Download National Centers - ナショナルセンター・バイオバンクネットワーク

疾患コホートを基盤とするナショナルセンター・
バイオバンクネットワーク（NCBN）の構築
National Center Biobank Network (NCBN) by an
Alliance of 6 National Centers in Japan for
Clinical Information-intensive Patient Cohort Research
中釜 斉
Hitoshi Nakagama
National Cancer Center Research Institute, Tokyo
#1
Six Mission-oriented National Centers
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National Cancer Center (NCC) 国立がん研究センター
National Cerebral and Cardiovascular Center
(NCVC) 国立循環器病研究センター
National Center of Neurology and Psychiatry
(NCNP) 国立精神・神経医療研究センター
National Center for Global Medicine
(NCGM) 国立国際医療研究センター
National Center for Child Health and
Development (NCCHD) 国立成育医療研究センター
National Center for Geriatrics and Gerontology
(NCGG) 国立長寿医療研究センター
History, Vision and Mission
of the National Cancer Center
History
Established in 1962; longest history among the
National Centers
Visions
1.Provide state-of-the-art cancer treatment and
conduct world-class clinical research
2. Make policies from patients' perspective
Missions
1. Research and prevent the incidence of cancer
2. Develop highly-advanced and pioneering
medical technology
3. Promote standard medical care
4. Collect and provide information
5. Develop human resources
6. Propose policies
7. Contribute internationally
2010年4月現在
NCC builds nation wide cancer-care
network as the center of the hospitals
National Cancer Center
Prefectural Designated Cancer Care Hosps--51
District Designated Cancer Care Hosps---346
Build a clinical support system
for the Prefectural + District-Designated
397 Cancer Care Hospitals in Japan
Research and Development
Initiative Center
Hospital
Prevention and Therapy
Myocardial Infarction
Stroke
Heart Failure
Hypertension
Hypercholesterolemia
Familiar Arrhythmia
Cardiomyopathy
Aortic Aneurysm
Peripheral Vascular Disease
Pulmonary Hypertension
Congenital Heart Diseases
Copyright © 2012 SAS Institute Inc. All rights reserved.
Research institute
Translational Medicine
Clincal Reseach
Adrenomedullin/Perip
heral Monocyte
Therapy to PVD
Left Ventricular Assist
System
Basic Research
Bioscience and Genetics
Biochemistry
Molecular Physiology
Molecular Pharmacology
Cell Biology
Molecular Pathogenesis
Genomic Medicine
Vascular Physiology
Cardiac Physiology
Molecular Innovation in Lipidology
Artificial Organs
Cardiovascular Dynamics
Biomedical Engineering
Biomedical Imaging
Regenerative Medicine
Copyright © 2012 SAS Institute Inc. All rights reserved.
“Lifestyle and Diseases”
Copyright © 2012 SAS Institute Inc. All rights reserved.
Biobank Project at National Centers
#9
Current Major Cohort and/or Biobank Projects in Japan
Prevention
Diagnosis and Treatment
・Therapeutic
development
・Personalized
medicine
Population-based cohorts
Patient cohorts
Tohoku Medical
Megabank
・Stress cohort of the
residents of the arch 2011
Quake and Tsunami area,
incl. trio birth cohort
・approx. 150K (plan)
・JPHC、
・J-MICC
・Nation-wide populationbased cohorts
・approx. 100K
・Nagahama 0th
prevention cohort
・Hisayama cohort
・Local community cohorts
・approx 10K
Biobank
Japan
・Nation-wide community hospitals, university hospitals.
