Moonshot Progress
The GDC is a single, scalable
repository for cancer genomics data,
patient information, pathologic
and radiologic images, and relevant
preclinical data. Researchers can
submit their data, followed by a pre-
processing period in which submitters
can “clean up” data before they are
processed and validated by the GDC
team. After processing is completed,
the data are made publicly available
and accessible through GDC tools.
“These are big data – almost too
big to wrap your head around,” Dr.
Staudt told ASH Clinical News. “We
are in the realm of multiple petabytes
of data for cancer genomics. That’s
Amazon- or Google-size data.”
At present, the GDC contains data
from several of the world’s largest
cancer genomics databases, such as he
Cancer Genome Atlas and Therapeuti-
cally Applicable Research to Generate
Effective Treatments.
“We also have opened the doors to
any comprehensive genomic profiling
in cancer for which we think the shar-
ing of data would benefit the commu-
nity,” Dr. Staudt said.
For example, in September the
NIH announced it had made 574 dif-
fuse large B-cell lymphoma (DLBCL)
biopsy samples available in the GDC
Data Portal. The data originated
from a study published in the New
England Journal of Medicine that
uncovered four prominent genetic
subtypes of DLBCL with distinct
genotypic, epigenetic, and clinical
characteristics. 10 In the future, the
NCI plans to capitalize on the suc-
cess of the GDC by building com-
parable data systems to share data
generated by proteomics, radiologic
imaging, histologic imaging, and
more, Dr. Staudt said. As part of its
precision-medicine efforts, the NIH
also launched the All of Us Research
Program, an initiative seeking to
build a national research cohort of
more than 1 million people. The
database will include information
about participants’ lifestyle, biology,
and environment “to inform thousands
of studies, covering a wide variety of
health conditions.”
“We want this program to reflect
the rich diversity of our country,” said
Eric Dishman, director of the All
of Us Research Program. “Working
with participants across the country,
we hope to contribute to medical
breakthroughs that may lead to more
tailored disease prevention and treat-
ment solutions in the future.” 11
Greater accessibility and sharing of
data is extremely important in theory,
Dr. Godley said, but she is worried
about reality, including the ability to
properly obtain informed consent
from patients.
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ASH Clinical News
medicine could be beneficial to
identify patients who would benefit
from more intense approaches like
bone marrow transplant or gene
therapy or who would benefit from
mild therapies like hydroxyurea.”
One relatively recent applica-
tion of precision medicine in classic
hematology is the use of genomics
to identify patients with inherited or
acquired aplastic anemia, Dr. Calado
said. The clinical presentation of these
patients may be the same, but genomic
information is required to confirm
a diagnosis of acquired vs. inherited
disease.
“In the big picture, yes, we want to
share data, but, when we get into the
details about who ‘owns’ a patient’s
data and how we can protect confi-
dentiality, things get complicated,”
she cautioned. “I would argue that
nothing is more identifying than your
DNA sequence. As soon as someone
has sequenced a certain number of
highly polymorphic regions, the pa-
tient has been identified.”
Those details tend to get glossed
over in discussions of data sharing and
data repositories, she said, because
people do not want to grapple with
these difficult issues. subtypes: estrogen receptor–positive
breast cancer, muscle-invasive bladder
cancer, AML, etc. “We looked at a
tumor under a microscope and gave a
histologic diagnosis, and that was how
patients were enrolled into trials,” Dr.
Godley said.
Now, more clinical trialists are
attempting to define patients’ diseases
molecularly and match patients with
a relevant targeted treatment under
investigation. This would mean, for
example, that patients with BRCA1
mutations may be enrolled in a trial
regardless of the histologic subtype of
their disease.
Rethinking Clinical Trials “Progress in precision medicine
won’t continue ... if people don’t
appreciate the connection
between basic research and
medical advances.”
—LUCY GODLEY, MD, PhD
Under the umbrella of the Moonshot,
regulators and researchers also are
looking for ways to design innovative
clinical trials and promote the review
of products to bring targeted drugs to
patients more efficiently – and to keep
pace with genomic discoveries.
