Download Program Book - New York Academy of Sciences

SOHN CONFERENCE:
Pediatric Cancer in a
Post-genomic World
March 30 – April 1, 2016
www.nyas.org/Sohn2016
#Sohn2016
The New York Academy of Sciences
New York City
Presented by
SCIENTIFIC ORGANIZING COMMITTEE
Scott Armstrong, MD, PhD,
Memorial Sloan Kettering Cancer
Center
Lauren Breslow, JD, MPH, The
Sohn Conference Foundation
Melanie Brickman Stynes, PhD,
MSc, The New York Academy
of Sciences
Brooke Grindlinger, PhD, The
New York Academy of Sciences
Lee J. Helman, MD, National
Cancer Institute, U.S. National
Institutes of Health
John M. Maris, MD, The
Children’s Hospital of
Philadelphia, University
of Pennsylvania
Kathy Pritchard-Jones, BM
BChir, Great Ormond Street
Hospital for Children NHS
Foundation Trust; University
College London
Daniel Radiloff, PhD, The New
York Academy of Sciences
Poul H. Sorensen, MD, PhD,
University of British Columbia
A. Thomas Look, MD,
Dana-Farber Cancer Institute
Tiffany Stevens, JD, The Sohn
Conference Foundation
David C. Lyden, MD, PhD,
Weill Cornell Medical College
Michael Taylor, MD, PhD,
The Hospital for Sick Children,
University of Toronto
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SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
WELCOME
On behalf of the New York Academy of Sciences, The Sohn Conference
Foundation, and the Scientific Organizing Committee, we are pleased
to welcome you to the scientific meeting, Sohn Conference: Pediatric
Cancer in a Post-genomic World. This landmark event will convene
basic, translational, and clinical researchers from academic institutions,
pharmaceutical companies, government agencies, and non-profit
organizations in an effort to improve understanding of the current and
future landscape of pediatric cancers.
Cancer continues to be one of the most challenging diseases to
treat despite improved survival rates, with pediatric forms causing
devastation to both young patients and their families. In the United
States, cancer is the leading cause of death by disease past infancy
among children and, globally, there are more than 250,000 children
diagnosed with cancer each year. Advances in biomedicine, including
extensive genomic analysis, have illustrated that the underlying
etiology of pediatric cancers may be far different than that of their
adult counterparts. These differences emphasize the need for not only
increased understanding of the genetic and molecular mechanisms
underlying these unique cancers but more precise therapeutic
options for this vulnerable population.
The Sohn Conference will assemble global experts in pediatric cancer
research, clinical care, and advocacy dedicated to finding ways to
improve childhood cancer treatment by building on our expanding
genomic knowledge of these cancers. This two-and-a half-day
conference will include Keynote Addresses by Richard Gilbertson,
MD, PhD, Director of The Cambridge Cancer Center and Craig B.
Thompson, MD, President and CEO of Memorial Sloan Kettering
Cancer Center. Plenary presentations and discussion panels will
focus on groundbreaking research in epigenetic drivers of pediatric
cancers, disease risk factors, mechanisms of metastasis and disease
recurrence, tumor metabolic reprogramming, immunotherapy, as
well as novel biological models and strategies to improve clinical
development and treatment access.
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
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We ask you to take a moment to give us your feedback and help
us further improve our scientific programming by completing the online
survey for this event at www.surveymonkey.com/r/SohnConference2016.
We hope that this conference will encourage informative discussions,
promote exchange of scientific ideas, and will lead to fruitful new
professional collaborations. Please do not hesitate to notify our staff of
any questions, concerns, or suggestions.
Melanie Brickman Stynes, PhD, MSc
Director, Life Sciences Conferences
The New York Academy of Sciences
Evan Sohn
Vice President and Co-Founder
The Sohn Conference Foundation
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SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
FACULTY DISCLOSURES
All faculty participating in this activity are required to disclose to
the audience any significant financial interest and/or other relationship with the manufacture(s) of any commercial product(s) and/or
provider(s) of commercial services discusses in his/her presentation
and/or the commercial contributor(s) of this activity.
Scott Armstrong, MD, PhD
Consultant: Epizyme/Imago
Biosciences
Eric Bouffet, MD
None
Melanie Brickman Stynes, PhD,
MSc
None
Stefan Burdach, MD, PhD
Shareholder: PDC BioPharma
Michael C. Jensen, MD
Research Support: Juno
Therapeutics, Inc.
Shareholder: Juno
Therapeutics, Inc.
Consultant: Juno
Therapeutics, Inc.
Javed Khan, MD
None
Richard Gilbertson, MD, PhD
None
Andrew Kung, MD, PhD
Other: Plans to discuss unlabeled
uses of commercial products
or an investigational use of a
product not yet approved for this
purpose. Product TBD
Nancy Goodman, JD
None
A. Thomas Look, MD
None
Brooke Grindlinger, PhD
Shareholder: General Electric Co.,
Gilead Sciences Inc.
David C. Lyden, MD, PhD
None
Michael Dyer, PhD
None
Lee J. Helman, MD
None
Elizabeth Maher, MD, PhD
None
David Malkin, MD
None
Nada Jabado, MD, PhD
None
Katherine A. Janeway, MD, MMSc
None
John M. Maris, MD
None
Yael Mossé, MD
Research Support: Novartis
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
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Kathy Pritchard-Jones, BM BChir
None
Poul H. Sorensen, MD, PhD
None
Daniel Radiloff, PhD
None
Kimberly Stegmaier, MD
None
Charles W. M. Roberts, MD, PhD
Research Support: Novartis
Institutes for Biomedical Research
Consultant: Novartis Institutes
for Biomedical Research
Michael Taylor, MD, PhD
None
Michel Sadelain, MD, PhD
Shareholder: Juno
Therapeutics, Inc.
Consultant: Juno
Therapeutics, Inc.
Paul M. Sondel, MD, PhD
None
Craig B. Thompson, MD
Employee: Memorial Sloan
Kettering Cancer Center
Shareholder: AGIUS Merck
Financial Support: NCI NIH
Matthew Vander Heiden, MD, PhD
None
Robert Wechsler-Reya, PhD
None
N/A – not available at time of printing.
An * after the speaker’s name indicates that the speaker intends to discuss
unlabeled uses of a commercial product, or an investigational use of a
product not yet approved for this purpose. The speaker will disclose this
information during his/her presentation.
