Download Dana-Farber Cancer Institute | Spring 2002

PROGRESS
UPDATE
The Prayers From Maria Foundation
August 2015
EXECUTIVE SUMMARY
As one of the leading experts in the study and treatment of pediatric brain
tumors, Dana-Farber Cancer Institute is dedicated to advancing our
understanding of these diseases and providing the finest patient care. New
opportunities afforded by genomic analysis and other advancements are
empowering our physician-scientists to learn more about the fundamental
biology driving rare and challenging forms of disease. Accounting for
approximately 10 percent of all pediatric nervous system tumors, diffuse
intrinsic pontine gliomas (DIPGs) are highly aggressive and continue to
present many treatment challenges.
Under the direction of Mark Kieran, MD, PhD, Director of Pediatric Medical
Neuro-Oncology, and Keith Ligon, MD, PhD, Director of Neuro-Oncologic
Pathology, Dana-Farber investigators are leading the way in uncovering new
information about the biological underpinnings of DIPG with the ultimate aim
of improving outcomes for young patients with these tumors. This report
highlights their ongoing efforts to understand the complex drivers of this
disease in order to identify and evaluate the most promising novel targets
and drugs. Your partnership plays a critical role in propelling this work and
expediting the discovery of effective new therapies and treatment strategies.
Mark Kieran, MD, PhD,
Director of Pediatric Medical
Neuro-Oncology
LEADING THE WAY WITH DIPG BIOPSIES
DIPGs develop in the pons, a highly sensitive area in the brain stem that, if
injured, can cause serious side effects. In the 1980s, due to this challenge,
surgeons ceased their attempts to biopsy the pons, limiting their ability to
learn more about the development of DIPG and which drugs might be most
effective against it. Since patients with DIPG almost always experience
treatment resistance and disease recurrence, researchers need to learn more
about the biology behind this disease to develop more impactful therapies.
Keith Ligon, MD, PhD, Director
of Neuro-Oncologic Pathology
In 2002, acknowledging recent surgical and genomic analysis advances that
would improve the safety of this procedure, Dr. Kieran began lobbying for
physicians, scientists, and surgeons to reconsider biopsying patients with
newly diagnosed DIPGs. Following more than 20 successful biopsies in 2007
by a medical team in France, Dr. Kieran had proof that DIPG biopsies could be
done safely. In 2010, Dr. Kieran launched a large-scale clinical trial to biopsy
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DIPGs at Dana-Farber and 24 other sites across the country, representing the
first study of its kind in North America. Investigators conducted molecular
analysis of these tumor samples and were sometimes able to make more
informed treatment decisions based on their findings. Dr. Kieran and his team
are now finalizing the results of the trial, which will clarify whether selecting
DIPG treatments based on biopsies and analysis can improve survival. Since
little was known about DIPGs prior to the trial, this tremendous new
knowledge is expanding understanding of these rare tumors.
In November 2014, Drs. Kieran and Ligon coordinated a work group session at
the Society of Neuro-Oncology annual meeting, inviting participants to
present innovative research strategies for DIPG based on the results of their
upfront biopsies studies. Drs. Kieran and Ligon are now drawing on the
findings and knowledge gained from the first study as they plan a new, more
informed clinical trial.
UNDERSTANDING DIPG THROUGH GENOMIC STUDIES
Dana-Farber investigators are leveraging this expanded access to DIPG
samples to better understand the drivers of this disease. Drs. Kieran and
Ligon are collaborating with researchers in the United States and
internationally to conduct genomic sequencing on these collections of DIPG
tumors. In the April 2014 Nature Genetics, they published findings detailing
their discovery of novel mutations linked to the development of DIPG,
including in the genes ACVR1, FGFR1, PIK3CA, and PDGFRA. The mutation to
ACVR1 was particularly significant since this mutation had never before been
identified in cancer. The investigators continue to advance this work by
evaluating these new targets and learning more about their complex role in
driving DIPG.
Dana-Farber investigators are also using DIPG samples to develop
sophisticated laboratory models that closely recapitulate actual patient
tumors, allowing investigators to study DIPG in a realistic model environment.
This work can help researchers to pinpoint more effective drugs to test in
patients, and could empower investigators to understand the diversity of
patient responses to various drugs. Using these models, investigators
recently discovered that even though almost all DIPGs have a histone
mutation (see sidebar), these mutations do not appear to cause DIPG on their
A histone is a type of protein that
provides structural support to
chromosomes. For DNA molecules
to fit into the cell nucleus, they wrap
around histones. Some histones also
play a role in regulating gene
expression.
