Diffuse Intrinsic Pontine Glioma is
a very rare form of pediatric brainstem cancer otherwise known as DIPG. DIPG
are extremely aggressive and hard to treat brain tumors that are found specifically
in the pons region of the brain. They are the most common type of brainstem
tumor. DIPG is a heterogeneous disease, meaning the disease is caused by
varying different genes. These tumors are comprised of glial tissues, which are
made up of cells that help to support and protect the brain’s neurons. They are
found specifically in the pons region, which is responsible for vital bodily
functions such as heart rate, breathing, and blood pressure. This region is
also responsible for walking, talking, seeing, hearing, and eating. This form
of cancer is responsible for approximately 10 percent of all central nervous
system (CNS) tumors. The tumors most commonly occur in children ages 5-9, but
can occur during any stage of childhood. There are two particular subgroups of
DIPG, histone H3F3A and HIST1H3B K27M. Each of these subgroups has a different
prognosis and phenotype.  About 300
children 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 the
brainstem. Many clinicians believed they could not be safely biopsied. Prior to
recent years, only MRIs and CT scans were
used. These techniques are still used today. The lack of surgical and
biopsy material has limited most studies of DPIG and histology to post-partum
tissue. Now that doctors do perform biopsies on these tumors, they are most
commonly discovered as grade III or IV, those being the most aggressive. DIPGs
are treated with surgery, radiation therapy, or chemotherapy. Due to the
extremely sensitive location of these tumors, surgery is almost always removed
as an option. Radiation is used in patients above the age of 3. This form of
treatment is typically only used as relief of the symptoms as opposed to actual
treatment or cure. Chemotherapy is most commonly used in combination with
radiation as well as other biologic agents. Pediatric cancers are extremely
important to fundamentally understand because they can lead to further
understandings in adult cancers. Much of our national
funding for cancer, 96% in fact, goes towards the research and treatment of
cancers in individuals over the age of 19. Many scientists believe that the
future in cancer treatment research can be found by looking into pediatric
cancers. The lessons that can be learned from studying pediatric cancers, and
understanding the biology and further applying those to treatment strategies
for adult cancers can prove to be extremely beneficial.

 

 

 

BODY 1, WHAT ARE
DIPG: (potentially expand)

           

DIPG are tumors that form from
glial cells in the brain. Like many cancers, they originate from irregular cell
replication. There is a tight correlation between DIPG and midline
glioblastomas, which could have potentially originated from recently identified
pontine precursors-like cells. The age range that these tumors affect is unique
to this form of cancer. Pediatrics ranging from ages 5-9 are the most commonly
affected individuals. These tumors are found equally in both boys and girls. Diagnosing
these tumors is extremely difficult because of their sensitive location in the
brain stem. Symptoms of these tumors present as symptoms of many other bodily
issues, which makes it very difficult. These include, fever, fatigue, blurry
vision, rapid eye movement, and other symptoms. Due to this, these tumors are
not normally diagnosed until they have reach stage III or stage IV, making them
highly unlikely to respond to treatments. This has caused the mortality rate of
this to be around 99% in child patients. The average survival rate for children
once diagnosed is 9 to 10 months.  These
tumors are seen to cause an up regulation of receptor tyrosine kinases (RTKs),
specifically PDGFR-alpha, MET, and IGF1R. Most standard therapies have shown
little to no success in these tumors. This may show that inhibiting RTKs alone
may not be enough for fight DIPG. The methodical way these tumors form is
caused by malignant cells originating in the brain stem and then becoming
intertwined with healthy brain stem cells, which makes surgical removal
virtually impossible. More advanced technologies, like genome editing, have been
aiding in the treatments of these tumors.   

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BODY 2: DIAGNOSIS
& TREATMENTS:

           