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SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
AGENDA
DAY 1: MARCH 30, 2016
4:00 PM
Registration and Poster Set Up
4:30 PM
Introduction and Welcome Remarks
Evan Sohn, The Sohn Conference Foundation
Daniel Radiloff, PhD, The New York Academy
of Sciences
4:45 PM
Keynote Address
The Successes and Future Direction of Pediatric
Cancer Research and Therapy
Richard Gilbertson, MD, PhD, Director, Cambridge
Cancer Center, The University of Cambridge
SESSION 1: THE EVOLVING LANDSCAPE OF PEDIATRIC
CANCER GENOMES
Session Chairperson: Michael D. Taylor, MD, PhD, The Hospital for
Sick Children, University of Toronto
5:30 PM
Clinical Implementation and Impact of Precision
Medicine in Pediatric Oncology: The PIPseq
Experience
Andrew Kung, MD, PhD, Columbia University
Medical Center
5:55 PM
Cancer Genomics to Identify Novel Biomarkers and
Drivers and to Enable Precision Therapeutics
Javed Khan, MD, National Cancer Institute,
U.S. National Institutes of Health
6:20 PM
Day 1 Closing Remarks
6:30 PM
Welcome Networking Reception and Poster Session
8:00 PM
Day 1 Adjourns
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
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DAY 2: MARCH 31, 2016
8:00 AM
Networking Breakfast and Registration
8:00 AM
Early Career Investigator and Underrepresented
Minority Mentoring Workshop
For Graduate Students, Post-doctoral Fellows,
and Junior Faculty
SESSION 2: EPIGENETIC AND CHROMATIN REMODELING AS
DISEASE DRIVERS IN PEDIATRIC CANCER
Session Chairperson: Scott Armstrong, MD, PhD, Memorial Sloan
Kettering Cancer Center
8:45 AM
SWI/SNF (BAF) Complex Mutations in Cancer:
Mechanisms and Vulnerabilities
Charles W. M. Roberts, MD, PhD, St. Jude Children’s
Research Hospital
9:10 AM
Targeting Epigenetic Mechanisms in Leukemia
Scott Armstrong, MD, PhD, Memorial Sloan Kettering
Cancer Center
9:35 AM
Spatial and Temporal Homogeneity of Driver
Mutations in Diffuse Intrinsic Pontine Glioma
Nada Jabado, MD, PhD, McGill University
10:00 AM
Networking Coffee Break
SESSION 3: GERMLINE ALTERATIONS AND CANCER
SUSCEPTIBILITY IN PEDIATRIC PATIENTS
Session Chairperson: John Maris, MD, The Children’s Hospital of
Philadelphia and the University of Pennsylvania
10:30 AM
Beyond Two-hits: The Complexity of Genetic
Susceptibility to Childhood Cancer
John M. Maris, MD, The Children’s Hospital of
Philadelphia and University of Pennsylvania
10:55 AM
Genetic Heterogeneity in Wilms Tumour and its
Evolution from Precursor Nephrogenic Rests
Kathy Pritchard-Jones, BM BCh, Great Ormond
Street Hospital for Children NHS Foundation Trust
and University College London
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SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
11:20 AM
The Prevalence and Functional Consequence
of TP53 Mutations in Pediatric Cancer
David Malkin, MD, The Hospital for Sick Children
HOT TOPIC TALKS FROM SUBMITTED ABSTRACTS
Session Chairperson: Daniel Radiloff, PhD, The New York Academy
of Sciences
11:45 AM
Human Tumorigenesis Induced by an Endogenous
DNA Transposase in Embryonal Tumors
Alex Kentsis, MD, PhD, Memorial Sloan Kettering
Cancer Center
12:00 PM
Elucidating the Epigenetic Consequences of ATRX
Mutations in Neuroblastoma
Zulekha A. Qadeer, Icahn School of Medicine at
Mount Sinai
12:15 PM
Histone H3K36 Mutations Promote Sarcomagenesis
through Altered Histone Methylation Landscape
Chao Lu, PhD, The Rockefeller University
12:30 PM
Networking Lunch / Continued Poster Viewing
SESSION 4: INSIGHTS INTO METABOLIC REPROGRAMMING
IN PEDIATRIC CANCER
Session Chairperson: Kathy Pritchard-Jones, BM, BCh, Great
Ormond Street Hospital for Children NHS Foundation Trust and
University College of London
2:00 PM
Targeting Folate Metabolism in Leukemia
Kimberly Stegmaier, MD, Dana-Farber/Boston
Children’s Cancer and Blood Disorders Center
2:25 PM
Role of Altered Metabolism in the Progression
of Malignant Gliomas
Elizabeth Maher, MD, PhD, University of Texas
Southwestern Medical Center
2:50 PM
Role of Metabolism in Supporting Tumor Growth
Matthew Vander Heiden, MD, PhD, The Koch
Institute, Massachusetts Institute of Technology (MIT)
3:15 PM
Networking Coffee Break
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
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SESSION 5: CLONAL SELECTION AND STRESS ADAPTATION
AS DRIVERS OF METASTASIS IN PEDIATRIC CANCERS
Session Chairperson: Poul H. Sorensen, MD, PhD, University
of British Columbia
3:45 PM
Acute Changes in mRNA Translation Drive Adaptation
to Cell Stress and Sarcoma Metastatic Capacity
Poul H. Sorensen, MD, PhD, University
of British Columbia
4:10 PM
Tumor Exosomes Determine Organotropic Metastasis
David C. Lyden, MD, PhD, Weill Cornell
Medical College
4:35 PM
The Biology of Medulloblastoma Metastases
Michael D. Taylor, MD, PhD, The Hospital for Sick
Children, University of Toronto
HOT TOPIC TALKS FROM SUBMITTED ABSTRACTS
Session Chairperson: Daniel Radiloff, PhD, The New York Academy
of Sciences
5:00 PM
The EEF2 Kinase Supports Metabolic
Reprogramming under Nutrient Stress
Gabriel Leprivier, PhD, Ben-Gurion University of
the Negev
5:15 PM
Hypermutation, Neoantigen Formation and Immune
Checkpoint Inhibition for Childhood Biallelic
Mismatch Repair Deficient Cancers
Brittany Campbell, The International bMMRD
Consortium and KiCS, the SickKids Cancer
Sequencing Program
5:30 PM
Identification of Drugs with Specific Activity in vivo
against High-risk Early Thymocyte Progenitor (ETP)
ALL Using Zebrafish Embryos
Shuning He, PhD, Dana-Farber Cancer Institute
5:45 PM
Day 2 Closing Remarks
5:55 PM
Day 2 Adjourns
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SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
DAY 3: APRIL 1, 2016
8:00 AM
Networking Breakfast
8:00 AM
Early Career Investigator and Underrepresented
Minority Breakfast
For Graduate Students, Post-doctoral Fellows,
and Junior Faculty
Editor’s Guide to Writing and Publishing Your Paper
Brooke Grindlinger, PhD, The New York Academy
of Sciences
Former Editor, The Journal of Clinical Investigation
In this 45-minute workshop participants will gain an
inside look into the editorial review process and how to
best present the results of their work for publication.
9:00 AM
Keynote Address
The Role of Epigenetic and Metabolic Mutations in
Stem Cell Maintenance and Pediatric Cancer
Craig B. Thompson, MD, President and CEO,
Memorial Sloan Kettering Cancer Center
SESSION 6: IMMUNOTHERAPEUTIC APPROACHES
TO PEDIATRIC MALIGNANCIES
Session Chairperson: David C. Lyden, MD, PhD, Weill Cornell
Medical College
9:45 AM
Augmenting CAR T-cell Potency and Safety with
Synthetic Control Systems
Michael C. Jensen, MD, Seattle Children’s Hospital
10:10 AM
CAR Therapy: The CD19 Paradigm
Michel Sadelain, MD, PhD, Memorial Sloan Kettering
Cancer Center
10:35 AM
NK-based Immunotherapy: Engaging Innate
and Adaptive Immunity with Tumor-Reactive
Immunocytokines
Paul M. Sondel, MD, PhD, University of Wisconsin
School of Medicine and Public Health
11:00 AM
Networking Coffee Break
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
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SESSION 7: NEW PARADIGMS IN MODELING PEDIATRIC CANCER
Session Chairperson: A. Thomas Look, MD, Dana-Farber
Cancer Institute
11:30 AM
Molecular Pathogenesis and Drug Synergism
in a Zebrafish Model of High Risk Neuroblastoma
A. Thomas Look, MD, Dana-Farber Cancer Institute
11:55 AM
Stem Cell Based Models of Medulloblastoma
Robert Wechsler-Reya, PhD, Sanford Burnham
Prebys Institute of Medical Discovery
12:20 PM
Identifying Druggable Mutations in Pediatric
Solid Tumors
Michael Dyer, PhD, St. Jude Children’s Research
Hospital, Howard Hughes Medical Institute
12:45 PM
Networking Lunch
Mentoring Lunch for Early Career Investigators and
Underrepresented Minorities in Biomedical Research
SESSION 8: INNOVATIVE STRATEGIES TO IMPLEMENTING PRECISION
MEDICINE-BASED THERAPEUTIC TRIALS FOR PEDIATRIC CANCER
Session Chairperson: Yael Mossé, MD, The Children’s Hospital of
Philadelphia
2:15 PM
Establishing New Rules for Pediatric Cancer Trials
in a Post-genomic World: Defining the Issues
Lee J. Helman, MD, National Cancer Institute,
U.S. National Cancer Institute of Health
2:40 PM
Next Generation Personalized Neuroblastoma Therapy
Yael Mossé, MD, The Children’s Hospital of
Philadelphia
3:05 PM
Harnessing Genomics for Diagnosis and Treatment
Selection in the Pediatric Oncology Clinic
Katherine A. Janeway, MD, MMSc, Dana-Farber/
Boston Children’s Cancer and Blood Disorders Center
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SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
3:30 PM
Panel Discussion
Overcoming Recurrent Failures in Clinical Trials for
Children with Cancer
Moderator: Lee J. Helman, MD, National Cancer
Institute, U.S. National Institutes of Health
Panelists: Eric Bouffet, MD, The Hospital for Sick
Children, Toronto
Stefan Burdach, MD, PhD Technical University of
Munich, Germany
Nancy Goodman, JD, Kids v Cancer
Katherine A. Janeway, MD, MMSc, Dana-Farber/
Boston Children’s Cancer and Blood Disorders Center
Yael Mossé, MD, The Children’s Hospital of Philadelphia
4:15 PM
Day 3 Closing Remarks
4:30 PM
Conference Adjourns
The New York Academy of Sciences requests that you do not take
photographs or make audio or video recordings of the conference
presentations, or present unpublished data on any open-access
websites, unless specific permission is obtained from the speaker.