Signed into law in December 2016,
the 21st Century Cures Act was de-
signed help accelerate medical product
development and more quickly and
efficiently bring new innovations to
patients. 12 This legislation included the
new Regenerative Medicine Advanced
Therapy (RMAT) designation, which
is available for drugs intended to treat,
modify, reverse, or cure a serious life-
threatening disease or condition or
for drugs with preliminary evidence
showing that they address an unmet
medical need for those conditions.
More than 20 products have re-
ceived RMAT designation, including
treatments for sickle cell disease and
lymphoma. 13
The Cures Act also created the
FDA’s Oncology Center of Excellence,
which leverages the combined skills of
regulatory scientists and reviewers to
expedite the development of oncology
and hematology products. The center
takes an integrated approach to the
clinical evaluation of drugs, biolog-
ics, and devices for the treatment of
cancer.
Since the Moonshot Initiative
launched, the RACE for Children
Act (Title V of the FDA Reauthoriza-
tion Act) has become law. It requires
companies developing cancer drugs to
also develop candidates for children
if the molecular target of the drugs
under development is relevant to a
pediatric cancer. 14 “From the pediatric
perspective this was a major advance,”
Dr. Mullighan said.
To get more drugs to the regulato-
ry process, experts guiding the Moon-
shot also are looking to incorporate
genomic data into clinical trials.
Traditionally, clinical trials have
studied an investigational drug in pa-
tients with distinct histologic disease
Dr. Godley acknowledged that this
approach has its pros and cons, includ-
ing that patients may still have to be
subdivided based on disease type. “With
BRCA1 mutations, for example, there
are different pathways of DNA repair
that are more or less active in different
tissue types,” she explained. “So, PARP
inhibitors may be effective in breast
or ovarian tumors, but less effective in
leukemia or pancreatic cancer because
maybe that DNA repair pathway is not
as important in that tissue.”
Changing clinical trials will be a
huge challenge for the field and will
require close evaluation, Dr. Godley
noted. “In the end, we may have the
same problem that we had with the
old way, because we just decided to
classify tumors in a different way.
Hopefully, we are not just exchanging
one problem for another.”
The Long Arm of Precision
Medicine
As more knowledge is gained about
the use of precision medicine in
cancer and hematologic malignancies,
there is hope that its application will
spread to benign hematologic condi-
tions as well.
“Precision medicine should be as
important for nonmalignant disease
as it is for malignant disease,” said
Rodrigo T. Calado, MD, PhD,
associate professor of hematology at
the University of São Paulo’s Ribeirão
Preto Medical School in Brazil. The
heterogenous clinical presentation of
sickle cell anemia makes it a prime
candidate for precision medicine
strategies, he added. “Precision
In one recent study, researchers
used next-generation sequencing to
look at the genomes of blood samples
from more than 400 patients with
acquired aplastic anemia. About
one-third had stem cell clones that
appeared with mutations in a few
genes, such as DNMT3A and ASXL1.
Patients with these mutations fared
worse than those without mutations,
and worse than patients with muta-
tions in other genes such as BCOR and
PIGA. 15
Distinguishing between the two
conditions provides important clinical
decision-making information, he not-
ed. “If a patient has inherited aplastic
anemia, he or she can be treated
with bone marrow transplantation
or other hormones, while someone
with acquired aplastic anemia could
be treated with immunosuppressive
therapy,” Dr. Calado said. “In the past,
we would have had to wait until a
patient didn’t respond to immunosup-
pression to identify a mutation that
was the cause of non-response. Today,
we can look at that before we treat.”
The Race to the Moon
With all these advances in precision
medicine, is the Cancer Moonshot
Initiative on its way to success? The
experts who spoke with ASH Clinical
News all agreed: Probably, but it’s still
too early to tell.
“The pace of progress is increas-
ing rapidly, thanks in part to the
technologies that we have available to
study cancers,” Dr. Ebert said, “but it
is challenging to quantify how much
progress has been made across this
December 2018