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The Need for Harmonization in Bio-banking to
Realize the Potential of 21st Century Medicine Dr.
Anna Barker, NCI PDF
"The
number one roadblock to our progress, as defined at the think tank
Dialogues on Cancer (2002),
is the lack of availability of high quality, highly
characterized
human specimens for translational research."
"Biospecimens are materials from the human
body, such as tissue, blood, plasma, and urine,
that can be used for cancer diagnosis and analysis." 27
"Currently there are no standardized
procedures for
collecting, processing, storing, and distributing biospecimens." 27
" Ultimately, it may well be that the optimal treatment will be determined
by patient
clinical and biological characteristics." ~ Dr. Bruce Cheson [4]
" As we move to consider these tumors by their genetic
abnormality (genotype) rather than their cellular
appearance (phenotype), one converts the generalities of
leukemia, lymphoma, and myeloma into hundreds of diseases
with distinct genetic causes, clinical manifestations, and
drug responsiveness." 29
Current
 |
Bio-bank Best Practices: Patient
Perspectives on the issue of transfer of tissue for clinical
use –
particularly for use in translational clinical research - PDF
"we may not have fully considered that requests for transfer
of tissue for clinical use could many
times be in harmony with the ultimate objective of achieving
“personalized medicine,” and the oft-stated
principle of “partnering with patients” –
particularly when used to determine eligibility for clinical
trials."
|
 The National Biospecimen Network (NBN)
is a blueprint for progress that will create a national
bio-informatics bank that's accessible to all scientist.
Today, we are still working in the dark against cancer; still testing drugs on ill-defined populations; still
limited in our ability to learn from clinical data
because we don't know why a drug works for some people and not for
others.
From our perspective, standardizing biorepository
networks is as essential to progress against cancer as the power infrastructure is to our economy. Consider the drag on
our society if each company had to generate it's own electric
power in addition
to doing it's primary business.
Key components
(1)
Standardized capture, storage, and analysis of large numbers of annotated biospecimens
(tissue, blood, urine)
- so that research findings are comparable and the results are statistically
powered;
(2) Bio-Informatics software that can store the considerable amounts of
clinical and molecular data, linked to the tissue.
(3) Common data elements, so that
each research group is reporting and describing data using the same terminology.
(4) Data sharing, including publishing
of failed research, so discovery and validation of biomarkers can be
accelerated and resources can be deployed efficiently.
(5)
Privacy protection - to inspire trust,
and ensure participation and continued public funding.
|
caBIG: Power of Connection™ - Dr.
Barker provides a preview. cabig.cancer.gov
The video explores the challenges of cancer research and how
caBIG™
will speed research discoveries and improve patient outcomes by
connecting
the cancer community.
|
The big picture: the purpose of the study, the need for
reliable findings that can be translated into clinical practice, such
as biomarkers that predict response to treatment or toxicity.
I think John Donne's meditation below applies well to clinical science, except that this ideal is rarely met. That is, the success or failure of a therapy is often a page torn out, which does not inform the science - the book we use to guide how to treat others, including ourselves. The same for our biopsy tissue. When it is not properly stored we are wasting precious information that encodes the pathways of the disease, which ultimately provides the context and explanation of the outcome. In an ideal world, every test, treatment, and outcome would inform the science while meeting the clinical needs of the patient.
"All mankind is of one author, and is one volume; when one man dies, one chapter is not torn out of the book, but translated into a better language; and every chapter must be so translated...As therefore the bell that rings to a sermon, calls not upon the preacher only, but upon the congregation to come: so this bell calls us all: but how much more me, who am brought so near the door by this sickness....No man is an island, entire of itself...any man's death diminishes me, because I am involved in mankind; and therefore never send to know for whom the bell tolls; it tolls for thee."
~ John Donne
Why now?
FDA
... the vast majority of investigational products that enter clinical trials fail. Often, product development programs must be abandoned after extensive investment of time and resources. This high failure rate drives up costs, and developers are forced to use the profits from a decreasing number of successful products to subsidize a growing number of expensive failures.
[6]
 Gene expression largely determines how
tumor cells behave: how aggressively or
slowly they will grow, how resistant they are to dying, how and why they
respond to different treatments.
New technologies,
particularly
microarrays, can help to characterize gene expression in
malignant cells, allowing scientists to see what is wrong, and compare
one person's cancer to another's. For the first time in history
we can begin to see what we are trying to fix at a
fundamental level.
"The trick with
molecular targeting is that you have to be able to match the drug to
the patient. And until you understand how the drugs work, why
they work, and for whom they work, your results might not be as
remarkable as you would like for them to be. Once we understand
how to match the drug to the patient, I think we will
see many, many examples like imatinib [Gleevec]."