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
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ABSTRACTS
The Successes and Future Direction of Pediatric Cancer Research
and Therapy
Richard Gilbertson, MD, PhD, Director, Cambridge Cancer Center,
The University of Cambridge
We have all read abstracts for meetings that begin with banner
headlines; for example, “Cancer remains the leading cause of death
by disease in childhood.” But the narrative behind these statements
includes a complex mix of stunning scientific advances, new and
exciting technologies, and a medical and clinical trials system that is
desperately trying to keep pace. In many ways the pediatiric oncology community has led the world of cancer research in the use of
‘omic technologies, the integration of developmental and cancer biology, and the conduct of collaborative clinical trials; however, making
these advances count for patients by translating them into impactful
diagnostics and treatments represents a new challenge for which we
are ill prepared. The challenge we face today is not so much the use
of advanced biological approaches to understand pediatric cancer
better, but how we sift this data for the most relevant information and
use its power in the clinic to eradicate cancer as a cause of death from
disease in childhood.
Clinical Implementation and Impact of Precision Medicine in
Pediatric Oncology: The PIPseq Experience
Andrew L. Kung, MD, PhD, Division of Pediatric Hematology,
Oncology and Stem Cell Transplantation, Columbia University
Medical Center
The outcome for children with cancer has steadily improved to the
point that currently 80% of all patients are cured using standard of
care therapy. However, cancer remains the leading cause of diseaserelated death in children, underscoring the need for more effective
medical therapies. We built the Precision in Pediatric Sequencing
(PIPseq) program to bring next generation sequencing technologies
to the care of children with cancer. Over the last two years, we have
been performing whole exome sequencing of tumor and normal
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SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
tissue as well as sequencing tumor RNA from children with solid
tumors and hematologic malignancies treated in our program. With a
turnaround of a few weeks, this CLIA compliant and New York State
approved platform has impacted clinical decisions in 65% of all cases.
In some instances, our findings have led to the treatment of patients
with targeted therapies that would not have been chosen based
on conventional disease classifications. In other cases, our results
have helped to avoid treatments that would have proved ineffective
or erroneous. The clinical impact of genomic characterization has
extended beyond the patient to their families in the cases where we
have found an underlying cancer predisposition. In addition to affecting
the care of patients in the clinic, the PIPseq program has been an engine
for discovery, including the identification of novel causes of childhood
cancer and new therapeutic approaches. Our results demonstrate the
compelling impact of genomic sequencing not only for research, but
also for the clinical care of patients with cancer.
Cancer Genomics to Identify Novel Biomarkers and Drivers
and to Enable Precision Therapeutics
Javed Khan, MD, National Cancer Institute, U.S. National Institutes
of Health
I will describe how first generation genomics identified the oncogenic
role of FGFR4 in Rhabdomyosarcoma (RMS). I will go on to to discuss
the use of next generation genomics to discover additional drivers
as well as the investigation of clonality and tumor evolution in RMS. I
will discuss how the exploration of the epigenetic landscape of RMS
allows us to identify mechanisms of tumorigenesis and suggest key
vulnerabilities. Next, I will discuss how transcriptomic analysis has
identified cell surface proteins differentially expressed in pediatric
cancers with a focus on FGFR4 as a potential target for immune
based therapy in RMS. Finally, I will describe the NCIs plan for the use
of these technologies to enable precision therapy trials for patients
with refractory or relapsed cancers.
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
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SWI/SNF (BAF) Complex Mutations in Cancer:
Mechanisms and Vulnerabilities
Charles W. M. Roberts, MD, PhD, St. Jude Children’s Research Hospital
Data emerging over the last several years implicate the SWI/SNF
(BAF) chromatin remodeling complex as a major tumor suppressor
as frequent inactivating mutations in at least nine different SWI/
SNF subunits, collectively identified in twenty percent of all cancers.
These include recurrent mutations of ARID1A (BAF250a) in ovarian,
endometrioid, bladder, stomach, colorectal and pancreatic cancers
and neuroblastoma; of the BRG1 (SMARCA4) subunit in medulloblastomas and non-small cell lung cancers; of the PBRM1 (BAF180)
subunit in renal carcinomas; of the ARID2 subunit in hepatocellular,
lung, and pancreas carcinomas as well as melanomas; of the BRD7
subunit in breast cancers. The SWI/SNF complex includes both
core and lineage-specific subunits and utilizes the energy of ATP to
modulate chromatin structure and regulate transcription.
My laboratory began studying the SWI/SNF complex when SNF5
(SMARCB1/INI1/BAF47) became the first SWI/SNF subunit linked to
tumor suppression over fifteen years ago when it was found to be
biallelically inactivated in nearly all cases of a highly aggressive type
of pediatric cancer called malignant rhabdoid tumor (MRT). Despite
the extremely aggressive and lethal nature of MRT we have shown that
these cancers are diploid and have remarkably simple genomes. We
now study the complex using mouse models, cell lines and primary
human tumor samples. Insights into the normal function of SWI/SNF
complexes, the mechanisms by which mutation of the complexes drive
cancer formation, and potential therapeutic vulnerabilities created by
mutation of the complex will be presented including our recent efforts
that identify EZH2 and polycomb complexes as potential therapeutic
vulnerabilities in these cancers.
Epigenetic Mechanisms and Stem Cell Programs in Leukemia
Scott A. Armstrong, MD, PhD, Memorial Sloan Kettering Cancer Center
Leukemias harboring mixed lineage leukemia (MLL) gene abnormalities are associated with poor clinical outcomes and new therapeutic
approaches are needed. Rearrangement of the MLL gene generates
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SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
chimeric proteins that fuse the NH3-terminus of MLL to the COOHterminus of its translocation partners. These MLL-fusion oncoproteins drive the expression of a stem cell associated gene expression
program in myeloid progenitors, thus initiating and and maintaining
leukemia stem cell self-renewal. Genes central to this program include
the HOXA cluster genes and MEIS1, which are also able to induce
leukemic transformation of hematopoietic progenitors. Genome-wide
histone methylation studies have revealed that the abnormal expression of MLL-fusion target genes is associated with specific chromatin
modifications that are critical for the maintenance of leukemogenic
gene expression. Critical modifications that maintain HOXA and
MEIS1 expression include H3K79 methylation and H3K9 acetylation.
The only known enzyme that catalyzes methylation of H3K79 is disruptor of telomeric-silencing 1-like (DOT1L). Loss-of-function mouse
models as well as small molecular inhibitors of DOT1L demonstrate
that leukemias driven by MLL-translocations are dependent on DOT1L
enzymatic activity for proliferation and for the maintenance of HOXA
gene expression. Furthermore, DOT1L also appears to be important
for HOXA gene expression in other settings including leukemias with
select genetic abnormalities. These discoveries have established
a foundation for disease-specific therapies that target chromatin
modifications in leukemias harboring specific genetic abnormalities.
I will discuss out latest attempts to understand the mechanisms by
which histone modifications control leukemic gene expression and
how these mechanisms are being targeted therapeutically.
Spatial and Temporal Homogeneity of Driver Mutations in Diffuse
Intrinsic Pontine Giloma
1
Nada Jabado, MD, PhD, McGill University, 2Jacek Majewski, PhD,
3
Javad Nazarian, PhD
Department of Human Genetics, McGill University, Montreal,
QC, Canada;
2
McGill University and Génome Québec Innovation Centre, Montreal,
QC, Canada;
3
Research Center for Genetic Medicine, Children’s National Health
System, Washington, DC, United States
1
Diffuse Intrinsic Pontine Gliomas (DIPG) are deadly pediatric brain
tumors where needle biopsies help guide diagnosis and targeted
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
17
therapies. To address spatial heterogeneity, we analyzed 134 specimens
from various neuroanatomical structures of whole autopsy brains from
nine DIPG patients. Evolutionary reconstruction indicates histone 3
(H3) K27M—including novel H3.2K27M—mutations potentially arise
first and are invariably associated with specific, high-fidelity obligate
partners throughout the tumor and its spread, from diagnosis to
end-stage disease, suggesting mutual need for tumorigenesis. These
H3K27M ubiquitously-associated mutations involve alterations in TP53
cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/
PIK3R1). Later oncogenic alterations arise in sub-clones and often
affect the PI3K pathway. Our findings are consistent with early tumor
spread outside the brainstem including the cerebrum. The spatial and
temporal homogeneity of driver mutations in DIPG implies they will
be captured by limited biopsies and emphasizes the need to develop
therapies specifically targeting obligate oncohistone partnerships.
