Diffuse Intrinsic Pontine Glioma isa very rare form of pediatric brainstem cancer otherwise known as DIPG. DIPGare extremely aggressive and hard to treat brain tumors that are found specificallyin the pons region of the brain. They are the most common type of brainstemtumor. DIPG is a heterogeneous disease, meaning the disease is caused byvarying different genes. These tumors are comprised of glial tissues, which aremade up of cells that help to support and protect the brain’s neurons. They arefound specifically in the pons region, which is responsible for vital bodilyfunctions such as heart rate, breathing, and blood pressure. This region isalso responsible for walking, talking, seeing, hearing, and eating.
This formof cancer is responsible for approximately 10 percent of all central nervoussystem (CNS) tumors. The tumors most commonly occur in children ages 5-9, butcan occur during any stage of childhood. There are two particular subgroups ofDIPG, histone H3F3A and HIST1H3B K27M. Each of these subgroups has a differentprognosis and phenotype. About 300children in the U.
S. are diagnosed with DIPG a year. Due to its location,little was understood about these tumors because of their location in thebrainstem. Many clinicians believed they could not be safely biopsied. Prior torecent years, only MRIs and CT scans wereused. These techniques are still used today. The lack of surgical andbiopsy material has limited most studies of DPIG and histology to post-partumtissue. Now that doctors do perform biopsies on these tumors, they are mostcommonly discovered as grade III or IV, those being the most aggressive.
DIPGsare treated with surgery, radiation therapy, or chemotherapy. Due to theextremely sensitive location of these tumors, surgery is almost always removedas an option. Radiation is used in patients above the age of 3. This form oftreatment is typically only used as relief of the symptoms as opposed to actualtreatment or cure. Chemotherapy is most commonly used in combination withradiation as well as other biologic agents.
Pediatric cancers are extremelyimportant to fundamentally understand because they can lead to furtherunderstandings in adult cancers. Much of our nationalfunding for cancer, 96% in fact, goes towards the research and treatment ofcancers in individuals over the age of 19. Many scientists believe that thefuture in cancer treatment research can be found by looking into pediatriccancers. The lessons that can be learned from studying pediatric cancers, andunderstanding the biology and further applying those to treatment strategiesfor adult cancers can prove to be extremely beneficial. BODY 1, WHAT AREDIPG: (potentially expand) DIPG are tumors that form fromglial cells in the brain. Like many cancers, they originate from irregular cellreplication. There is a tight correlation between DIPG and midlineglioblastomas, which could have potentially originated from recently identifiedpontine precursors-like cells.
The age range that these tumors affect is uniqueto this form of cancer. Pediatrics ranging from ages 5-9 are the most commonlyaffected individuals. These tumors are found equally in both boys and girls. Diagnosingthese tumors is extremely difficult because of their sensitive location in thebrain stem. Symptoms of these tumors present as symptoms of many other bodilyissues, which makes it very difficult. These include, fever, fatigue, blurryvision, rapid eye movement, and other symptoms.
Due to this, these tumors arenot normally diagnosed until they have reach stage III or stage IV, making themhighly unlikely to respond to treatments. This has caused the mortality rate ofthis to be around 99% in child patients. The average survival rate for childrenonce diagnosed is 9 to 10 months. Thesetumors are seen to cause an up regulation of receptor tyrosine kinases (RTKs),specifically PDGFR-alpha, MET, and IGF1R. Most standard therapies have shownlittle to no success in these tumors. This may show that inhibiting RTKs alonemay not be enough for fight DIPG. The methodical way these tumors form iscaused by malignant cells originating in the brain stem and then becomingintertwined with healthy brain stem cells, which makes surgical removalvirtually impossible. More advanced technologies, like genome editing, have beenaiding in the treatments of these tumors.
BODY 2: DIAGNOSIS& TREATMENTS: DIPGs are typically diagnosed too late,which is what gives rise to the extremely low survival rate. They are normallydiagnosed by the physical symptoms they cause, which are notable symptoms formany diseases. They are also diagnosed by MRI and CT scans. Up until recently,these tumors were not even biopsied safely because of their intrinsic locationin the brain stem. Currently, biopsy of these tumors is controversial becauseof the high risk of neurological damage.
The findings from a biopsy also do not alter how the patient is treated.However, biopsy may be helpful if biological information gleaned from thetissue may guide therapy or provide additional prognostic information. Biopsiesare much more common today because their risk of causing damage has beengreatly reduced. This is due to the fact that the procedure is now known as a”stereotactic” biopsy and uses MRI scans of the children’s brains in order toguide a thin needle into the tumor in order to extract cells. This procedurehelps to avoid the crucial nerve that runs through the pons. Many DIPG patientswill not typically undergo a biopsy in the in United States.