・47 diseases, approx 300K cases by approx 200K patients
・Blood samples, predetermined list of clinical information
・(Mostly) distribution-type biobank
National
Center
Biobank
Network
（NCBN）
・Centers for Highly Advanced and Specialized Medical Care
・Incl. diseases and subtypes relatively few in BBJ
・Blood and pathological tissue specimens with rich
longitudinal clinical information
・(Mostly) collaboration/ contract-research biobank (cluster
of the disease specialists, focused research and clinical
trials）
Rare dis.
bank
・Specific rare and intractable diseases
#10
Two Types of Patient Banks：①Different Stages in Clinical Care
Community and General
Hospitals
all over Japan
Development of Personalized
Medicine in the standard best
daily clinical practice
BBJ
National Centers
(NC)
Research on disease
etiology and
pathogenesis,
development of
innovative diagnosis and
treatment beyond
standard practice
NCBN
#11
Two Types of Patient Bank：②Different Major Target
Omics analyses of disease NCBN
tissues
(incl. infected blood)
Identify disease-specific therapeutic action point
(Achilles heel)
Development of novel therapeutics to target the Achilles heel
Genomic analysis of
heritable traits
(normal cells)
BBJ
Individualization of existing treatment
Personalized prevention of disease development and
progression
#12
Biobank 1) Generates and 2) Validates Hypotheses of Medical Innovation
Generation
of novel
drug seeds
Biobank
• NC researchers
• Researchers in academia/ industrial sectors
Validation
and
prioritization
of seeds
• Outside NC
Drug R&D theme/ seeds
#13
Biobank
at National Cancer Center
#14
Chronology of the NCC Biobank (Part 2)
1995
1994
1999/5
2000
2005
2011/5
2002/1
(Former)
Prototypical
biobank started
in Pathology Div
IC for "medical
research use" of
left-over samples
from surgery
2010
2002/10
Banking
of leftover
serum/
plasma
Broad consent
2004/1
 +Research blood
"New"
Hospitaldrawing
Broad
based
 +Germline Consent
cancer
registry
analyses
2010/4
 Change to Opt-in
Independet
Administrative
Agency
2001/4
Ethical Guidelines for Human
Genome/Gene Analysis Research
#15
#16
Frozen Tissue Sample Division in the NCC Biobank (Tsukiji Campus)
Biobank
Pathology Division
Routine work by pathologists
–macroscopic examination
Research
Group
Snap-frozen in LN2
Pathologists,
clinicians
Surgically resected specimen
Viable tissue is taken by
pathologists avoiding
disadvantage for pathological
diagnosis
Filing by the organs
Researchers
Security system
Catalogue database
液体窒素タンク計10台現有
現在1台/年ペースで増設
 Current inventory (as of 9/30/2012)
12,700 cases/ 50,351vials
 FY 2011
・In: 1,457 cases/ 7,694 vials
・Out: 778 cases/ 1,421 vials
Institutional
Review Board
#17
Germline specimens
Ⅰ. PGt: Prediction of AE and effectiveness
Ⅱ. Cancer susceptibility and risk assessment
Ⅲ. Paired control for somatic genomic analyses
Hospital-based
Cancer
Registry+
Clinical Div DB
Patient cohort biobank
Various hypothesis
generation and testing
Ⅳ.Characteristic changes of cancer tissues
 Pathogenesis and pathophysiology
Somatic  New classifications and subtypes
 Mol target for diagnosis
specimens
Cancer tissues − Relapse/ progression risk diagnosis
Serum/ Plasma − Early detection of primary and relapse
− Prognostic/ predictive markers
 Body fluids
(ascites, etc.)  Mol target for treatment
Ⅴ. Model and assay development
#18
Workflow of Translational Research by
Utilizing Biobank Resource at NCC
Target
Identification
Seed
Compounds
Basic Research
Library
HTS, CADD
Lead
Compound
s
Medicinal
Chemistry
Biobank
Resource
Research Institute
Pathology Div
Preclinical
Clinical Trials
PK, PD
Tox, CMC
Phase I,II,III
Biobank
Resource
Res. Inst.
Pathol Div.
Pharmaceutical
Company
Commercialization
Patient
Hospital
Pharmaceutical
Company
Examples of Therapeutic (left) and Diagnostic (right) Development
Involving Patient Samples/ Information: NCC
Research Theme
Clinical development of Arctium lappa
extract GBS-0
(Patent pending, Kracie Holdings, Ltd.)