Genetic Heterogeneity in Wilms Tumour and Its Evolution from
Precursor Nephrogenic Rests
Kathy Pritchard-Jones, BM BCh, Great Ormond Street Hospital for
Children NHS Foundation Trust and University College London
Abstract not available at the time of printing.
Beyond Two-hits: The Complexity of Genetic Susceptibility
to Childhood Cancer
John M. Maris, MD, The Children’s Hospital of Philadelphia and
University of Pennsylvania
Pediatric cancers arise during the process of human development
with presumably very little influence from the environment. Thus,
host DNA variation plays a significant role on disease initiation and
progression. Knudson and Strong predicted that neuroblastoma, like
retinoblastoma, would arise due to two genetic hits, and while the
general concepts have been largely validate, the complexity of the
genetic basis of human neuroblastoma. Rare familial neuroblastomas
arise most commonly in the setting of an inherited gain of function
mutation in the ALK oncogene, but we still do not have a firm grasp on
what constitutes the second genetic event required for tumorigenesis.
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SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
Ongoing research has identified additional candidate causal mutations
in other cancer susceptibility genes such as APC, BARD1, and BRCA2,
but it remains unknown whether or not these defects impacted
neuroblastoma initiation, or signal risk for subsequent tumors later in
life, or both. In parallel with the identification of classical mutations
in cancer susceptibility genes, genome wide association study
efforts have identified multiple genes and pathways that collaborate
in tumor initiation. We are still in the early days of understanding
the mechanisms underlying these highly statistically significant
associations, but it is clear that subsequent tumors frequently rely
on the cellular networks impacted by these GWAS-discovered genes.
With our ongoing mapping of chromatin states and key transcription
factor binding sites, are now poised to uncover germline and somatic
DNA alterations outside of the protein coding genome that impact
neuroblastoma initiation and progression.
The Prevalence and Functional Consequences of TP53 Mutations
in Pediatric Cancer
David Malkin, MD, The Hospital for Sick Children
Somatic mutations of the TP53 tumor suppressor gene are the most
frequent alterations in human cancer. Germline TP53 mutations are
found in >75% of people with Li-Fraumeni syndrome, an autosomal
dominantly inherited disorder in which TP53 mutation carriers are at
an almost 100% lifetime risk of developing a wide range of early onset
cancers. The LFS phenotype conferred by a TP53 mutation is likely
modified by inherited or acquired genetic, genomic or epigenetic
events. This presentation will discuss and evaluate how emerging next
generation sequencing platforms, novel Trp53 animal models and
functional assays are being used to address the following challenges
facing LFS patients: 1) is it possible to predict the age of onset and
type of cancers in TP53 mutation carriers; 2) is it possible to detect
cancers before they manifest clinically; and 3) is it possible to develop
effective treatment regimens for LFS patients?
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
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Human Tumorigenesis Induced by an Endogenous DNA
Transposase in Embryonal Tumors
Anton Henssen, MD, Richard Koche, PhD, Eileen Jiang, BS, Casie
Reed, BS, Amy Eisenberg, BS, Eric Still, BS, Christopher Mason, PhD,
Elisa de Stanchina, PhD, Mithat Gonen, PhD, Elizabeth Perlman, MD,
Cristina Antonescu, MD, Hanno Steen, PhD, Elizabeth Mullen, MD,
Scott Armstrong, MD, PhD, and Alex Kentsis, MD, PhD
Sloan Kettering Institute, Department of Pediatrics, Memorial Sloan
Kettering Cancer Center, New York, New York, United States
Recent cancer genome surveys have revealed extremely low rates
of coding gene mutations in distinct tumor subtypes, suggesting
that alternative mechanisms must contribute to their pathogenesis.
Transposons are mobile genetic elements that are found in all living
organisms. Their mobilization can cause structural rearrangements in
normal and cancer .cells. However, it remains unknown whether transposition is a cause of cellular transformation or merely a bystander
effect of dysregulated gene expression. Using proteomic profiling of
pediatric patients with renal tumors, we identified PGBD5, a human
homolog of the piggyBac DNA transposase from the cabbage looper
moth, to be aberrantly expressed in the majority of rhabdoid and
other embryonal tumors including neuroblastoma and medulloblastoma. Consistent with its potential tumorigenic function, transient
expression of PGBD5 in non-transformed human cells is sufficient to
induce fully penetrant tumor formation in immunodeficient mice in
vivo. PGBD5-induced cell transformation is associated with morphologic de-differentiation and induction of embryonal gene expression
programs similar to those observed in primary rhabdoid tumors.
PGBD5 expression is sufficient to induce genomic mobilization of
DNA transposons in human cells, and its catalytic activity is required
for cell transformation. DNA transposition catalyzed by PGBD5 in human
cells occurs genome-wide, with precise transposon excision, preference
for insertion at TTAA sites, and requirement for functional end-joining
DNA repair. These findings reveal an unanticipated mechanism of human
tumorigenesis and genomic alterations in human cancer. Functional
requirements of DNA transposition suggest immediate rational therapeutic strategies for rhabdoid and other childhood tumors involving
endogenous DNA transposases.
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Elucidating the Epigenetic Consequences of ATRX Mutations
in Neuroblastoma
Zulekha A. Qadeer1,2,3, Lyra M Griffiths4, David Valle-Garcia1,2,5, Anqi
Ma1, Maged Zeineldin4, Jian Jin1, Nai-kong V. Cheung6, Michael A.
Dyer4, and Emily Bernstein1,2,3
Department of Oncological Sciences, Icahn School of Medicine at
Mount Sinai, New York, New York, United States;
2
Department of Dermatology, Icahn School of Medicine at Mount
Sinai, New York, New York, United States;
3
Graduate School of Biomedical Sciences, Icahn School of Medicine
at Mount Sinai, New York, New York, United States;
4
Department of Developmental Neurobiology, St. Jude’s Children’s
Research Hospital, Memphis, Tennessee, United States;
5
Institute for Cellular Physiology, Molecular Genetics, National
Autonomous University of Mexico, Mexico City, Mexico;
6
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center,
New York, New York, United States
1
ATRX is a SWI/SNF-like chromatin remodeler that has emerged as a
critical player in chromatin regulation. The protein contains several
conserved domains, including an ADD (ATRX-DNMT3-DNMT3L)
domain that binds H3K9me3, HP1αand EZH2 interacting regions, and
an ATPase domain, responsible for its remodeling activities. Recent
whole genome sequencing studies have identified ATRX as being
frequently altered in a subset of aggressive neuroblastoma (NB)
patients. The mechanism of how ATRX mutations promote tumorigenicity remains poorly understood.
We have identified two human NB cell lines harboring distinct in-frame
fusions that result in truncated forms of ATRX, devoid of EZH2 binding
domains, which are enriched in chromatin with dramatically altered
nuclear localization. Using RNA-Sequencing comparing the ATRX
mutant transcriptome to two ATRX wild-type NB cell lines derived
from patients of the same stage and age, we discovered a group of
genes deregulated in ATRX mutant NB cells that are associated as
Polycomb H3K27me3 marked targets. Employing ChIP-Sequencing
for H3K27me3 in the same NB cells, we identified genes critical in
neurogenesis and neural differentiation that have gained H3K27me3
domains in both ATRX mutant NB cells compared to wild-type cells.
We treated the same panel of NB cells with EZH2 inhibitors and found
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21
a striking decrease in proliferation and increase in apoptosis specifically in ATRX mutant NB. We hypothesize that ATRX in-frame fusions
culminate in EZH2 mis-targeting and subsequent transcriptional
deregulation of a distinct set of genes. Overall, we propose utilization
of EZH2 inhibitors as a novel therapeutic strategy for ATRX mutant NB.