~ Dr. Brian
Druker, Howard Hughes Medical Institute [2]
The NBN approach to research starts with obtaining fresh frozen
tissue. Importantly, standardized methods of collecting and
testing tumor and normal tissue, open access to the tissue, test results, and associated clinical data will:
| Enable scientist to more rapidly identify the
gene expressions that distinguish normal from malignant cells and
assist in the "development of molecularly targeted therapies
that have specificity and potency for defined cancer types." [1]
|
| Enable scientists to link clinical behavior (how
aggressive or indolent the cancer is likely to be) to gene
expression, and thus better advise patients about treatment
selection and timing. |
The variable clinical course of
patients given the same diagnosis stems, in part, from the
underlying molecular diversity among their tumors. [1]
~ NBN blueprint
Note that the NBN should not represent a challenge to existing systems that are
functioning at high levels. Rather the NBN will incorporate the
"best practices" in existing systems of excellence.
Identifying, developing, and sharing standards for "best
practices" is a process and not an end. Thus, the NBN
blueprint will incorporate new ideas and innovations as they occur. It
will constantly improve and lead to innovations that will make a real
difference.
Briefly, the NBN is a blueprint for creating standards for how to:
| Obtain and store fresh frozen tissue
suitable for consistent molecular analysis |
| Apply disease-specific
cDNA microarrays in order to measure the expression level of
several thousand mRNA, simultaneously in biological tissue,
and conduct tests to validate the tools and the procedures |
|
"Screen for genes
that are differentially expressed between normal and diseased
tissue in order to find novel targets for drug development or to
find new single-gene markers of clinical outcome." 10 |
| Protect donor
confidentially |
| Create an open and usable informatics
data system, which can provide open access to tissue and data - including longitudinal data (case data followed over
time) - thus enabling the correlation of gene profiles with treatment
outcomes |
* Standards is not a "sexy" word, but adopting
standards is the key to
releasing the potential of technologies in any age. The Internet was made possible by adopting
standards (TCP/IP), as are the infrastructures we all take for granted:
electricity, telephone, plumbing, etc.
* Shared and open access means small companies can compete
as well as large. It shifts the advantage from financial muscle to ideas and
creativity. Open access will create productive competition, and capital interest
will be sure to follow. Openness will replace the practice of restricting access in order to gain or
maintain a commercial advantage - buying up DNA patents, for example.
* Importantly, the data obtained from tissue is patient DNA. Thus,
it should not be "owned" by any group. The NBN blueprint cites this basic
fact.
The following is one example of how the NBN approach
can
foster more rapid approval of new drugs. It should be noted that
it's not a futuristic example, as this approach has already been applied to a drug
called Herceptin. A drug that would not have won FDA approval without
rationally selecting patient populations. This according to NBN background text.
And Gleevec is a well-known example of a rationally-developed targeted drug
that has made an enormous impact on patients with CML, a type of
leukemia.
Translational
or targeted drug development and
assessment using NBN resources could go as follows
|
Standardized collection of biospecimens. |
|
Find novel targets using microarrays. |
|
Refine diagnosis and
identify high- and low-risk disease. |
|
Find clinically useful biomarkers by identify correlations between gene expression profiles and treatment responders. |
|
Select the appropriate patients for targeted-phase studies. |
The result is that smaller studies will be needed to achieve statistically significant results, providing relief from the competition for patients.
Fewer patients will be subjected to the toxicity of drugs that cannot help them.
The new favorable circumstances causing increased interest in trials and cancer research among patients, investigators, commercial entities ...
Obviously, it will be best if all
organizations work cooperatively and support broad adoption
and full funding of the NBN blueprint. But it will also help if support
for the idea is expressed by the patient community.
Since, the blueprint is not cancer-specific, the rationale and need should
have broad appeal. Since
cancer affects almost everyone in the long run, it should have broad support
in the general public when they become educated about the potential and
the need.
~ Karl Schwartz
Click
here to comment on the NBN
Resources
-
The NBN blueprint
document: (~226 pages) PDF
(It may take some time for this large document to appear in your browser.)
-
Molecular Targeting in the Treatment of Cancer: An Interview With
Brian Druker, MD Medscape
(free login req.)
Related commentary: See the National
Biospecimen Network
-
Staudt, Gene Expression
Profiling of Lymphoid Malignancies -
Annu.Rev.Med.2002.53:303–18 PubMed
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Advances in the Treatment of Non-Hodgkin's
Lymphoma - Dr. Cheson Medscape
(free login)
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Innovation or Stagnation? Challenge and Opportunity on
the Critical Path to New Medical Products PDF
2004 FDA 2004
-
Molecular Diagnostics
Rita M. Braziel, Margaret A. Shipp, Andrew L. Feldman, Virginia Espina, Mary Winters, Elaine S. Jaffe, Emanuel F. Petricoin III and Lance A. Liotta
asheducationbook.org
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Primer on Medical Genomics Part III: Microarray Experiments and Data Analysis
Ayalew Tefferi, et al. Mayo Clin Proc. 2002;77:927-940 PDF
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Clinical Application of cDNA Microarrays in Oncology ~ Full
text theoncologist.alphamedpress.org/
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Gene expression profiling in Follicular Lymphoma to assess
clinical aggressiveness and to guide the choice of treatment.
