Funding Childhood Cancer Research
The Andrew McDonough B+ Foundation® is proud to announce the recipients of the Fall 2018 Research Grant Cycle. A total of $1,500,000 was awarded across 10 two-year grants of $75,000/year. Please see below for a list of the awardees.
Part of our mission is to provide childhood cancer funding. We are humbled and appreciative to have such a distinguished panel of world-class pediatric oncology clinicians and researchers on The B+ Foundation® Scientific Advisory Board. Upon the recommendations of this esteemed group, The B+ Foundation® looks forward to continuing to play a very active role in childhood cancer research funding.
Scientific Advisory Board
The members of The B+ Foundation® Scientific Advisory Board are:
Dr. Peter C. Adamson
Peter C. Adamson, MD is Chair of the Children’s Oncology Group (COG), a National Cancer Institute (NCI) supported international consortium of more than 220 childhood centers that conducts clinical-translational research, including phase 1, 2 and 3 clinical trials, in children with cancer. He is Professor of Pediatrics and Pharmacology of the University of Pennsylvania School of Medicine at The Children’s Hospital of Philadelphia. Dr. Adamson is Board Certified in both Pediatric Hematology/Oncology and in Clinical Pharmacology. He is an internationally recognized leader in pediatric cancer drug development, having served until 2008 as Chair of the COG’s Developmental Therapeutics Program. Prior to becoming Chair of the COG, Dr. Adamson served as Director for Clinical and Translational Research at The Children’s Hospital of Philadelphia. His laboratory focuses on the clinical pharmacology of new drugs for childhood cancer. In June 2015, Dr. Adamson was appointed by President Obama to be a Member of the National Cancer Advisory Board.
Dr. Andy Kolb
Andy Kolb, MD received his undergraduate education at the University of Pennsylvania and his medical degree from Jefferson Medical College. After a residency in pediatrics at St. Christopher’s Hospital for Children, Dr. Kolb completed his fellowship training at Memorial Sloan-Kettering Cancer Center. He now serves as the Director of the Nemours Center for Cancer and Blood Disorders in Wilmington, DE. Dr. Kolb is a clinician scientist primarily focused in the laboratory and in the clinic on the efficient and effective translation of novel therapies into children. He is a founding member of the National Cancer Institute funded Pediatric Preclinical Testing Program and has successfully completed preclinical evaluations of numerous compounds and aided in the translation of these agents into clinical trials. In exploring the mechanism of action of targeted compounds, Dr. Kolb has developed an expertise in proteomics and cell signaling. Dr. Kolb serves within the Children’s Oncology Group (COG) as Chair of the Myeloid Disease Committee, Member of the Scientific Council, and Member of the Bone Tumor Committee. Through this work, Dr. Kolb has also developed expertise and experience in collaborative science, resource stewardship, clinical research development, clinical trial design and implementation, and in the necessities of young investigator development.
Dr. Julie R. Park
Julie R. Park, MD is attending physician at Seattle Children’s Hospital, professor in pediatrics at the University of Washington School of Medicine and associate in the Clinical Research Division at Fred Hutchinson Cancer Research Center (FHCRC). She is director of the pediatric hematology-oncology fellowship at the University of Washington.
Dr. Park is an active member of the Children’s Oncology Group Consortium and as chair of the COG Neuroblastoma Scientific Committee provides leadership for the development of neuroblastoma clinical research within COG. Dr. Park’s primary research focus has been investigating novel therapies for the treatment of high-risk neuroblastoma, a rare but aggressive form of childhood cancer. She has conducted a multi-center clinical trial to determine the feasibility and toxicity of a novel induction chemotherapy regimen for high-risk neuroblastoma and has collaborated with local and national investigators to optimize the use of radiation therapy as part of treatment for neuroblastoma. Dr. Park’s work has led to her development of the current national randomized phase III trial within COG for treatment of newly diagnosed high-risk neuroblastoma. Dr. Park has ongoing collaborations with Dr. Michael Jensen and is currently the primary investigator on an early phase clinical trial that uses adoptive immunotherapy approaches to treat neuroblastoma. Dr. Park also leads the Advanced Therapeutics Program at Seattle Children’s Hospital and has steered Seattle Children’s into becoming a leading participant in the Phase I Consortium of COG and the New Approaches to Neuroblastoma Therapy Consortium. She has been actively involved in the development of novel chemotherapeutic agents that may block critical tumor cell pathways necessary for tumor cell growth and survival.
