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The Children’s Brain Tumor Tissue Consortium

Annual Report 2015 CBTTC Operations Center

The Children’s Brain

Tumor Tissue Consortium

Annual Report

Acknowledgments

The Consortium enrolled its 1500th subject in 2015 and is

expected to reach 3000 unique tissue specimens during the 2nd

quarter of 2016. These achievements are the result of the hard work

and dedication of the CBTTC Institutional Members at The

Children’s Hospital of Philadelphia (CHOP), The University of

Pittsburgh Children’s Hospital, Seattle Children’s Hospital, Lurie

Children’s Hospital in Chicago, Meyer Children’s Hospital in

Florence, Italy and the dedication and support of the Children’s

Brain Tumor Foundation, the Licensing Industry Merchandisers’

Association, countless volunteers and dedicated donors. The

commitments of these partnerships and others being forged will

only further ensure the shared vision to identify better testing,

treatments, and outcomes for children diagnosed with these

devastating diseases.

Growth of the Repository

Enrollment

In 2015, three additional institutions were approved by the

CBTTC Executive Committee to join the consortium. Two as

primary members, The UCSF Benioff Children’s Hospital led by

Sabine Mueller M.D., Ph.D. and Joanna Phillips M.D. and The

Lucile Packard Children’s Hospital at Stanford led by Michelle Monje M.D., Ph.D. Gerald

Grant M.D., FACS, and one new satellite member, The Bristol-Myers Squibb Children's

Accelerating

Pediatric

Brain Tumor

Research

‘The CBTTC is a

collaborative

research program

dedicated to

improving prognostic

testing, treatments

and outcomes for

children diagnosed

with these

devastating

diseases’

Hospital at Robert Wood Johnson University Hospital led by Dr. Wilbur Pan. We are

extremely excited to welcome these institutional leaders in the field of pediatric brain

tumor community research.

The 2015 calendar year has seen substantial advances in the CBTTC clinical database,

specimen numbers, and histological diversity within the repository. 2015 also

represented our focus on prospectively enrolling subjects within the CBTTC.

Current enrollment numbers are represented in Table 1 below.

Table1. Enrollment by Site To Date*

CBTTC Subject

Site Totals

CHOP 881

Seattle 288

PITT 105

Lurie 328

Meyer 95

East Tennessee** 1

Total 1698

*Clinical Database Subject Numbers as of January 2016

**One time specimen transfer

Specimens

The CBTTC Operations Center (OC) at CHOP received over 600 specimens from CBTTC

member institutions’ subjects during this reporting period including frozen tissue,

cerebral spinal fluid, and blood from the children and their parents as detailed in Table

2 below. All sites will continue prospective enrollment and, per the CBTTC Constitution,

our goal is to submit 75% of all brain tumor cases to the CBTTC OC. In 2016, our efforts

to obtain parent samples for genomic analysis will be facilitated by the use of saliva

samples. The method is less invasive and logistically more convenient for parents to

contribute to the research process. The saliva kits will be readily available in each clinic

at each consortium site and can be taken home and returned via mail as well.

Table 2. Specimen Inventory Submitted by Site and Specimen Type in 2015 (Specimens are totaled by aliquot – multiple aliquots for one collected date equal 1; all received in 2015)

CBTTC Blood Blood Blood CSF Tissue Tissue

Site Child Maternal Paternal Child Flash Frozen Freezing Media

CHOP 83 0 0 12 78 45

Seattle 80 0 0 6 53 3

PITT 5 0 0 0 13 0

Lurie 52 0 0 12 89 8

Meyer 53 0 0 0 54 32

Total 273 0 0 30 287 88

Histological Subtypes

There are over 28 different histological subtypes within the CBTTC repository. As we

receive more specimens and subtypes, the clinical data is regularly reviewed to update

the repository status. The objective of the CBTTC is collect all pediatric brain tumor

subtypes to provide the largest and most comprehensive repository of specimens. The

volume of available specimens along with the clinical annotations are provided in real

time on the CBTTC Clinical Data and Specimen Repository Portal. The portal can be

accessed via this link https://eig.research.chop.edu

New users must register for access which is received by the CBTTC Operations center for

approval.