Clin dev of RPN2-siRNA therapeutics for
breast cancer stem cells
(Pat pend, 3D Matrix, Bonac）
Drug Target
Identification
Search
Seed
Lead
Preidentifi- optimizaclinical
caton
tion
Clinical
P1
P2
P3
Research Theme
Search
Methodology
Clinical
Identifi-cation development Development
Commercialization
Lung cancer clinical diagnostic marker
ProGRP
(Patented, Advanced Life Science Inst.)
Diagnostic marker TSLC1
(Patented, Johns Hopkins Univ)
Dev of RET inhibitors and companion
diagnostics (Pat pend, Company D)
Dev of diagnostic marker for pancreatic
cancer (Patented, Company A)
Clin dev of miRNA therapeutics for
osteosarcoma (Pat pend, Company E)
Prognostic marker for esophageal
cancer (Patent pending, Company B)
Dev of small molecule inhibitor of kinase
A (Pat pend, Compnay F)
Development of companion diagnostics
of kinase inhibitors (Pat pend)
Dev of miRNA therapeutics for durg
resistant cancers #1
(Pat pend, Company G)
Dev of miRNA therapeutics for durg
resistant cancers #2
(Pat pend, Company H)
Dev of cancer diganostics by DNA array
(Pat pend)
Dev of diagnostic marker for lung cancer
(Pat pend, Company C)
Dev of cancer pain control drug
(Pat pend)
Dev of prognostic marker for ovarian
cancer (Pat pend, Company D)
Cancer stem cell therapeutics by
antagonist B (Pat pend)
Dev of clinical diagnostics by DNA
methylation analysis (Company E)
Screening of small molecules by cancer
model mice (Company I)
Dev of prognostic evaluation method for
esophageal cancer
(Pat pend, Company F)
Search for inhibitors of cancer related
factors (Company J)
Blood biomarker for cancer
(Pat pend, Company G)
Search for inhibitors of siganling pathway
C (Company K)
Diagnostic Target
“Therapeutic”
Diagnostic method for colorectal cancer
(Pat pend, Company H)
Dev of anticancer agents #1
(Research Institute A)
Identification of novel fusion gene
(Pat pend)
Dev of anticancer agents #2
(Research Institute B)
Dev of early detection method for
pancreatic cancer by duodenal fluid
Search for inhibitors of cancer related
molecules (Company K)
Dev of prognostic prediction for
hepatocellular carcinoma (Pat pend)
Dev of anticancer agents to target
pathway C (Research Institute C)
Dev of prognostic prediction for renal
cancer (Pat pend)
Screening of compounds to target
cancer stem cells (Research Institute D)
Dev of blood miRNA marker
(Pat pend, Company I)
Screening of anticancer agents
(Research Institute E)
Search for biomarker
(Companies J, K, L and M)
Generation of anticancer agents targeting
cancer related molecules
(Universities A and B)
Dev of exsosome miRNA marker
(Company N)
Dev of sensitizers of radiochemotherapy
(Company L)
Identification of miRNA for diagnosis and
treatment of oral cavity cancers
(Company O)
Search for anticancer compounds to
target pathway D (Company D)
Search for miRNA marker for prostate
cancer (Company P)
Dev of antibody therapeutics against
cancer related proteins (Company N)
Search for biomarkers by proteomics
(Companies Q, R, S, T, U and V)
“Diagnostic”
Dev of anticancer agents to target
kinases (Company O)
Analysis of cancer receptor signaling and
application for drug development
(Research Institute E)
Search for biomarkers by proteomics
(Company P)
Blue: Patent pending or patented
Red: Collaborative contract with an industry
#20
Biobank Projects
at Other National Centers
#21
Research and Development
Initiative Center
Research institute
Hospital
Bio resource
Frozen Tissues
Fixed and Embedded Tissues
Plasma
Serum
DNA
Lived Cells
Data resource
Data Base
Analysis System
Dissection
Tissue
Data Analysis
Hospital
Cohort
Descriptive
Statistics
Clinical
Research
Data Search
FileMaker etc
MySQL (DB)
SAS
Windows
Linux
Windows
Electrical Data Capturing
Myocardial Infarction
Stroke
Heart Failure
Hypertension
Familiar Arrhythmia
Cardiomyopathy
Aortic Aneurysm
Hypercholesterolemia
Pulmonary Hypertension
Congenital Heart Diseases
Virtual Operating System (VMware ESX)
Copyright © 2012 SAS Institute Inc. All rights reserved.