Dr. Todd Druley
Todd Druley, MD, PhD is a board-certified pediatric hematologist/oncologist and Assistant Professor of Pediatrics, Developmental Biology and Genetics at Washington University School of Medicine. He obtained a BS in Cell and Structural Biology and a minor in Chemistry from the University of Illinois. He then completed the MD/PhD program at the University of Illinois, where he studied mechanisms of chemotherapy resistance. In 2002, Dr. Druley joined Washington University as a pediatric resident and has remained, completing his fellowship in Pediatric Hematology and Oncology and joining the faculty in 2008. He is a member of the Children’s Oncology Group (COG) Myeloid Disease Committee and Epidemiology Committee. Research in the Druley Lab is based on characterizing the link between abnormal human development and early childhood cancer, particularly infant leukemia. The lab has a track record for genomic methodology development and is currently applying that technology with the COG to improve molecular diagnostics in pediatric AML. Clinically, Dr. Druley is focused on pediatric cancer predisposition and serves as the co-director of the Pediatric Cancer Predisposition Program at St. Louis Children’s Hospital.
Dr. Michael Jensen
Michael Jensen, MD is director of the Ben Towne Center for Childhood Cancer at Seattle Children’s Research Institute and professor of hematology-oncology at the University of Washington School of Medicine. He is member of the clinical division in the Program in Immunology at Fred Hutchinson Cancer Research Center (FHCRC). Jensen holds the Janet and Jim Sinegal Endowed Chair in Pediatric Solid Tumor Research in Honor of Korey Rose.
Dr. Michael Jensen graduated from the University of Pennsylvania School of Medicine then completed training in Pediatric Hematology and Oncology at the University of Washington/Fred Hutchinson Cancer Research Center. His laboratory work began under the mentorship of Dr. Philip Greenberg, Program Head in Immunology, FHCRC and focused on the immunobiology of tumor-specific T-cells. Following completion of his fellowship, Dr. Jensen joined the faculty at the City of Hope National Medical Center where he built a translational research program integrating gene therapy and cellular immunotherapy for cancer. This program grew in to the Department of Cancer Immunotherapeutics & Tumor Immunology within the Beckman Research Institute and was incorporated into the institution’s NCI-Comprehensive Cancer Center as the Cancer Immunotherapeutics Program with Dr. Jensen as its leader. During his tenure at City of Hope, Dr. Jensen’s research program placed a strong emphasis on bench-to-bedside translational research and resulted in seven FDA-authorized Investigational New Drug Applications covering first-in-human applications of adoptive transfer of genetically engineered T-cells having re-directed tumor specificity for lymphoma, neuroblastoma, and malignant gliomas. In 2010, Dr. Jensen joined the University of Washington School of Medicine faculty as a Professor of Pediatrics and is the founding director of the Ben Towne Center for Childhood Cancer Research. Dr. Jensen is an Adjunct Professor of Bioengineering and Neurological Surgery at the University of Washington School of Medicine and a Joint Member of the Clinical Research Division at Fred Hutchinson Cancer Research Center. Dr. Jensen is an Associate Head of the Immunology and Vaccine Development Program of the UW-FHCRC Cancer Consortium and is a SU2C Dream Team Principal Investigator on the recently awarded Pediatric Cancer Research Immunogenomics Dream Team award.
Dr. A. Thomas Look
A. Thomas Look, MD, is a Professor of Pediatrics at Harvard Medical School and Vice Chair for Research in the Department of Pediatric Oncology at the Dana-Farber Cancer Institute, as well as co-leader of the Dana-Farber/Harvard Cancer Center’s Leukemia Program. Over the past three decades, Dr. Look has published multiple peer-reviewed papers about the molecular basis of cancer and the application of molecular genetic findings to improve the treatment of childhood malignancies, particularly T-cell acute leukemia, myelodysplastic syndrome and neuroblastoma. He moved from St Jude Children’s Research Hospital to Dana-Farber Cancer Institute in 1999 specifically to establish a research program in the zebrafish model, to conduct genetic studies aimed at the identification of novel targets for cancer therapy, and he is now internationally recognized as a leader in this field.
His initial work led to the first transgenic model of leukemia in the zebrafish, paving the way for small-molecule drug and targeted genetic modifier experiments in a vertebrate disease model. More recently, his laboratory has developed the first zebrafish transgenic model of childhood neuroblastoma, opening up the opportunity to apply the powerful genetic technology available in the zebrafish to identify new molecular targets for therapy in this devastating childhood tumor.