The graph below identifies the type and number of diagnoses within the database and

provides an up-do-date snap shot with the real time specimen counts available on the

CBTTC Clinical Data and Specimen Repository Portal. The count represents numbers of

individual diagnoses per subject. For example, if a subject has an initial diagnosis of

Medulloblastoma and a recurrent diagnosis of Medulloblastoma, this is counted twice.

0 100 200 300 400 500 600 700

Gliomatosis Cerebri

Langerhans Cell histiocytosis

Neurocytoma

Chordoma

Malignant peripheral nerve sheath tumor (MPNST)

Pineoblastoma

Non-germinomatous germ cell tumor

Teratoma

Adenoma

Germinoma

Dysplasia/Gliosis

Oligodendroglioma

Choroid plexus carcinoma

Choroid plexus papilloma

Schwannoma

Neurofibroma/Plexiform

Metastatic secondary tumors

Dysembryoplastic neuroepithelial tumor (DNET)

Brainstem glioma- Diffuse intrinsic pontine glioma

Meningioma

Atypical Teratoid Rhabdoid Tumor (ATRT)

Craniopharyngioma

Supratentorial or Spinal Cord

Ganglioglioma

Medulloblastoma

High-grade glioma/astrocytoma (WHO grade III/IV)

Ependymoma

Low-grade glioma/astrocytoma (WHO grade I/II)

Histological Subtypes

Focused Working Groups

Due to the CBTTC’s unprecedented growth, we identified a need for focused working

groups within the consortium. The first to launch was the Clinical Working Group,

developed and led by Dr. Angela Waanders. The group is composed of clinicians,

within and outside of the consortium as well as CBTTC clinical research coordinators

and is tasked with evaluating the clinical data that will be collected by the CBTTC and

providing these recommendations to the Executive Board and Scientific Committee for

review. The Clinical Working Group meets monthly by conference calls to determine

recommendations. The initial set of changes included, but wasn’t limited to, updates to

the list of tests performed in pathology and clarifications to treatment data, such as

radiation sites and dates of radiation and/or chemotherapy. Those recommendations

have since been approved and implemented. Moving forward, the group will continue

its efforts to ensure standardization and evaluation of the CBTTC clinical data models.

This will position the CBTTC to continually support robust longitudinal clinical data

annotation of the repository.

The Coordinator Working Group was also initiated in 2015 to address the workflow

complexities we are encountering in this multi-institutional effort. The Coordinator

Working Group is led by Emily Golbeck, Clinical Research Coordinator at the Ann and

Robert Lurie Children’s Hospital of Chicago. Early initiatives partnered Emily directly with

the CBTTC Operations Center informatics teams to improve the clinical data collection

informatics portal. This group meets monthly to address issues around standard

operating procedures, best practices, guidelines feasibility, efficiency, and quality

control. The Coordinating Working Group’s finding are communicated as

recommendations to the CBTTC Executive Board. We look forward to the additional

finding from this group to ensure the continued operational success of the CBTTC.

Looking forward, a Pathology Working Group will be created in 2016 to bring together

the pathology expertise among the consortium members, create a more robust central

pathology review of the specimen received by the repository, continue work on

standardization of pathology practices and nomenclature, and provide new platforms

for research such as tissue microarrays (TMA). The pathology working group will be led

by Dr. Ron Hamilton, Associate Professor of Neuropathology at Pittsburgh Children’s

Hospital. This group will work with the BioInformatics group at CHOP and an outside

vendor, Blackfynn, to also create a web-based pathology portal space for the CBTTC.

We anticipate that this will facilitate the sharing of digital images for pathology central

review with real-time collaborative opportunities within the consortium members.