Infrastructures for
Clinical and Basic
Study of
Cardiovascular
Diseases
Archive Library
of
Cardiovascular
Diseases
NCGG-Biobank
The Biobank of National Center for Geriatrics and Gerontology
Biobank Bldg.
BioResorces
Clin. info
samples
NCGG.Hosp.
◇Dementias
◇Bone and Joint Diseases
◇other geriatric diseases
◇Medical Checkup
Clin. Info.
BioResources
（Blood, Tissues, etc）
NCGG
Research Inst.
data
IC
The building is near its completion!
◇Omics data
◇Cohort studies
Biobnak
Collection:
Alzheimer’s disease (AD),
Mild cognitive impairment (MCI),
Non-AD neurodegenerative diseases,
Lumbar spine scoliosis (LSS),
osteoarthritis, etc.
Raw data
Residual samples from studies
Sample type:
DNA, RNA, Buffy coat, Plasma,
Serum, Cerebrospinal fluid, Bone,
Joint cartilage, ligament, urine
info
IC (informed consent)
Database
User
repositry
sample
Integrated, Multi-layered Medical Omics Analyses
by an Alliance of Six National Centers
Integrated, Multi-layered Medical Omics Analyses
Reaching single pathway
by integrative omics
Reaching single
gene/locus by integrative
omics
e.g. 3-layered candidate
of drug target
Candidates from single omics
(many false positives)
Each single omics analysis
e.g. 5-layered candidate
of drug target
#25
Medical Omics Analyses Alliance
NCNP
NCGG
NCCHD
1） Biobank and
detailed clinicopathological info DB
Academia, industries
NCVC
Selected clinical info
and samples
NCGM
Drug
development, etc
NCC
Data
Samples
3）Validation,
biological analyses
and prioritization
4）Integrated DB
Genome
Metabolome
Epigenome
2）Omics analysis cores
Proteome
Transcriptome
Data for
public
DB
Central
BB/DB
Drug development is an
integrated science and
may consider various
action points, which
needs an omics
approach.
#26
NCC Biobank→NiBio Integrated Omics Project→MHLW grant IIT
Cancer Tissues
from Biobank
Novel fusion gene
of Lung AdC: KIF5B-RET)
Deep sequencing
(RNAseq)
DNA
RNA
Informatics
pipeline
RET kinase
inhibitors
RET fusion
protein
Kohno T, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med 18:375-7,
2012. A collaboration between NCC and NCGM
 A versatile multipurpose
infrastructure
unable to sustain
by competitive
short-term grants
 Deep & real-time
clinicopathological
information
beyond the
management of
private sectors
 Development of companion
diagnostics
 Investigator Initiated Trial or
other registration trial
5/29/2012 Nihon Keizai Shinbun
#27
Genome-Wide DNA Methylation Analysis in Renal Cell Carcinomas
Quality tissue samples and detailed clinicopathological information
Identifying genes which can
discriminate both clusters
Disease-free survival (%)
Nephrectomy
specimen
Noncancerous
renal tissue of
RCC patients
Renal tissue at
Normal renal
precancerous stages
tissue
Favorable
outcome cluster
【Practical application of prognostication】
Prognostic indicators: DNA methylation
status of 18 CpG sites
Chromosome
8
5
19
4
・・
19
P=4.16×10-6
Poor-outcome cluster
(CpG island methylator
phenotype: CIMP)
Position
53,478,454
178,422,244
38,042,472
188,916,867
・・
58,238,928
Gene
P-value
FAM150A 4.60×10-12
3.84×10-11
GRM6
ZNF540 3.64×10-8
9.91×10-8
ZFP42
・・
・・
ZNF671 1.98×10-6
Patent application: May 12, 2012 (61/646,044 )
Time after surgery (days)
Renal cell
carcinoma
Cluster showing
poorer outcome Cluster showing favorable outcome
Multilayer-omics analysis
Merge with the results of genome (exome),
transcriptome and proteome analyses
Epigenome profiles
Epigenome analysis
Infinium HumanMethylation27 Bead Array
Evaluation of DNA methylation status on 27,578
CpG sites with single CpG resolution
Unsupervised hierarchical clustering using
probes showing DNA methylation
abnormalities even from precancerous stages
Identification of disease subtypes
associated with aggressive
clinicopathological parameters and
accumulation of DNA hypermethylation
on CpG islands
=Driver mutation of CIMP and effector
genes determining malignant potentials of
tumors are being explored
【Identification of therapeutic targets】
In silico analysis
National Center Biobank Network (NCBN)
#30
National Center Biobank Network (NCBN)
Enterprise of clinical-platform improvement for next-generation medical treatment