Histone H3K36 Mutations Promote Sarcomagenesis through
Altered Histone Methylation Landscape
Chao Lu, PhD1, Siddhant U. Jain, BSc2, Dominik Hoelper, MSc2, Denise
Bechet, BSc3, Sriram Venneti, MD, PhD4, Nicolas De Jay, BSc3, Simon
Papillon-Cavanagh, BSc3, Jacek Majewski, PhD3, Craig B. Thompson,
MD4, Ping Chi, MD, PhD4, Benjamin A. Garcia, PhD5, Nada Jabado,
MD, PhD3, Peter W. Lewis, PhD2, and C. David Allis, PhD1
The Rockefeller University, New York, New York, United States;
University of Wisconsin, Madison, Wisconsin, United States;
3
McGill University, Montreal, Quebec, Canada;
4
Memorial Sloan-Kettering Cancer Center, New York, New York,
United States;
5
University of Pennsylvania, Philadelphia, Pennsylvania,
United States
1
2
Several types of pediatric cancers reportedly contain high frequency
missense mutations in histone H3, yet the underlying oncogenic
mechanism remains poorly characterized. Here, we report that the
H3 lysine 36 to methionine (H3K36M) mutation, identified in >90%
of chondroblastomas, impairs the differentiation of mesenchymal
progenitor cells and generates undifferentiated sarcoma in vivo.
H3K36M mutant nucleosomes inhibit the enzymatic activities of several
H3K36 methyltransferases, resulting in globally diminished H3K36
methylation. Depletion of H3K36 methyltransferases, or expressing an
H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient
to phenocopy H3K36M mutation. Following the loss of H3K36
methylation, a genome-wide gain in H3K27 methylation leads to a
redistribution of Polycomb Repressive Complex 1 and de-repression of
polycomb target genes known to block mesenchymal differentiation.
Our findings are mirrored in human undifferentiated sarcomas where
novel K36M/I mutations in H3.1 are identified in rare pediatric cases.
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Targeting Folate Metabolism in Leukemia
Kimberly Stegmaier, MD, Dana-Farber/Boston Children’s Cancer
and Blood Disorders Center
The targeting of folate metabolism as an approach to treat patients
with cancer was first described by Dr. Sidney Farber in the 1940s.
This study established that acute lymphoblastic leukemia (ALL) cells
are highly dependent on folate metabolism and demonstrated the
first ever clinical responses in children with ALL to drug therapy. The
perturbation of folic acid metabolism has subsequently become the
backbone of successful ALL treatment. We have explored two new
approaches to targeting folate metabolism for acute leukemia. In
the first, we developed and evaluated a folate-drug conjugate that
leverages the expression of folate receptor on ALL cells for tumor cell
specificity and the activity of a natural product with specificity for
mutant NOTCH1, a protein recurrently mutated in T-cell ALL. In the
second, we discovered a new dependency in acute myeloid leukemia
(AML) on the mitochondrial enzyme involved in folate metabolism:
methylene tetrahydrofolate dehydrogenase 2 (MTHFD2). MTHFD2
is the most differentially expressed metabolic enzyme in cancer
compared to normal cells, and MTHFD2 suppression impairs AML
cell growth and induces myeloid differentiation in vitro and impairs
leukemia progression in multiple mouse models of AML.
Role of Altered Metabolism in the Progression of Malignant Gliomas
Elizabeth Maher, MD, PhD, University of Texas Southwestern
Medical Center
It is now widely accepted that mutations in isocitrate dehydrogenase
1 and 2 (IDH1/2) represent one of the earliest genetic events in
gliomagenesis and contribute to driving tumor initiation in a subset of
patients. The IDH gain-of-function mutations catalyze the reduction of
α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), a metabolite that
is structurally similar to αKG and leads to a block in differentiation and
unregulated cellular growth. However, using 2HG quantitation by MR
spectroscopy in gliomas, we have observed that 2HG concentrations
do not appreciably change during the months to years of stable
disease in low grade gliomas and abruptly increase at the time of
tumor progression or transformation to high grade disease. Given
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23
the well-described differences in the high-grade versus low-grade
glioma genome, it appears that the period when 2HG levels are stable
encompasses the time during which acquisition of new mutations is
occurring. How these additional genetic changes drive transformation
is poorly understood. We have explored differences in 13C-glucose/
acetate tracing in glycolysis and the citric acid cycle in vivo to dissect
the role of metabolic reprogramming in driving tumor progression.
Understanding the metabolic phenotype of low grade gliomas could
identify new targets for treatment that may prevent the transformation
to high grade glioma.
The Role of Metabolism in Supporting Tumor Growth
Matthew G. Vander Heiden, MD, PhD, Koch Institute for Integrative
Cancer Research at Massachusetts Institute of Technology
Cells adapt metabolism to meet their needs, and metabolic regulation
influences tumor initiation and progression. To proliferate, cancer
cells must support anabolic processes and allow the accumulation
of biomass. We have focused on identifying the metabolic pathways
that are most limiting for the proliferation of cancer cells in different
environmental and tissue contexts. We find that nucleotide synthesis
is often limiting, and how cells generate nucleotides is dictated in
large part by the tissue environment and tumor cell of origin. For
many tumors, access to oxygen or other electron acceptors limits the
production of aspartate, which is necessary for purine, pyrimidine and
protein synthesis. Analysis of metabolism in animal cancer models
suggests that tumors can use different nutrients to allow tumor growth,
and recent insights into how metabolism is regulated to control cell
proliferation and how this affects new cancer drug development will
be discussed.
Acute Charges in mRNA Translation Drive Adaptation to Cell Stress
and Sarcoma Metastatic Capacity
Poul H. Sorensen, MD, PhD, University of British Columbia, Vancouver
Cells respond to stress by blocking global protein synthesis to preserve
energy, while maintaining translation of stress adaptive mRNAs such
as HIF1A. However, the basis for such selective mRNA translation
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remains largely unknown. One conserved mechanism for inhibiting
translation under stress is to sequester mRNAs in ribonucleoprotein
(RNP) complexes known as stress granules (SGs). SGs are composed
of RNA binding proteins, stalled translation initiation complexes and
silenced mRNAs, which are temporarily stored in SGs until the stress is
abated. Emerging evidence implicates SGs in cancer biology, whereby
SGs confer survival under stress and chemotherapeutic resistance to
tumor cells. Recently, we found that the RNA binding protein, YB-1,
facilitates childhood sarcoma metastasis through two mechanisms.
First, it directly binds to the HIF1A 5’-UTR to enhance HIF1α mRNA
translation under hypoxia and drive metastatic capacity in vivo.
Second, under diverse stress forms, YB-1 mediates formation of SGs
through 5’-UTR binding and translational activation of the G3BP1 SG
nucleator. Unexpectedly, we found that YB-mediated SG formation is
also critical for in vivo metastasis of childhood sarcoma cells. We now
find that HIF1α is essential for YB-1 mediated SG formation in tumor
cells under stress, with HIF1α lying upstream of G3BP1 in this process.
Moreover, inactivation of the YB-1-HIF1α-G3BP1-SG signaling axis
inhibits AMPK energy signaling and reduces mitochondrial functions,
thus blocking adaptation to metabolic stress. We hypothesize that
the YB-1-HIF1α-G3BP1-SG axis mediates selective mRNA translation
and resistance to diverse stresses in tumor cells, and that this process
is critical for metastatic capacity.
Tumor Exosomes Determine Organotropic Metastasis
David C. Lyden, MD, PhD1, Ayuko Hoshino, Bruno Costa-Silva, Irina
Matei, Volkmar Muller, Klaus Pantel, Benjamin A. Garcia, Yibin Kang,
Cyrus M. Ghajar, Hector Peinado, Jacqueline Bromberg
1
Weill Cornell Medical College
Metastasis to distant vital organs such as lung, liver, and brain is the
most devastating feature of cancer progression, responsible for over
90% of cancer-associated deaths. In 1889, Stephen Paget first proposed that organ distribution of metastases is a non-random event,
yet metastatic organotropism remains one of the greatest mysteries
in cancer biology. Our recent studies uncovered that tumor-derived
exosomes alter the microenvironment at future sites of metastasis
to form pre-metastatic niches, creating a favorable “soil” for incoming metastatic “seeds”. However, by what mechanism this occurs,
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
25
and the role of exosomes in tumor metastasis, remains unknown. To
investigate the role of exosomes in organotropic metastasis, we have
used two established organotropic human tumor models: the MDA-231
breast cancer (BC) cell line, and its variants known to metastasize to the
lung, brain and bone, respectively, as well as two liver metastatic pancreatic cancer (PC) cell lines, BxPC3 and HPAF-2. We first analyzed the
biodistribution of fluorescently-labeled exosomes derived from lung
metastatic, brain metastatic or bone metastatic MDA-231 BC variants
or PC cell lines, and found that BC exosomes follow the organ-specific
distribution of the cells of origin, while PC exosomes home to the liver.