Scientific Projects

A primary objective of the CBTTC is to provide high-quality biospecimens annotated

with clinical and genomic data to facilitate and advance childhood brain tumor

research. Investigators do not have to be part of the CBTTC to submit a scientific

proposal to the CBTTC Scientific Committee. If the Scientific Committee approves the

proposal, materials are provided without charge to that investigator on the condition

that all data generated will be shared with the CBTTC. Scientific proposals can be

submitted at any time and are evaluated as soon as they are received. The current

time from approved scientific proposal to release of specimens by the CBTTC

Operations Center is less than one month and is expected to be faster once a new

automated request system is launched in 2016. The process follows a review of the

project proposal by the scientific committee along with a detailed report of the

specimens being requested. In this way, the committee can evaluate the use of the

very limited specimens to maximize their use. Additionally, a rigorous quality control

check is done on the clinical data and the specimens before scientific committee

review and release of the materials. To maximize specimen use, the CBTTC will provide

the DNA and/or RNA extractions from the requested tissue rather than releasing the

primary tissue specimen itself. This approach maximizes and conserves valuable

specimens for future studies. DNA and RNA extractions are done by the Biorepository

Core at the Children’s Hospital of Philadelphia to ensure standardization unless there is

an overriding scientific rationale that mandates processing by a outside facility.

Genomic sequencing may be performed at CHOP by the Sequencing Core Facility

(BGI@CHOP) or at a facility identified by the investigator. To date, 56 whole genomes

and 50 RNA profiles have been sequenced.

Currently, the CBTTC is supporting five pediatric brain tumor research projects.

Project 1. Genomic Investigation of Gangliogliomas. This study, funded by the Voices

Against Brain Cancers Foundation, characterizes the genomic landscape of

gangliogliomas by whole genome sequence analysis of 8 matched tissue/blood

samples. Principal Investigator: Adam Resnick Ph.D. Assistant Professor of Neurosurgery

at The Children's Hospital of Philadelphia

Project 2. Genomic Investigation of Craniopharyngiomas. This project, a joint effort

between investigators at CHOP, The University of Pennsylvania, and the Dana Farber

Foundation. Seeks to identify the genomic characteristics of craniopharyngiomas by

means of whole genome sequencing of 5 matched pairs of tumor/blood, whole exome

sequencing of 7 tumor/blood, and targeted sequencing of 30 additional formalin fixed

paraffin embedded craniopharyngioma samples. Principal Investigator: Adam Resnick

Ph.D. Assistant Professor of Neurosurgery at The Children's Hospital of Philadelphia

Project 3. Genomic Evaluation of Malignant Pediatric Cortical Tumors. This is the first

research project launched by a CBTTC member site that uses CBTTC specimens and

clinical data. Dr. Sarah Leary, Associate Professor of Pediatrics at Seattle Children’s

Hospital aims to describe genomic alterations and tumor subtypes within a large cohort

of well-characterized supratentorial malignant pediatric brain tumors. The goal of this

project is to evaluate the association between genetically determined subtypes and

standard clinical factors such as histology, location, metastatic status, and survival. In

collaboration with Dr. Angela Waanders, Assistant Professor of Pediatric Oncology at

Children’s Hospital of Philadelphia and Dr. Annie Huang, Associate Professor of

Pediatrics from Toronto Hospital for Sick Children.

Project 4. Whole Genome Sequencing of Medulloblastoma. This study, led by Dr. Tom

Curran while at the Children’s Hospital of Philadelphia, is designed to genomically

characterize a subsets of medulloblastoma tumor specimens tumors either express or

do not express Gab1 or Nestin as determined by Tissue Microarray staining. Dr. Curran

will continue this work as he takes his new position as the Chief Scientific Officer and

Executive Director of the Children’s Mercy Hospital Research Institute at the University of

Kansas School of Medicine.

Project 5. Exploration of IDO1 as a Therapeutic Target in pCNS tumors. This project, led

by Dr. Rishi Lulla MD, Assistant Professor of Pediatrics at The Ann and Robert Lurie

Children’s’ Hospital of Chicago, together with a team of scientists with specific

expertise in IDO1, aims to measure the level of IDO1 expression in pediatric CNS tumors,

specifically focus on low-grade glioma, high-grade glioma, medulloblastoma, and

ependymoma. Published studies suggests that IDO1 is a promising target for

immunotherapy in adult gliomas. However, similar data for pediatric brain tumors is not

available and may have significant translational implications in children.