Central Biobank Secretariat
(Catalog database release +
contact function)
Application of sample use
from industry-academicgovernment researchers
Establishment of a federation-type network by use of 6NC’s common platform
Disease name
record
National Cancer Center
Cancer-related
Biobank DB
Shared interview sheet
for medical examination
Ethics review board
National Cerebral and
Cardiovascular Center
Cardiovascular
disease-related
Biobank DB
Collection and
management of samples
National Center for
Neurology and Psychiatry
Psychoneurotic &
neuromuscular
disease-related
Biobank DB
National Center for
Global Health and
Medicine
Infectious diseases,
metabolic disorder,
immune disorderrelated Biobank DB
Related
procedures
Standardization and sharing of
things mentioned in the left
columns
National Center for Child
Health and Development
National Center for
Geriatrics and
Gerontology
Growth diseaserelated Biobank
DB
Geriatric diseaserelated Biobank
DB
The disease-specific network construction harnessing the NC’s expertise is examined.
(It works together through catalog-based database, storage of samples, etc.)
(collaborating hospitals, etc.)
(collaborating hospitals, etc.)
(collaborating hospitals, etc.)
(collaborating hospitals, etc.)
(collaborating hospitals, etc.)
It is planned that the biobank network with collaborating organizations is extended step by step.
(collaborating hospitals, etc.)
6NC President Meeting
6NC Biobank Management Conference
NC Central Biobank (practice organization)
Secretariat
(NCGM)
Central Ethics
Support Sector
Central DB
Management Sector
Working Group (preparation organization)
Working Group leader
meeting
Ethics Review
Working Group
Information Interface
Working Group
Information DB
Working Group
Joint Research
Arrangement Sector
DB: database
Sample Handling
System Working Group
Bio-resource
Infrastructure
system
Method of
analysis
Medical / epidemiological information
Serum / plasma
Comprehensive analysis
of molecular pathogenesis
(Omics analysis)
Peripheral blood
mononuclear cells
（PBMC）
Data server
Return ● whole-genome SNP
● transcriptome
● epigenome
Practical use
purpose
Life sciences
academic research
Drug discovery
Search for seeds
● proteome
● whole-genome
DNA
sequence
Biobank Information System
Drug discovery
Biomarker
development
Sample storage facilities
adaptable to
high-throughput system
Drug discovery
Evaluation of in vitro
efficacy (toxicity)
BIS
Formalin-fixed, paraffinembedded tissue
(FFPE)
Lymphoblastoid
cell line (LCL)
iPS cells
Others
e.g., animal disease
models
Sample processing
(e.g., iPS cells preparation)
Frozen tissue
Protein
science
● analysis of
structure
● analysis of
function
(antibody drug)
Genetic
engineering
● siRNA
Cell
technology
Development of new
diagnostic method
Individualized
medicine
Proactive / preventive
medicine
2011
Ethics
2012
2013
Create explanation/
IC document
2014
2015
2016
Obtain a comprehensive informed consent by 6NC shared format
Work to structure network
Structure a shared platform
Make the shared
interview sheet and
disease-name record
Data
Review an
anonymization system
Review the state of catamnestic follow-up
Maintain each NC’s system
Implement the catamnestic follow-up
Refurbish each NC’s system
Standardize the way of sample
collection and maintenance
Bioresource
Start to distribute bio-resources collected and managed, and standardized among
6NC
Review the state of a shared
platform
Review the sample transfer
procedure and joint research
agreement
Investigate
samples held
at each NC
Support
system
Create database &
release β-version
Collect and manage bio-resources at each NC
Consider depositing some bio-resources to the Central
Biobank of 6NC network
Implementation of
research application
Start the research that utilizes bio-resources collected at each NC
Cooperation with
other organizations
Scheduled
Release and manage database via HP
Organize 6NC Central Biobank
Secretariat function
Collection and
management of bioresources
Started
Structure 6NC’s information-network and manage the shared platform
Consider the way of cooperating
with Tohoku Medical Megabank, etc.