DIPGs are typically diagnosed too late,
which is what gives rise to the extremely low survival rate. They are normally
diagnosed by the physical symptoms they cause, which are notable symptoms for
many diseases. They are also diagnosed by MRI and CT scans. Up until recently,
these tumors were not even biopsied safely because of their intrinsic location
in the brain stem. Currently, biopsy of these tumors is controversial because
of 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 the
tissue may guide therapy or provide additional prognostic information. Biopsies
are much more common today because their risk of causing damage has been
greatly 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 to
guide a thin needle into the tumor in order to extract cells. This procedure
helps to avoid the crucial nerve that runs through the pons. Many DIPG patients
will not typically undergo a biopsy in the in United States. Surgery is not a
treatment option for DIPG as with some other cancers occurring in the brain.
Attempting to remove these tumors would most likely cause severe neurological
damage and in many cases may be fatal. Since the pons region is located within
the center of the brain, a surgeon would have to damage other parts of the
brain in order to gain access. DIPG tumors are typically discovered once they
have already begun an extensive infiltration of the area. Another issue that
arises with DIPG is that they are not solid, well defined tumors,
therefor-total removal would never be possible. The cells that are left would
then continue to divide and spread. Radiation is one of the more standard
treatments for DIPG. It is the only form of treatment that has proven benefits
in shrinkage of the tumors. The benefits of radiation last only temporarily and
typically do not increase the patient’s survival due to the fact that the tumor
tends to grow back immediately. Proton radiation therapy is a form of treatment
that has shown extreme success in other cancers, but many radiologists do not
see the benefit in using it for DIPG tumors. Proton radiation therapy primary
benefit is that it relies on a proton beam that is more precise than the
electron beam that is used in standard radiation. Since DIPG tumors do not have
well-define lines or a solid structure, this technology would not be successful.
Chemotherapy does not typically show any benefit in the treatment of DIPG nor
does it show any extension in the length of survival. Currently, many
scientists are looking into the combination of radiation, chemotherapy, and
epigenetic treatments for DIPG.  Major
obstacles in the development of effective treatments include the extensive  

 

Of late, epigenetic treatments of DIPG
have shown the most success. A recent discovery of how somatic oncogenic
histone gene mutation that affects the chromatin regulation in DIPG has
drastically improved how scientists are able to understand the pathogenesis in
these tumors. These studies have helped to stimulate the various therapeutic
approaches that target epigenetic regulators for disease treatment. Altered
epigenetic in combination with gene mutations can play a crucial role in tumor
initiation along with progression. In an attempt to understand and attempting
to reverse epigenetic changes caused by the cancer, this can increase the
precision of the epigenetic treatments. There are some drugs currently used
that target the epigenetic modifiers which include: methyltransferases,
demethylases, HDAC’s and BET proteins. These are all currently being tested in
clinical trials.            

 

Current Treatment: Mostly
Done

Experimental Treatment:
EXPAND

 

 

BODY 3: HISTONES:

            Identification
of the role of histone modification and the functional involvement of chromatin
machinery is crucial in understanding the biology of the cancer and in the
development effective therapies for treatment. Recently, scientists have seen
that recurrent H3F3A mutations affect two critical amino acids, K27 and G34 of
histone H3.1 in one third of all pediatric gliomas. Mutations at K27
specifically accounts for about 60% of all DIPG. Mutations at amino acid 27
causes a replacement of lysine by methionine or at amino acid 34 causes a
replacement of glycine by valine or arginine, as the molecular drivers of a
particular subgroup of DIPG. These H3.3 mutations also overlap much with
mutations in TP53 and ATRX, which encodes a subunit of a chromatin-remodeling
complex required for H3.3 incorporation at pericentric heterochromatin and
telomeres. The overlap of these mutations may further be looked at to see how
prevalent they are in DIPG and whether or not this is similar to what is seen
in other glioblastomas. The median survival rate for this 60% is around one
year. Each heterozygous H3F3A mutation defines a smaller epigenetic group or
subgroup of glioblastomas that contain a distinct global methylation pattern.
These mutations can directly or indirectly target important positions on the
histone tail for posttranslational modifications. H3.3 G34 mutations may
represent an alternative mechanism, which overexpresses MYCM, causes an
increase of glioma formation in vivo and could potentially be targeted by
bromodomain inhibition. Mutations in H3F3A that result
in mutations at K27 occur in 70-80% of midline gliomas and DIPG. Without
extensive research, it appears that mutations at K27 seem to confer a dismal
prognosis, while mutations at G34 might be associated with slightly prolonged
overall survival. K27 mutations lead to a down regulation of a repressive mark,
which interferes with the enzymatic activity of EZH2. Mutation at the K27
causes loss of a key lysine, which results in the loss of trimethylation of
lysine 27 on all histones H3 molecules whether wild type or mutated. DNA
methylation is an epigenetic mechanism that is used by cells to control gene
expression. Many different mechanisms exist in order to control gene expression
in eukaryotes. DNA methylation is the most commonly used epigenetic signaling
tool that can fix genes in the off position. DNA copy-number aberrations are
commonly seen in gliomas, and can affect a large number of the tumor genome. The
loss of H3K27me3 has been observed in more than 90% of all DIPG cases, making
it the “Hallmark” for DIPG. The type of histone targeted by K27 alterations has
an extremely large influence on the survival length of patients. H3.1 mutated
tumors typically respond better to treatment then H3.3 mutations. They also
have a less aggressive course and metastasize less frequently. New techniques
in research have allowed for the precise characterization of local copy-number
aberrations target regions, and use of sequencing large portions of the genome
are beginning to show more complex structural rearrangements and unknown fusion
events

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