SOHN CONFERENCE: Pediatric Cancer in a ... - München Klinik

March 30 – April 1, 2016 www.nyas.org/Sohn2016 #Sohn2016The New York Academy of Sciences New York City

SOHN CONFERENCE:Pediatric Cancer in a Post-genomic World

Presented by

2 SOHN CONFERENCE: PEDIATRIC CANCER IN A POST-GENOMIC WORLD

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

A. Thomas Look, MD, Dana-Farber Cancer Institute

David C. Lyden, MD, PhD, Weill Cornell Medical College

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

Tiffany Stevens, JD, The Sohn Conference Foundation

Michael Taylor, MD, PhD, The Hospital for Sick Children, University of Toronto

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3SOHN 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.


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, MScDirector, Life Sciences ConferencesThe New York Academy of Sciences

Evan SohnVice President and Co-Founder The Sohn Conference Foundation


FACULTY DISCLOSURES

All faculty participating in this activity are required to disclose to the audience any significant financial interest and/or other relation-ship 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 Dyer, PhD None

Richard Gilbertson, MD, PhD None

Nancy Goodman, JD None

Brooke Grindlinger, PhD Shareholder: General Electric Co., Gilead Sciences Inc.

Lee J. Helman, MD None

Nada Jabado, MD, PhD None

Katherine A. Janeway, MD, MMSc None

Michael C. Jensen, MD Research Support: Juno Therapeutics, Inc. Shareholder: Juno Therapeutics, Inc. Consultant: Juno Therapeutics, Inc.

Javed Khan, MD 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

A. Thomas Look, MD None

David C. Lyden, MD, PhD None

Elizabeth Maher, MD, PhD None

David Malkin, MD None

John M. Maris, MD None

Yael Mossé, MD Research Support: Novartis


Kathy Pritchard-Jones, BM BChir None

Daniel Radiloff, PhD None

Charles W. M. Roberts, MD, PhD Research Support: Novartis Institutes for Biomedical Research Consultant: Novartis Institutes for Biomedical Research

Michel Sadelain, MD, PhD Shareholder: Juno Therapeutics, Inc. Consultant: Juno Therapeutics, Inc.

Paul M. Sondel, MD, PhD None

Poul H. Sorensen, MD, PhD None

Kimberly Stegmaier, MD None

Michael Taylor, 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.


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


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


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


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


5:55 PM Day 2 Adjourns


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


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


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


4:30 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.


ABSTRACTS The Successes and Future Direction of Pediatric Cancer Research and TherapyRichard 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 oncol-ogy community has led the world of cancer research in the use of ‘omic technologies, the integration of developmental and cancer biol-ogy, 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 disease-related 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


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.


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 medullo-blastomas 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 abnormali-ties are associated with poor clinical outcomes and new therapeutic approaches are needed. Rearrangement of the MLL gene generates


chimeric proteins that fuse the NH3-terminus of MLL to the COOH-terminus of its translocation partners. These MLL-fusion oncopro-teins 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 expres-sion 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 dis-ruptor 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 Giloma1Nada Jabado, MD, PhD, McGill University, 2Jacek Majewski, PhD, 3Javad Nazarian, PhD

1 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

Diffuse Intrinsic Pontine Gliomas (DIPG) are deadly pediatric brain tumors where needle biopsies help guide diagnosis and targeted


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.


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?


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 trans-position 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 medulloblas-toma. 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 morpho-logic 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 ther-apeutic strategies for rhabdoid and other childhood tumors involving endogenous DNA transposases.


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

1 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

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 tumorige-nicity 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


a striking decrease in proliferation and increase in apoptosis specifi-cally 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

1 The Rockefeller University, New York, New York, United States; 2 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

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.


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


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


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 pro-posed 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 incom-ing metastatic “seeds”. However, by what mechanism this occurs,


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 pan-creatic 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 predomi-nantly 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 redi-rected 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


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

1 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

During tumour progression, pediatric brain tumour cells experi-ence 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 depri-vation, 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.


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 asso-ciated 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 check-point 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


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 neo-antigen 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 High-risk 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 Dana-Farber Cancer Institute, Boston, Massachusetts, United States;2 Department of Hematology, UCL Cancer Institute, University College

London, WC1E 6BT, United Kingdom

The often aggressive and unpredictable behavior of the “early thy-mocyte 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 sur-vival, 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


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 CancersCraig B. Thompson, MD, Memorial Sloan Kettering Cancer Center

Pediatric cancers are distinguished by a paucity of traditional onco-genic 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 differ-entiation. 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 genetically-modified 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


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 bench-to-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.


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.


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 RAS-MAPK 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


to the therapy. Patients whose tumors exhibit overexpression or amplifi-cation 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 trans-planting these cells into the cerebellum of naïve mice. Recipients develop tumors that resemble human MYC-driven MB at a histological and molec-ular 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, pedi-atric 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.


Establishing New Rules for Pediatric Cancer Trials in a Post-genomic World: Defining the IssuesLee 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 spec-imen, 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 tar-geting 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 investiga-tional 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.


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 translocation-associated 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.


NOTES


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speakers who are also honored grantees of the Foundation:

SCOT T ARMSTRONG , MD, PhD Memorial Sloan Kettering Cancer Center

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DAVID C . LYDEN , MD, PhDWeill Cornell Medical College

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Ozlem Aksoy, PhD, University of California, San Francisco

Amanda L. Balboni, PhD, Dana-Farber Cancer Institute

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Scott Haihua Chu, PhD, Memorial Sloan Kettering Cancer Center

Stacy L. Cooper, MD, Johns Hopkins University

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