Osteosarcoma and Wilms’ tumor-derived exosomes adhere predominantly to cells in the lung. In each target organ exosomes are taken up
by different cell types: fibroblasts/epithelial cells in the lung, Kupffer
cells in the liver, and endothelial cells in the brain. In the organotropic
MDA-231 model, prior education with the lung tropic exosomes redirected metastasis of the bone tropic cells to the lung, demonstrating
the unique capacity of exosomes to determine the site of metastasis.
Unbiased proteomic profiling of exosomes revealed distinctive integrin
expression patterns, and analysis of plasma exosomes from BC and
PC patients that later developed site-specific metastasis revealed that
specific exosomal integrins could predict metastatic spread.
The Biology of Medulloblastoma Metastases
Michael D. Taylor, MD, PhD, The Hospital for Sick Children,
University of Toronto
Abstract not available at the time of printing
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The EEF2 Kinase Supports Metabolic Reprogramming under
Nutrient Stress
Gabriel Leprivier, PhD1, Raffaele Teperino, PhD2, Jordan Cran, MSc1,
Nick Olsen, PhD1, J. Andrew Pospisilik, PhD3, and Poul H.B. Sorensen,
MD, PhD1
British Columbia Cancer Research Centre and University of British
Columbia, Vancouver, Canada;
2
Institute of Experimental Genetics, Munich, Germany;
3
Max Planck Institute of Immunobiology and Epigenetics, Freiburg,
Germany
1
During tumour progression, pediatric brain tumour cells experience nutrient deprivation due to defective tumour vasculature. The
mechanisms supporting tumour metabolic adaptation need to be
better defined as they represent potential therapeutic targets. We
previously reported that the translation elongation factor 2 kinase
(eEF2K), which controls mRNA translation at the step of elongation,
supports adaptation of medulloblastoma (MB) to nutrient stress. This
has clinical relevance as high eEF2K expression is strongly associated
with poor survival in MB.
To decipher the basis for eEF2K protective function under nutrient deprivation, we performed gene expression analysis of control versus eEF2K
deficient cells under nutrient stress. We found that genes involved in
fatty acid oxidation (FAO) are downregulated upon eEF2K loss under
starvation. Metabolic measurements indicate that eEF2K deficient cells
exhibit defects in FAO, which is correlated with low amount of most
acylcarnitines in these cells, as compared to control cells. In addition,
levels of ATP and NADPH, which are normally produced through FAO
under nutrient deprivation, are lower in eEF2K deficient cells. Strikingly,
reactivation of FAO in eEF2K deficient cells, with a pharmacological
inducer, was sufficient to rescue cell death occurring under nutrient
depletion. Mechanistically, our data show that eEF2K is required for
the expression and activity of the PPARa transcription factor, which
stimulates the expression of a number of FAO genes.
Altogether, our work indicates that eEF2K is critical for driving FAO
activity under nutrient deprivation, which may support tumor adaptation
to nutrient stress by maintaining the energy and redox balance.
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27
Hypermutation, Neoantigen Formation and Immune Checkpoint
Inhibition for Childhood Biallelic Mismatch Repair Deficient Cancers
Brittany B. Campbell, Eric Bouffet, MD, Valerie Larouche, MD, Daniele
Merico, PhD, Richard de Borja, Brian Chung, Melissa Galati, Melyssa
Aronson, MSc, Carol Durno, MD, Joerg Kruger, MD, Vanja Cabric,
Nataliya Zhukova, MD, Vijay Ramaswamy, MD, Gary Mason, MD, Roula
Farah, MD, Samina Afza,l MD, Michal Yalon, MD, Gideon Rechavi, MD,
Vanan Magimairajan, MD, Michael F. Walsh MD, Shlomi Constantini,
MD, Rina Dvir MD, Ronit Elhasid, MD, Alyssa Reddy MD, Michael
Osborne, MD, Michael Sullivan, MD, Jordan Hansford, MD, Andrew
Dodgshun, MD, Nancy Klauber-Demore, MD, Lindsay Peterson, MD,
Sunil Patel, MD, PhD, Scott Lindhorst, MD, Jeffrey Atkinson, MD,
Rachel Laframboise, MD, Zane Cohen, MD, Peter Dirks, MD, Michael
Taylor, MD PhD, David Malkin, MD, Steffen Albrecht MD, Roy Dudley,
MD, Nada Jabado, MD PhD, Cynthia Hawkins, MD PhD, Adam Shlien,
PhD, and Uri Tabori, MD
On behalf of the International bMMRD consortium and KiCS, the
SickKids Cancer Sequencing Program, Toronto, Ontario, Canada
Biallelic mismatch repair deficiency (bMMRD) is an aggressive cancer
predisposition syndrome resulting in rapid onset of various malignancies
before age 18. Patients harbor homozygous mutations in mismatch repair
genes, resulting in a systemic loss of replication repair. Secondary loss of
polymerase proofreading due to acquired mutations in POLE during
tumorigenesis occurs frequently in bMMRD tumors. Consequently,
bMMRD tumors harbor an exceptionally high mutation burden.
Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibitors (ICIs). Exome
sequencing and neoantigen prediction was performed on 37 bMMRD
cancers and compared to childhood and adult neoplasms. Immune checkpoint inhibitors were offered to BMMRD patients with recurrent tumors.
While bMMRD brain tumors demonstrate the highest mutation loads
(mean 17,740+/-7703), all other high-grade tumors were hypermutant
(mean 1589+/-1043). bMMRD GBM harbored mean neoantigen load
7-16 times higher than immunoresponsive adult tumors (p=0.00001).
Strikingly, mutation load varies dramatically between primary and
recurrent cancers and is related to prior therapy. Spatial and temporal
sampling of individual bMMRD tumors revealed large variations in
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mutation load and neoantigen landscape. Based on these preclinical
data, bMMRD patients with recurrent cancers are treated with ICIs
with clinical and radiological responses.
This report is the first to delineate the mutable nature of the neoantigen landscape in cancers where new mutations are constantly
arising due to lack of replication repair. The encouraging responses of
recurrent cancers to ICIs can inform treatment for other hypermutant
cancers arising from primary (genetic predisposition) or secondary
mismatch repair deficiency.
Identification of Drugs with Specific Activity in vivo against Highrisk Early Thymocyte Progenitor (ETP) ALL Using Zebrafish Embryos
Shuning He, PhD1, Marc R. Mansour, MD, PhD1,2, Zhaodong Li1, and
A. Thomas Look, MD1
1
2
Dana-Farber Cancer Institute, Boston, Massachusetts, United States;
Department of Hematology, UCL Cancer Institute, University College
London, WC1E 6BT, United Kingdom
The often aggressive and unpredictable behavior of the “early thymocyte progenitor” or ETP form of high-risk T-cell ALL continues to
pose major clinical management problems. Despite whole genome
sequencing efforts, the reasons underlying the poor survival in this
T-ALL patient subgroup remain unknown. Here we identify the bZIP
transcription factor JDP2 as a novel T-ALL oncogene, overexpressed
in the ETP-ALL subgroup, and associated with poor outcome.
Furthermore, JDP2 is one of few oncogenes capable of initiating
T-ALL in transgenic zebrafish. JDP2 is required for T-ALL cell survival, as its depletion leads to apoptosis. Mechanistically, we show by
ChIP-seq that JDP2 regulates pro-survival signaling through direct
transcriptional upregulation of MCL1. Notably, thymocytes from
rag2:jdp2 transgenic zebrafish embryos express high levels of mcl1,
and demonstrate resistance to steroids, vincristine, mercaptopurine,
and methotrexate in vivo in our embryo assay, thus validating this
model system. The embryo assay, conducted in 96-well plates with
3 embryos per well, is well suited for analysis of multiple compounds
or combinations of compounds. We are analyzing drugs from the
Prestwick library of FDA approved drugs and targeted drugs that are
in phase I trials for other human cancers. Drugs that are the most
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
29
active in our ETP leukemia model include bromodomain inhibitors
and XPO-1 nuclear export inhibitors. These drugs are being tested in
combination to determine synergy by isobologram analysis. We are
now evaluating additional compounds based on the hypothesis that
it will take at least three highly active and non-cross-resistant drugs
with synergistic activity to cure ETP-ALL.