Blood. 2004 Sep 2 PMID:
15345589 | Related
abstracts
[2266] Follicular Lymphoma: Design of a
Protein-Based Survival Predictor Using Tissue-Microarrays (TMA).
Session Type: Poster Session 479-II ASH
2004
[1125] Gene Expression Profiling Analysis in Splenic
Marginal Zone Lymphoma Allows To Predict Survival and Histological
Transformation. Session Type: Poster Session 279-I ASH
2004
Scientists Unlocking Lymphoma's Secrets - The
microenvironment accessatlanta
"Genetic differences -- not in lymphoma cells, but in immune
cells surrounding the tumor -- may determine how aggressive a
particular case of follicular lymphoma turns out to be"
Molecular Diagnostics on Lymphoid Malignancies ~ Wing C. Chan, MD; Kai Fu, MD, PhD
allenpress.com
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Study Demonstrates Gene Expression Microarrays Are Comparable
And Reproducible sciencedaily.com
"A study funded by the National Cancer Institute, part
of the National Institutes of Health, shows for the first time
that microarray data generated in different laboratories can
produce highly comparable results. For this comparison study,
appearing in the Jan. 15, 2005, Clinical Cancer Research*, four
separate laboratories analyzed gene expression (whether genes are
turned on or off) for the same set of human tumor tissues.
Overall, the expression profiles of portions of individual samples
were highly comparable, and the experimental correlation between
separate labs was only slightly lower than correlation of
duplicated experiments within the same labs."
-
Researchers Use Novel Technology To Extract RNA From
Archive
Formalin-fixed Paraffin-embedded Tissue sciencedaily.com
"Recent advances in both laser-capture microdissection (LCM)
technology and microarray technology have revolutionized our
investigation of the genetic basis of human cancer," ...
"Pure cell populations can now be isolated ... and evaluated
for changes in gene expression that accompany the development of
cancer. However, applying these techniques to archived clinical
specimens has been limited by our inability to extract
high-quality genetic material from routinely processed clinical
samples."
-
How patients can help accelerate advanced tissue-based
research http://biospecimens.cancer.gov/
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Improving Diagnosis and Treatment of Lymphomas with Gene
Expression Profiling hematology.org
Joseph M. Connors, M.D.
"Major new insights into the biology of lymphomas have
resulted from the use of microarray gene expression technology to
elucidate their underlying biology and to identify novel pathways
for therapeutic intervention."
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Biobank Central biobankcentral.org
BioBank Central aims to describe the
activities of modern biobanks in all their breadth, ranging from
the absolute requirement to protect the interests of patients and
healthy volunteers who choose to donate samples and data, to the
critical role of these biorepositories in enabling modern
biomedical research.
-
caBIG: Power of Connection™ - Dr.
Barker provides a preview. cabig.cancer.gov
The video explores the challenges of cancer research and how
caBIG™
will speed research discoveries and improve patient outcomes by
connecting
the cancer community.
-
caIMAGE:
Enabling Standardization and Collaboration cabig.cancer.gov
Greater reliance on imaging in clinical care and biomedical
research, the current structure of clinical studies, and other
advances in technology have led to an enormous increase in the
quantity and complexity of cancer imaging data. Despite this
increase, however, there is little standardization of protocols
used to acquire, analyze, and annotate images among cancer centers
and other research facilities.
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GenePattern - Integrated
Genomics - now a part of caBIG cabig.cancer.gov
One feature unique to GenePattern is the ability to track the
different steps that a researcher takes when analyzing a set of data.
These computational and research steps, known as a “pipeline,” are
stored along with their parameters on the GenePattern server.
Researchers with access to the dataset can request that the same
analytical steps, or “pipeline,” be repeated and/or combined with
other pipelines. Reproducibility, an essential feature of many
successful research projects, can be easily accomplished using
GenePattern. Also, the ability to string together pipelines opens the
door to new discoveries by enabling the exploration of increasingly
complex hypotheses.
-
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Modernizing
Cancer Research PAL PDF
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Tissue preparation (devil in the details)
www.nature.com
According to experts, there are more than a billion tissue samples
archived in hospitals and tissue banks around the world, most of
them formalin-fixed and paraffin-embedded (FFPE). Today, these
samples present both an incredible opportunity and a huge
challenge to researchers. FFPE tissue samples have been
extensively annotated and well preserved, allowing detailed study
of the progression of diseases such as cancer. But due to the
method of preservation, obtaining biomolecules from these samples
is proving difficult, to say the least.
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Biobanking of fresh frozen tissue: RNA is stable in nonfixed
surgical specimens www.nature.com
| PDF
Our data indicate that nonfixed tissue specimens may be
transported on ice for hours without any major influence on RNA
quality and expression of the selected genes. However, further
studies are warranted to clarify the impact of transport logistics
on global gene expression.
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