Informatics

The informatics portals that connect the clinical and genomic data to specimens

available to request from the bank represent the backbone of the CBTTC repository.

These allow any researcher around the world to access the repository in real time and

collaborators to deposit data remotely, thereby positioning the CBTTC as a sustainable

research resource.

The BioInformatics Group (at CHOP) continues to fine-tune the Harvest Portal, which links

the clinical and specimen inventories, allows investigators worldwide the ability to

access the CBTTC Biorepository and view the available samples based on queryable

fields from the clinical database. In 2016, the harvest portal team will launch a new

automated request system for Scientific Projects with real-time analytics. This process will

identify specific specimens that are requested for study, compare them to tests already

performed, and identify overlap of simultaneous requests. By removing a large portion

of manual work, the system will ultimately reduce the amount of time for scientific

project review and approval by the Scientific Committee and provide a greater level of

transparency. Additionally, a new information analyst has joined the Bioinformatics

Group at CHOP team to facilitate data quality assurance assist in ensuring quality data,

both within the clinical database and in Nautilus (the specimen management

database). Automating quality control and allowing coordinators at each site to

quickly identify errors within the data will improve our data quality and data entry

procedures.

The informatics team grew in 2015 and added 10 new members, which was funded by

CHOP institutional funds. This expanded team supports two new informatics portals

designed to extend CBTTC data sharing and advance collaborative research. The first

portal, CBIO+, was developed to support genomic data visualization. This portal is a

collaboration with Memorial Sloan Kettering and builds upon the success of CBIO+

portal created for genomic data visualization of the adult NIH supported TCGA (define

TCGA) data. The CBIO+ portal allows for the deposition of any cancer or normal

genomic data set for pediatric or adults. The genomic data visualization tools allow

researchers to identify new mutations through pan-cancer analysis, target mutations of

interest across cancer types, and provide interface functionality for integration into the

CHOP Harvest portal described above.

The second portal, called Cavatica, is a pediatric genomic cloud that began

development in 2015 and is expected to launch version 1 in the second quarter of 2016.

This platform will interfact with Harvest and CBIO+ to remove obstacles researchers

currently face in efforts to analyze, collaborate and store very large raw genomic data.

The informatics team partnered with Seven Bridges Genomics (SBG) an NCI Cancer

Genomic Cloud grant recipient to develop Cavatica.

Operations

The Operations Center at CHOP continues to receive, process, store and perform

quality control on specimens and clinical data obtained from the member sites as well

as those from CHOP subjects. The group has made tremendous strides in

standardization. documenting the processes and procedures within Manual Operating

Procedures (MOPS). CHOP continues its commitment to this program with over twenty

institutional leaders and personnel contributing to the project. The Operations Center

team led by Peter Phillips MD, Director of CHOP’s Pediatric Neuro-Oncology Program,

Adam Resnick Ph.D., Assistant Professor of Neurosurgery, Phillip (Jay) Storm MD, Chair,

Division of Neurosurgery, and Angela Waanders M.D. MPH, Assistant Professor of

Pediatric Oncology.

The efforts and dedication of our consortium partners is a critical part of the CBTTC’s

continued successes. Working with highly commited researchers, clinicians,

coordinators, pathologists and support staff at all of our sites ensures a consistency of

purpose and focused vision. The Children’s Hospital of Pittsburgh led by Ian Pollack

M.D., The Ann and Robert Lurie Children’s Hospital of Chicago is led by Stewart

Goldman M.D., Rishi Lulla M.D. and Seattle Children’s Hospital is led by Russ Geyer MD,

Sarah Leary MD and the Meyer Children's’ Hospital in Florence Italy led by Anna Maria

Buccoliero M.D. PhD. Joining the consortium and collaboration in 2015 was UCSF

Benioff’s Children’s Hospital and is led by Joanna Phillips M.D. Ph.D. and Sabine Mueller

M.D. Ph.D.

