Sohn Conference: Pediatric Cancer in a Post-genomic World

Agenda

* Presentation titles and times are subject to change.

Abstracts

Keynote: The Successes and Future Direction of Pediatric Cancer Research and Therapy
Richard Gilbertson, MD, PhD, 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 pediatric 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 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, Cancer Genomics to Identify Novel Biomarkers and Drivers and to Enable Precision Therapeutics, National Cancer Institute, National Institutes of Health

I will describe how first generation genomics identified the oncogenic role of FGFR4 in Rhabdomyosarcoma (RMS). I will go onto 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 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, PhD MD, 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 chimeric proteins that fuse the NH3-terminus of MLL to the COOH-terminus 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
Nada Jabado, MD, PhD, McGill University

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.
 
Coauthors: Jacek Majewski, McGill University and Génome Québec Innovation Centre, Montreal; and Javad Nazarian, Research Center for Genetic Medicine, Children's National Health System, Washington, DC.

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?

Targeting Folate Metabolism in Leukemia
Kimberly Stegmaier, MD, Dana-Farber Cancer Institute

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

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, PhD, 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, 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.
 
Coauthors: Ayuko Hoshino, Bruno Costa-Silva, Irina Matei, Volkmar Muller, Klaus Pantel, Benjamin A. Garcia, Yibin Kang, Cyrus M. Ghajar, Hector Peinado, and Jacqueline Bromberg.

Keynote: The Roles of Epigenetic and Metabolic Mutations in Stem Cell Maintenance and Pediatric Cancers
Craig B. Thompson, 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 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.

NK-based Immunotherapy: Emerging Innate and Adaptive Immunity with Tumor-Reactive Immunocytokines
Paul M. Sondel, MD, PhD, 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.
 
Coauthors: 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, and Paul M. Harari.

Molecular Pathogenesis and Drug Synergism in a Zebrafish Model of High Risk Neuroblastoma
A. Thomas Look, MD, Dana-Farber Cancer Center, Harvard University

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 3 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.
 
Coauthors: Shuning He, Marc R. Mansour, Mark W. Zimmerman, and Koshi Akahane.

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 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.

Next Generation Personalized Neuroblastoma Therapy
Yael Mosse, 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.

New Strategies in Sarcoma Therapy: Linking Biology and Novel Agents
Katherine A. Janeway, MD, MMSc, Dana-Farber Cancer Institute, 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.

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