The Roles of Epigenetic and Metabolic Mutations in Stem Cell
Maintenance and Pediatric Cancers
Craig B. Thompson, MD, Memorial Sloan Kettering Cancer Center
Pediatric cancers are distinguished by a paucity of traditional oncogenic mutations. Instead, an increasing number of genes involved in
chromatin structure and cellular metabolism have been found to be
recurrently mutated in pediatric gliomas and sarcomas. A common
feature of these gene mutations is that they impair cellular differentiation. How this information contributes to our understanding of
pediatric tumors will be discussed.
Augmenting CAR T-cell Potency and Safety with Synthetic
Control Systems
Michael C. Jensen, MD, Seattle Children’s Hospital
Recent conceptual as well as technological advances in the areas
of molecular immunology, gene transfer, and cell processing have
fostered increasingly sophisticated translational applications of
adoptive T-cell therapy for oncologic disease employing geneticallymodified T-lymphocytes. My laboratory’s work focuses on T-cell
genetic modification for re-directing antigen specificity to tumors
utilizing recent advances not only in the composition and specificity
of receptor antigen recognition domains, but also the evolution of
multifunctional cytoplasmic signaling domains developed for these
chimeric antigen receptors (CARs) that provide dual activation and
co-stimulatory signaling. My group is also investigating the context
of adoptive transfer with respect to the conditioning of the recipient
for enhanced T-cell engraftment and expansion, the grafting of CARs
on to central memory T-cells having endogenous TCR specificities for
viral epitopes to which the host has robust immunity, and, the provision
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tumor microenvironment survival capabilities. The increasingly broad
array of genetic manipulations including not only transgene insertion,
but targeted gene knock out using engineered targeted nucleases
such as TALEN’s and ZFN, as well as expression regulatory constructs
provides for the creation of synthetic biology of orthogonal immune
responses based on gene modified T-cell adoptive transfer. The next
decade of advances in this arena will depend on iterative benchto-bedside back-to-the-bench translational studies capable of
sustaining the evolution of these technologies in the context of clinical
parameters relevant to the pediatric oncology patient population.
CAR Therapy: The CD19 Paradigm
Michel Sadelain, MD, PhD, Memorial Sloan Kettering Cancer Center
T-cell engineering provides a means to rapidly generate therapeutic
T-cells of any specificity. In oncology, its purpose is to generate potent
immune responses that eradicate tumor cells and overcome immune
barriers in the tumor microenvironment. T-cell engineering is predicated
on the transduction of receptors and other molecules to redirect T-cell
specificity and enhance T-cell function. Chimeric antigen receptors
(CARs) are synthetic receptors that mediate antigen recognition, T-cell
activation, and, in the case of second generation CARs, costimulation.
We demonstrated over a decade ago that human T-cells engineered
with a CAR specific for CD19 eradicated B cell malignancies in mice.
We were the first to report the remarkable complete remission rate
obtained with CD19-specific, second generation CARs in adults with
chemorefractory, relapsed acute lymphoblastic leukemia and have
recently obtained similarly striking outcomes in pediatric patients. Novel
engineering modalities, including auto- and trans-costimulation and
combinatorial antigen recognition, hold the promise of further enhancing
the effectiveness of CAR therapy against a broad range of cancers.
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31
NK-based Immunotherapy: Emerging Innate and Adaptive
Immunity with Tumor-Reactive Immunocytokines
Paul M. Sondel, MD, PhD1, Zachary S. Morris, Emily I. Guy, David
M. Francis, Monica M. Gressett, Lauren R. Werner, Lakeesha L.
Carmichael, Richard K. Yang, Eric A. Armstrong, Shyhmin Huang,
Fariba Navid, Stephen D. Gillies, Alan Korman, Jacquelyn A. Hank,
Alexander L. Rakhmilevich, Paul M. Harari
1
University of Wisconsin School of Medicine and Public Health
We have explored a novel approach to augmenting anti-tumor immune
response by combining two established cancer treatments, ionizing
radiation and tumor-specific antibodies. In single-tumor murine models
of melanoma, neuroblastoma, and head and neck squamous cell
carcinoma we observed cooperative anti-tumor interaction between
local radiation therapy and intratumoral injection of tumor-specific
antibodies resulting, in part, from enhanced antibody-dependent
cell-mediated cytotoxicity. Combined radiation and intratumoral
immunocytokine, a fusion-protein linking tumor-specific antibody to
IL2, improved this anti-tumor immune response resulting in complete
regression of established (~5-week) tumors in most animals and a
tumor-specific memory T-cell response. T-cell checkpoint blockade
is becoming a standard of oncologic care in certain cancer settings,
particularly when there is evidence of a pre-existing T-cell response.
Given the T-cell response elicited by combined local radiation
and intratumoral immunocytokine, we tested the potential benefit
of adding this treatment to checkpoint blockade. In mice bearing
large primary tumors (~7-week) or disseminated metastases, the
triple-combination of intratumoral immunocytokine, radiation, and
systemic anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody
improved primary tumor response and animal survival compared to
combinations of any two of these three interventions. Combining
radiation and intratumoral immunocytokine in murine tumor models
is an effective means to eliminate measurable tumors and elicit an in
situ vaccination effect capable of augmenting anti-tumor response to
T-cell checkpoint blockade. This combined treatment approach holds
immediate translational potential for the spectrum of human tumors
in which radiation and tumor-specific antibodies are commonly used.
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Molecular Pathogenesis and Drug Synergism in a Zebrafish Model
of High Risk Neuroblastoma
A. Thomas Look, MD1, Shuning He, PhD, Marc R. Mansour, MD, PhD,
Mark W. Zimmerman, PhD and, Koshi Akahane, MD, PhD
1
Dana-Farber Cancer Institute
We have developed a transgenic zebrafish model that overexpresses
MYCN and harbors loss-of-function mutations of the nf1 tumor
suppressor. In this model, loss of nf1 leads to aberrant activation of
RAS-MAPK signaling, promoting both increased tumor cell survival
and rapid tumor cell proliferation. These neuroblastomas are very
aggressive in that almost all of the fish develop neuroblastoma by three
weeks of age. Three-week old juvenile fish are very small, making it
feasible to test the effectiveness of many drugs and drug combinations
in vivo for activity against the primary tumors. We demonstrate these
advantages of the model by showing marked synergistic anti-tumor
effects of a MEK inhibitor (trametinib) and a retinoid (isotretinoin) in
vivo at several different dosage combinations by in vivo isobologram
analysis. Thus, inhibition of RAS-MAPK signaling can significantly
improve the treatment of this very aggressive form of neuroblastoma
when it is combined with the inhibition of other key pathways. Because
of the very high penetrance and rapid onset of neuroblastoma in our
nf1-deficient, MYCN-transgenic zebrafish model, it is one of the only
model systems in which extensive analysis of the synergistic activity
of two or more drugs can be evaluated in primary tumors in vivo. This
capability is especially valuable given that mutations causing RASMAPK pathway hyperactivation have been shown to arise frequently
at the time of relapse of childhood neuroblastomas, indicating the
need to eliminate these mutated tumor cells as a component of the
primary treatment.
Stem Cell Based Models of Medulloblastoma
Robert J. Wechsler-Reya, PhD, Tumor Initiation & Maintenance
Program, NCI-Designated Cancer Center, Sanford Burnham Prebys
Medical Discovery Institute
Medulloblastoma (MB) is the most common malignant brain tumor in
children. Despite aggressive multimodal therapy, many patients succumb
to the disease, and survivors suffer severe long-term side effects related
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33
to the therapy. Patients whose tumors exhibit overexpression or amplification of the MYC oncogene have an extremely poor prognosis, but until
recently there have been no animal models for this form of the disease.
We have generated models of MYC-driven MB by infecting cerebellar
stem cells with viruses encoding Myc and other oncogenes, and transplanting these cells into the cerebellum of naïve mice. Recipients develop
tumors that resemble human MYC-driven MB at a histological and molecular level, and depend on MYC for tumor initiation as well as maintenance.
Moreover, like their human counterparts, these tumors metastasize
through the meninges and down the spinal cord. We are using these
models to study the signaling pathways that regulate tumor growth and
metastasis. In addition, we are carrying out high-throughput drug screens
to identify novel therapeutic agents. Robust animal models are essential
tools understanding tumor biology and for developing more effective
therapies for pediatric brain tumors.