Image credit: Darryl Leja, NHGRI
www.genome.gov
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own. Drs. Kieran and Ligon aim to learn which combinations of mutations
lead to DIPG and which arise during treatment, enabling them to elucidate
the genomic landscape of this complex disease.
These discoveries are already driving the development of novel therapeutic
strategies for DIPG. Since existing drugs can target PI3K and PDGFRA
mutations, the team is establishing clinical trials to explore the possibility of
repurposing compounds to inhibit these alterations in DIPG. In collaboration
with other Boston-area scientists, the team also created a novel diagnostic
test that can identify patients with specific histone mutations that have been
linked to poor outcomes. In the November 2014 Acta Neuropathologica, Drs.
Kieran, Ligon, and their collaborators published their findings about the
efficacy of this method, which is now used for clinical testing to screen for
patients these mutations.
EXPLORING DIPG AT A SINGLE CELL LEVEL
Through these studies, Dana-Farber researchers are learning that DIPGs are
highly heterogeneous and complex, which can make them challenging to
treat (see sidebar). One drug might only knock out the tumor cells driven by
one mutation, leaving other cancer cells to survive and continue growing. To
overcome this challenge, Dana-Farber investigators are exploring
combinations of targeted therapies. However, traditional “bulk” sequencing
methods—which identify all of the cancer-promoting mutations in a tumor
sample—can only give researchers a snapshot of the diversity in a tumor.
While often effective in less complex cancers, bulk sequencing cannot
indicate whether mutations are common to all tumor cells. To uncover the
best ways to treat complex DIPGs, investigators need to identify not only the
collective mutations, but the specific mutations within individual tumor cells.
In the August 2014 Cancer Discovery, Dr. Ligon and his collaborators published
a study aimed at addressing this problem in glioblastoma (GBM), another
aggressive and complex brain tumor related to DIPG. Working with the
laboratory of Matthew Meyerson, MD, PhD, Director of Dana-Farber’s Center
for Cancer Genome Discovery, Dr. Ligon and his team developed a new singlecell sequencing method to identify specific DNA mutations within individual
GBM tumor cells. This pioneering strategy—which provides a new, higher
Mutation A
Mutation B
Mutation C
Mutation D
Mutation D
Mutation A
Mutation C
Mutation A
Mutation B
Heterogeneity— genetic and
molecular variability— is a
common feature of malignant
tumors. This means that the
mutations that drive growth in one
DIPG tumor cell might be
completely different from the
mutations driving cancer in a
nearby cell—even within the same
tumor.
Top: Bulk analysis may reveal the
presence of multiple mutations
within a sample, but it doesn’t
reveal how those mutations are
distributed in sub-populations of
cancer cells within the tumor.
Bottom: Single-cell analyses allow
scientists to identify tumor subpopulations bearing distinct
combinations of mutations.
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level of resolution for scientists to examine the mutations driving cancer—
specifically revealed that a single GBM tumor is comprised of diverse
populations of cancer cells bearing different cancer-promoting mutations.
This information is already helping investigators to identify the mutations
that contribute to GBM and fine-tune treatment strategies accordingly.
Dr. Ligon and his colleagues are now exploring ways to apply single cell
sequencing technology to learn more about the complex drivers of DIPGs.
This strategy could allow investigators to understand the interplay between
DIPG cancer cells and how they work together to drive tumor growth. This
new knowledge will empower physicians to assemble the most promising
combinations of therapies and deliver maximally effective treatments.
A SINCERE THANK YOU
Your meaningful commitment has helped Dana-Farber investigators to
establish pioneering projects that advance our understanding of DIPGs. Their
discoveries strengthen the foundation for uncovering new targets and
improving treatment plans, keeping Dana-Farber at the forefront of pediatric
cancer research and care. On behalf of our patients, thank you for your
generous support in these critical efforts.
Report written by Brittany Flaherty.
Due to the sensitive location of DIPGs,
researchers cannot collect large or
numerous tissue samples, making it
difficult to conduct broad analysis. To
reduce the amount of tissue needed,
the team recently developed a new
technique to analyze various
components in a single tumor sample
rather than requiring multiple samples.
“We are the ones developing this
technology for DIPG. There is no place
where the micro scale is as important
as in DIPG samples, which are a
millimeter in size.” - Dr. Mark Kieran
The image above demonstrates the
relative size of one millimeter.
Image credit: Teresa Winslow
FOR MORE INFORMATION
Amy Trapasso
Director, Corporate and Foundation Relations
(617)-632-6601
[email protected]
© 2015 Dana-Farber Cancer Institute. All Rights Reserved.
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