.facebook.com/search/top/?q=H3K27%20%20Diffuse%20Intrinsic%20Pontine%20Glioma
Abstract
Diffuse intrinsic pontine glioma (DIPG) mainly affects children with a median age of 6-7 years old. It accounts for 10% of all pediatric tumors. Unfortunately, DIPG has a poor prognosis, and the median survival is generally less than 16-24 months independently from the treatment received. Up to now, children with DIPG are treated with focal radiotherapy alone or in combination with antitumor agents. In the last decade, ONC201 known as dopamine receptor antagonist was uncovered, by a high throughput screening of public libraries of compounds, to be endowed with cytotoxic activity against several cancer cell lines. Efforts were made to identify the real ONC201 target, responsible for its antiproliferative effect. The hypothesized targets were the Tumor necrosis factor-Related Apoptosis-Inducing Ligand stimulation (TRAIL), two oncogenic kinases (ERK/AKT system) that target the same tumor-suppressor gene (FOXO3a), dopamine receptors (DRD2 and DRD3 subtypes) and finally the mitochondrial Caseynolitic Protease P (ClpP). ONC201 structure-activity relationship is extensively discussed in this review, together with other two classes of compounds, namely ADEPs and D9, already known for their antibiotic activity but noteworthy to be discussed and studied as potential "leads" for the development of new drugs to be used in the treatment of DIPG. In this review, a detailed and critical description of ONC201, ADEPs, and D9 pro-apoptotic activity is made, with particular attention to the specific interactions established with its targets that also are intimately described. Pubmed published patents and clinical trial reports of the last ten years were used as the bibliographic source.
________________________________________________________________________
If you search Facebook https://www.facebook.com/search/top/?q=H3K27%20%20Diffuse%20Intrinsic%20Pontine%20Glioma you will find heart-breaking story after story like the one below.
It is with a heavy heart that Lynn and I write this post.
Mackenzie Lynn Barron, our beautiful 3 year old daughter was just diagnosed with a super rare brain cancer.
Diffuse Intrinsic Pontine Glioma.
She fell about 8 weeks ago and hit her head hard enough that we had to take her to the emergency room. During a routine CT scan, they saw a bright spot on her brain. At the time they didn't know if it was something or just static. They ordered up and MRI that was finally performed on June 15th, 2018.
Lynn and I learned of the diagnoses Yesterday at the MRI reading with the doctor.
The Doctor was visibly shaken while trying to give us the news. As of now, there is no chemo therapy available, no cure, no treatments outside of radiation. Radiation therapy may reduce the tumor, thus prolonging the inevitable.
There are less then 300 children diagnosed with this cancer every year. We were informed that the average expected time is 18 mos.
We go see her Oncologist and radiologist this coming Monday to discuss all options available. We are requesting a second opinion be performed through St. Jude's Hospital.
Our hearts are broken and we need all the prayer and love our family and friends can give. We are so far away and feel so alone, it is unbearable.
Please ask God to look over our Mackenzie and move those mountains.
At this time we request that no phone calls or text messages until Monday evening. Allow us this weekend with our baby girl to make some memories and process this news.
Thank you everyone for your thoughts and prayers
Thomas, Lynn, Noah, Kayla and Mackenzie
_________________________________________________________________________
A 13-year-old named Lucas from Belgium has become the world's first known child cured of diffuse intrinsic pontine glioma (DIPG), a rare and aggressive brain cancer.
After a seven-year journey through treatments, there is no trace of the tumour remaining, according to Dr Jacques Grill, head of the brain tumour program at the Gustave Roussy Cancer Center in Paris.
DIPG, aka diffuse intrinsic pontine glioma, is known for its aggressive nature and lack of effective treatment options, with only around 300 children in the United States and 100 in France diagnosed each year.
This type of childhood cancer forms in the brainstem. It is very rare and almost always occurs in the paediatric population.
However, the outlook for DIPG remains bleak, with most children not surviving beyond a year post-diagnosis, and only 10 percent alive two years later, according to recent studies.
Lucas and his family participated in the BIOMEDE trial in France, testing potential new drugs for DIPG. Remarkably, Lucas responded positively to the cancer drug Everolimus, which he was randomly assigned, leading to the complete disappearance of the tumour.
Dr Grill, as per news agency AFP, noted that Lucas's case is unique globally. But the exact reasons for his full recovery and its potential implications for other children are yet to be fully understood.
While seven other children in the trial survived for years after diagnosis, Lucas's case is exceptional as his tumour vanished entirely.
Dr Grill suggested that the unique response could be linked to the "biological particularities" of each child's tumour, with Lucas having an extremely rare mutation that made his tumour cells highly sensitive to the drug.
https://www.indiatoday.in/health/story/13-year-old-becomes-worlds-first-child-to-beat-rare-brain-cancer-in-drug-trial-2502682-2024-02-15?fbclid=IwY2xjawLlWS5leHRuA2FlbQIxMQABHiytoD0GQ-rfRYL4nCcDi6ry2F2CE7toOqIOkRUJZRiRe_Ci0sEMfkQrfy9z_aem_F8rAkgaCw8LthjewUFYfHw
25 years. A quarter century. 25 years ago I was diagnosed with terminal brain cancer called Diffuse Intrinsic Pontine Glioma (DIPG). Like so many other parents, mine were told there was almost no hope and that they should go home and make memories while they could, because I probably wouldnt make it a year. 25 years of hospital visits, MRIs, PET scans, blood tests, and meeting with doctors from around the world. 25 years of worrying about what my next check up would show. 25 years of meeting new kids who have the same diagnosis, none of whom deserved it. I think the most frustrating thing is that 25 years later, the treatment options and survival rate have not changed.
Its pretty fitting that September, the month I celebrate making it another year, is childhood cancer awareness month. Childhood cancers are the leading cause of death by disease for children under the age of 19 yet only 4 percent of government cancer funding is devoted to researching childhood cancers. This is unacceptable. We need to do better. These kids deserve better. Even if kids survive their cancer, they are usually left with health problems down the line. I havent had any treatment since I was 12, but im still dealing with the effects of that treatment. I’m a lucky one though because im still able to live a normal life, many kids don’t get that chance. The first step in helping is awareness. Awareness is power. Awareness leads to funding. Funding leads to research, and research leads to a cure. As I’ve grown older, I've realized just how lucky I am. No one can explain why I've remained stable for so long. I was given a second chance and I will not stop using my voice to raise awareness and to help these families.
https://www.facebook.com/search/top/?q=H3K27%20%20Diffuse%20Intrinsic%20Pontine%20Glioma
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