Surgery is not atreatment option for DIPG as with some other cancers occurring in the brain.Attempting to remove these tumors would most likely cause severe neurologicaldamage and in many cases may be fatal. Since the pons region is located withinthe center of the brain, a surgeon would have to damage other parts of thebrain in order to gain access. DIPG tumors are typically discovered once theyhave already begun an extensive infiltration of the area. Another issue thatarises with DIPG is that they are not solid, well defined tumors,therefor-total removal would never be possible. The cells that are left wouldthen continue to divide and spread. Radiation is one of the more standardtreatments for DIPG. It is the only form of treatment that has proven benefitsin shrinkage of the tumors.
The benefits of radiation last only temporarily andtypically do not increase the patient’s survival due to the fact that the tumortends to grow back immediately. Proton radiation therapy is a form of treatmentthat has shown extreme success in other cancers, but many radiologists do notsee the benefit in using it for DIPG tumors. Proton radiation therapy primarybenefit is that it relies on a proton beam that is more precise than theelectron beam that is used in standard radiation. Since DIPG tumors do not havewell-define lines or a solid structure, this technology would not be successful.Chemotherapy does not typically show any benefit in the treatment of DIPG nordoes it show any extension in the length of survival.
Currently, manyscientists are looking into the combination of radiation, chemotherapy, andepigenetic treatments for DIPG. Majorobstacles in the development of effective treatments include the extensive Of late, epigenetic treatments of DIPGhave shown the most success. A recent discovery of how somatic oncogenichistone gene mutation that affects the chromatin regulation in DIPG hasdrastically improved how scientists are able to understand the pathogenesis inthese tumors.
These studies have helped to stimulate the various therapeuticapproaches that target epigenetic regulators for disease treatment. Alteredepigenetic in combination with gene mutations can play a crucial role in tumorinitiation along with progression. In an attempt to understand and attemptingto reverse epigenetic changes caused by the cancer, this can increase theprecision of the epigenetic treatments. There are some drugs currently usedthat target the epigenetic modifiers which include: methyltransferases,demethylases, HDAC’s and BET proteins. These are all currently being tested inclinical trials. Current Treatment: MostlyDoneExperimental Treatment:EXPAND BODY 3: HISTONES: Identificationof the role of histone modification and the functional involvement of chromatinmachinery is crucial in understanding the biology of the cancer and in thedevelopment effective therapies for treatment. Recently, scientists have seenthat recurrent H3F3A mutations affect two critical amino acids, K27 and G34 ofhistone H3.1 in one third of all pediatric gliomas.
Mutations at K27specifically accounts for about 60% of all DIPG. Mutations at amino acid 27causes a replacement of lysine by methionine or at amino acid 34 causes areplacement of glycine by valine or arginine, as the molecular drivers of aparticular subgroup of DIPG. These H3.3 mutations also overlap much withmutations in TP53 and ATRX, which encodes a subunit of a chromatin-remodelingcomplex required for H3.3 incorporation at pericentric heterochromatin andtelomeres. The overlap of these mutations may further be looked at to see howprevalent they are in DIPG and whether or not this is similar to what is seenin other glioblastomas. The median survival rate for this 60% is around oneyear.
Each heterozygous H3F3A mutation defines a smaller epigenetic group orsubgroup of glioblastomas that contain a distinct global methylation pattern.These mutations can directly or indirectly target important positions on thehistone tail for posttranslational modifications. H3.3 G34 mutations mayrepresent an alternative mechanism, which overexpresses MYCM, causes anincrease of glioma formation in vivo and could potentially be targeted bybromodomain inhibition. Mutations in H3F3A that resultin mutations at K27 occur in 70-80% of midline gliomas and DIPG. Withoutextensive research, it appears that mutations at K27 seem to confer a dismalprognosis, while mutations at G34 might be associated with slightly prolongedoverall survival. K27 mutations lead to a down regulation of a repressive mark,which interferes with the enzymatic activity of EZH2.
Mutation at the K27causes loss of a key lysine, which results in the loss of trimethylation oflysine 27 on all histones H3 molecules whether wild type or mutated. DNAmethylation is an epigenetic mechanism that is used by cells to control geneexpression. Many different mechanisms exist in order to control gene expressionin eukaryotes. DNA methylation is the most commonly used epigenetic signalingtool that can fix genes in the off position. DNA copy-number aberrations arecommonly seen in gliomas, and can affect a large number of the tumor genome. Theloss of H3K27me3 has been observed in more than 90% of all DIPG cases, makingit the “Hallmark” for DIPG.
The type of histone targeted by K27 alterations hasan extremely large influence on the survival length of patients. H3.1 mutatedtumors typically respond better to treatment then H3.3 mutations.
They alsohave a less aggressive course and metastasize less frequently. New techniquesin research have allowed for the precise characterization of local copy-numberaberrations target regions, and use of sequencing large portions of the genomeare beginning to show more complex structural rearrangements and unknown fusionevents