Identifying Druggable Mutations in Pediatric Solid Tumors
Michael Dyer, PhD, St. Jude Children’s Hospital, Howard Hughes
Medical Institute
Pediatric solid tumors are remarkably diverse in their cellular origins,
developmental timing, and clinical features. Over the last 5 years,
there have been significant advances in our understanding of the
genetic lesions that contribute to the initiation and progression of
pediatric solid tumors. To date, over 2,000 pediatric solid tumors have
been analyzed by Next-Generation Sequencing. These genomic data
provide the foundation to launch new research efforts to address one
of the fundamental questions in cancer biology—why are some cells
more susceptible to malignant transformation by particular genetic
lesions at discrete developmental stages than others? Because of
their developmental, molecular, cellular, and genetic diversity, pediatric solid tumors provide an ideal platform to begin to answer this
question. However, this diversity is also a major clinical challenge.
There have not been significant improvements in overall survival for
children with solid tumors over the past 25 years. In this seminar, I
will highlight the diversity of pediatric solid tumors and provide a
new framework for studying the cellular and developmental origins of
pediatric cancer to identify novel druggable pathways.
34
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
Establishing New Rules for Pediatric Cancer Trials
in a Post-genomic World: Defining the Issues
Lee J. Helman, MD, National Cancer Institute, U.S. National Institutes
of Health
Abstract not available at the time of printing.
Next Generation Personalized Neuroblastoma Therapy
Yael Mossé, MD, The Children’s Hospital of Philadelphia
Relapsed high-risk neuroblastoma remains largely incurable despite
a dramatic increase in our knowledge of the genetic basis of the
disease. Our group and others have recently completed large
sequencing projects designed to define the genomic landscape of
diagnostic high-risk NB. These studies had remarkably similar results,
showing a relatively low frequency of somatic mutation, challenging
the concept of genomics-based targeted therapy. However, because
biopsies of relapsed neuroblastomas are seldom obtained, our ability
to understand the relapsed NB genome has been challenging. We
addressed this unmet need through an international collaboration
where we gathered every available case of banked diagnostic and
relapsed NB tumor material with a matched constitutional DNA specimen, and performed whole genome sequencing of these “trios”. We
hypothesize that genomic aberrations in NB act as potent oncogenic
drivers and can be used to select rational and effective therapies targeting the ALK-RAS-MAPK Pathway. The primary objective of this study
is to assess the anti-tumor efficacy of selected combinations of targeted
agents following biopsy and next-generation sequencing (NGS) defined
biomarker identification for assignment of therapy. This study will assess
the objective response rate (ORR) of novel combinations of investigational agents selected by evidence-based NGS biomarker assessment of
tumor tissue at the point of entry into the trial. This proposal will also
monitor clonal evolution through the serial assay of mutational flux in
circulating tumor DNA, a novel new aspect of this trial that will further
enhance the potential translational impact of this work.
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
35
Harnessing Genomics for Diagnosis and Treatment Selection
in the Pediatric Oncology Clinic
Katherine A. Janeway, MD, MMSc, Dana-Farber/Boston Children’s
Cancer and Blood Disorders Center
Childhood sarcomas can be categorized in terms of their genome
based on the presence of absence of a translocation. The translocationassociated sarcomas have relatively few additional mutations while
many translocation negative sarcomas have targetable genomic
alterations. An understanding of genomic mechanisms in sarcoma
and the impact of genomic alterations on biology has led to interest
in rational trials of novel agents in both translocation positive and
translocation negative sarcomas such as trials of EZH2 inhibitors in
synovial sarcoma. In addition, recent evidence from clinical sequencing
studies in children with relapsed and refractory cancer supports a
precision cancer medicine approach and the use of advanced molecular
diagnostics to clarify diagnosis in some children with sarcoma.
36
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
NOTES
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
37
PROMOTIONAL PARTNERS
38
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
ACADEMY PUBLICATIONS
Annals of the New York Academy of Sciences
volume
1346
Companion
Diagnostics
From Biomarker Identification
To Market Entry
June 2015
Volume 1346 Companion Diagnostics: From
Biomarker Identification to Market Entry
Pages v–vi, 1–89
Edited by Claudio Arini
http://onlinelibrary.wiley.com/doi/10.1111/
nyas.2015.1346.issue-1/issuetoc
eBriefings
Academy Members receive unlimited online access to our entire
collection of eBriefings. Here are some eBriefings that may be of
interest to you.
Cancer Cell Metabolism: Unique Features Inform New
Therapeutic Opportunities
www.nyas.org/TumorMetabolism-eB
From Tumor Suppressors to Oncogenic Dynamics:
The 2015 Dr. Paul Janssen Award Symposium
www.nyas.org/Janssen2015-eB
Dendritic Cell Therapies for Cancer: Biotech’s Bumpy Road
to the Market
http://www.nyas.org/DendriticCells-eB
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
39
The Sohn Conference Foundation thanks the Scientific
Organizing Committee for its tremendous work to
create the inaugural scientific Sohn Conference with
the New York Academy of Sciences.
The Foundation extends special recognition to three Conference
speakers who are also honored grantees of the Foundation:
SCOTT ARMSTRONG , MD, PhD
Memorial Sloan Kettering Cancer Center
ANDREW KUNG , MD, PhD
Columbia University Medical Center
DAVID C . LYDEN, MD, PhD
Weill Cornell Medical College
The Foundation also extends a warm welcome to the
Damon Runyon-Sohn Pediatric Cancer Fellows.
Ozlem Aksoy, PhD, University of California, San Francisco
Amanda L. Balboni, PhD, Dana-Farber Cancer Institute
Kenneth Chen, MD, University of Texas Southwestern Medical Center
Scott Haihua Chu, PhD, Memorial Sloan Kettering Cancer Center
Stacy L. Cooper, MD, Johns Hopkins University
Lara E. Davis, MD, Oregon Health & Science University
Shuibin Lin, PhD, Boston Children’s Hospital
Zhipeng Lu, PhD, Stanford University (Layton Family Fellow of the
Damon Runyon-Sohn Foundation Pediatric Cancer Fellowship Award)
Amit Sabnis, MD, University of California, San Francisco Medical Center
Angela J. Sievert, MD, Children’s Hospital of Philadelphia
Ly P. Vu, PhD, Memorial Sloan Kettering Cancer Center
Leo D. Wang, MD, PhD, Dana-Farber Cancer Institute
David W. Woessner, PhD, St. Jude Children’s Research Hospital
Mark W. Zimmerman, PhD, Dana-Farber Cancer Institute
40
SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
INTRODUCING A NEW BOOK SERIES
A co-publication of the New York Academy of Sciences and
John Wiley & Sons, the series will cover a wide variety of
topics in the life and physical sciences in several different
formats, including educational textbooks, professional
research books, handbooks, and techniques books.
The Academy will consider proposals in all life and physical sciences, including:
Addiction • Antibiotics/Antimicrobial Therapeutics • Biomarkers • Cancer
Climate Change • Cognitive Neuroscience • Early Child Development
Ecology and Conservation Biology • Genomics/Genetic Diseases • Immunology
Microbiology/Infectious Diseases • Neuroscience • Nutrition • Obesity
Physiology/Pathophysiology • Psychiatry/Psychology • Stem Cells
STEM Education • Systems Biology
If you are interested in discussing a project, please contact:
Dr. Douglas Braaten | [email protected]
In your proposal please include author/editor CV(s), a brief description of the book
and target audience, and a table of contents (with contributors, if relevant).
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The Academy invites conference proposals in a variety of fields:
biomedical sciences, chemistry, physical sciences, engineering, technology, and others. The Academy will give priority to conferences in
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SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD
43
The New York Academy of Sciences is an independent, not-for-profit
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Since 1996, the world-renowned Sohn Investment Conference has been
the premier investment forum, bringing together the world’s savviest
investors to share fresh insights and strategies in support of pediatric
cancer research and treatment. Wall Street’s best and brightest investors
participate in this unique, “must attend” event to share their expertise
with an audience of more than 3,000 people, comprised of portfolio
managers, asset allocators and private investors. Most speakers manage
large proprietary investment portfolios that have outperformed the
market for many years and do not share their insights in any public
forum, but they volunteer their time to the Conference for the benefit
of the Foundation. All contributions support the Foundation’s mission to
support pediatric research and care.
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