The Ann and Robert Lurie

Children’s Hospital of Chicago

CBTTC Core Member

Seattle Children’s Hospital

CBTTC Core Member

The Children's Hospital of

Philadelphia

CBTTC Operations Center

Children’s Hospital of Pittsburgh

CBTTC Core Member

UCSF Benioff Children’s Hospital

Funding

In 2015 The Children’s Brain Tumor Foundation (CBTF) committed $350,000 to support

the CBTTC Operations Center at CHOP. This funding support, defined in the annually

executed grant terms agreement, provides partial salaries and laboratory supply

support as summarized below:

• Partial salaries for:

Laboratory technical staff

Operations Manager

Clinical Data Coordinator

• Purchase of laboratory supplies and equipment to maintain the CBTTC

infrastructure

The CBTF also provides funding for each primary member institution at $75,000 annually.

These funds are distributed directly from the CBTF to the member institution. This funding

is a key to the success of the CBTTC, and the consortium is continually grateful for the

partnership with CBTF and LIMA.

Additional funding, totaling approximately $1.3 million for the CBTTC Operational

activities at CHOP, came from philanthropic foundation support and CHOP institutional

funding in 2015. These activities include support for the biorepository core, informatics

teams, specimen technicians, clinical data coordinators, bioinformaticians, research

projects, data generation, equipment, service contracts with commercial partners and

one-time pilot grants to support new sites. Leveraging the support of the CBTF the

consortium has been able to secure these addition funds to support the growth, new

initiatives and sustainability of the CBTTC.

Alan Stallings Fund

Alex Munoz Foundation

Andrew Noten Hudson Foundation

At Least Kids Foundation

Avery Lubrecht Foundation

BethAnn Telford, TeamBT

Brain Tumor Avengers

Brandles Joy of Hope

Joseph T. Lentz Pediatric Brain Cancer Research Fund

Kayla’s Hope for Kids Fund

Kyle Daniel Kerpan Foundation

Lauren’s First and Goal

Miriam’s Kids Research Foundation

Naya Foundation

Pearce Q. Foundation, Inc.

PLGA Foundation

Brendan Bovard Fund for Brain Tumor Research

Bryce Hansen Bridge of Hope Fund

Charles and Pat Genuardi

Chester County Community Foundation

Children’s Brain Tumor Foundation and the Licensing

and Merchandiser’s Association

David and Deborah Calvaresi

Derrick and Lauren Roamelle

Dragon Master Foundation

Eaise Family Foundation, Inc.

Grayson Saves Foundation

Hanna Duffy Foundation

James and Nancy Minnick

Smiles for Jake Foundation

Stanley’s Dream

Suzanne Gilligan - Luke Forward

The Christopher Court Foundation

The CJR Memorial Foundation

The Kortney Rose Foundation

The Matthew Renk Foundation

The Timothy Pauxtis Foundation

Thea’s Star of Hope

Vs Cancer Foundation

Why Not Me? Foundation

Wylie’s Day Foundation

Looking Forward: CBTTC 2016

The CBTTC will hold its Annual Investigator Meeting in New Orleans in May 2016. The

member sites will join with supporting philanthropic foundations to communicate recent

achievements, discuss ongoing projects and preview new initiatives. Our 2015

Investigator’s Meeting in Philadelphia set the stage for many of the advances we

describe in this report and reconfirmed our commitment to a shared, collaborative

vision. In 2016 we anticipate continued growth of the CBTTC by the addition of new

consortium institutions, substantially more tumor specimens and types as well as

advances in our ability to share data through our new informatics portals (i.e., CBIO+

and the pediatric genomic data cloud, Cavatica). Additionally, the CBTTC will be

launching a new website which will better inform researchers and supporters of CBTTC,

and the lay public, of CBTTC activities, projects and future initiatives. A portion of the

website will also allow [CBTTC]members and external collaborators, to access CBTTC

Standard Operating Procedures, process documentation as well as meeting agendas

and minutes. We anticipate that this will enhance our shared vision globally and further

the collaborative mission of the CBTTC. We gratefully acknowledge the support of The

Children’s Brain Tumor Foundation and LIMA and look forward to a strong and

productive partnership in 2016.