To do
Cooperate with Tohoku Medical Megabank, etc.
Biobank 1) Generates and 2) Validates Hypotheses of Medical Innovation
An NCC example: number of patent filings
and/or on-going collaborations with
industries for a purpose of specific drug R&D
●Therapeutics・・・ 17
●Diagnostics・・・ 21
Generation
of novel
drug seeds
Biobank
• NC researchers
• Researchers in academia/ industrial sectors
Validation
and
prioritization
of seeds
• Outside NC
Drug R&D theme/ seeds
#35
An Image: Genomic Biomarker-driven Targeted Therapy Trial
by Multi-Pharma Consortium
① Systematic survey and validation of driver mutations in each cancer case
IC on whole ①+②
scheme to the patients
Image-guided
w/o standard
research biopsy, etc.
therapeutic option
Genome screen followed
by validation on minute
clinical materials
② Clinical trial targeted to the identified driver mutation
Report of results
On-going clinical trials at NCC
Industry-sponsored clinical trial on
Compound X (Phase I, II, III)
②A：Gene A
alteration
IIT or "Highly Advanced Medical
Technology Assessment System"
on Compound Y (Phase I, II)
②B：Gene B
alteration
②C：Gene C
alteration
Multidisciplinary
Sequencing Tumor
Board
IC of available clinical trial
Clinical trial for indication
expansion of Drug Z
#36
Two Types of Patient Banks: BBJ and NCBN
Community and General
Hospitals
all over Japan
Development of Personalized
Medicine in the standard best
daily clinical practice
BBJ
National Centers
(NC)
Research on disease
etiology and
pathogenesis,
development of
innovative diagnosis and
treatment beyond
standard practice
NCBN
#37
BBJ and NCBN：Connect Each Strength in Series #1
●BBJ：A powerful genome-wide screen based on its large sample size
Disease A
OR=1.2
●NCBN：In-depth personalization based on detailed clinico-pathological i
Sub type A1
Subtype A2
Subtype A3
Subtype A4
OR=1.0
OR=2.5
OR=1.1
OR=0.9
#38
BBJ and NCBN：Connect Each Strength in Series #2
● BBJ：A powerful genome-wide screen based on its large sample size
● NCBN：Analysis of the functional involvement of the
genes and/or pathways in the pathology of the
disease and explore therapeutic/ diagnostic target
● Drug
development by an
academia-industry
collaboration
#39
BBJ and NCBN: Connect Each Strength in Parallel
Biopsy
IC to Patient A
1
Expression profile #1
.8
e.g. Transcriptome
analysis of cancer tissue
Survival
Prediction of
Response
.6
.4
Expression profile #2
.2
0
0
500
1000
1500 2000
2500 3000
3500
Days
Peripheral
blood
Prediction of
ADR/ side effect
Biomarker-based prediction
to maximize therapeutic
response and minimize ADR
for Patient A
e.g. Germline polymorphisms
Choose this!
#40