He is the principal investigator on several NIH-funded grants, including a Program Project focusing on T-ALL pathogenesis. He has won numerous awards, including the Allison Eberlein Award for Childhood Leukemia Research, the Award for Excellence from the American Academy of Pediatrics, the Pediatric Oncology Lectureship of the American Society of Clinical Oncology, the ASPHO Frank A. Oski Memorial Lectureship Award of the American Society of Pediatric Hematology and Oncology, and he is a Fellow of the American Association for the Advancement of Science.
Dr. Look received his MD degree and postgraduate training in Pediatrics from the University of Michigan, and his fellowship training in Pediatric Oncology at St. Jude Children’s Research Hospital. Prior to his appointment at Harvard, he was a professor at the University of Tennessee College of Medicine.
Dr. Stephen Skapek
Stephen Skapek, MD holds the Distinguished Chair in Pediatric Oncology Research at the University of Texas Southwestern Medical Center, where he serves as the Chief of the Division of Hematology-Oncology in the Department of Pediatrics, and the Medical Director the Pauline Allen Gill Center for Cancer and Blood Disorders at Children’s Medical Center in Dallas.
Dr. Skapek graduated from the Duke University School of Medicine, completed his pediatric residency training at the Wilford Hall Medical Center at Lackland AFB in San Antonio, Texas, and completed fellowship training in pediatric hematology and oncology at the Harvard Medical School’s Dana Farber Cancer Institute and Boston Children’s Hospital.
After completing his training, Dr. Skapek has focused clinical work on caring for children with rhabdomyosarcoma and other soft tissue sarcomas, and he has carried out both laboratory-based research in cancer and developmental biology and clinical research through the Children’s Oncology Group, which he serves as a member of the Scientific Council and Executive Committee and also as vice-Chair of the Soft Tissue Sarcoma Committee.
Dr. Lewis Silverman
Dr. Silverman is Director of the Pediatric Hematologic Malignancy Program at Dana-Farber Cancer Institute and Boston Children’s Hospital and is a Professor of Pediatrics at Harvard Medical School. He leads the DFCI ALL Consortium, a multi-institutional clinical trials group focused on developing more effective and less toxic therapies for children and adolescents with newly diagnosed ALL. He is the Principal Investigator of an international Phase III trial in pediatric Philadelphia chromosome-positive ALL being conducted by the Children’s Oncology Group (COG) and the multi-national European EsPhALL group. Other leadership roles include serving on the COG Scientific Council and as Scientific Chair for the TACL Consortium, which conducts trial for children with relapsed and refractory leukemia and lymphoma.
Recent B+ Grants Awarded to:
Dr. Alexander Bishop - University of Texas Health Science Center at San Antonio, San Antonio, TX
Targeting RNA Processing Defects of Ewing Sarcoma
Ewing sarcoma (EwS) is a disease driven by the fusion of two genes, EWSR1 and FLI1, creating EWSR1-FLI1. In normal cells, EWSR1 has the ability to bind RNA and plays a role in RNA processing. EwS cells have problems properly processing RNA which is thought to be due to the fusion gene interfering with the normal function of EWSR1. We recently discovered that EWSR1 controls the activity of the RNA producing machinery (RNA polymerase) and that in EwS cells this machinery is overactive, producing more RNA than in normal cells. We believe that EwS cells are unable to process the increased amount of RNA efficiently and therefore these cancer cells may be more sensitive than normal cells to agents that target RNA processing. We screened the whole genome, targeting each gene individually, and found that EwS are very sensitive to targeting RNA processing genes. This is a key finding that could lead to alternate targeted treatment options for this disease. We propose to further investigate the results, identify which RNA processes are particularly important for EwS and whether available pharmaceuticals targeting these processes can be used effectively to treat this disease. As with any strategy to specifically target cancer, the key is to identify how these cancers differ from the norm and then explore whether this difference can be therapeutically targeted. Clinically relevant RNA processing inhibitors currently exist and we will test them in preclinical models of EwS.
Dr. Kara Davis - Stanford University, Stanford, CA
Predicting Post-Treatment Relapse in Pediatric AML Using Single-Cell Proteomics
Roughly 500 children are diagnosed with acute myeloid leukemia (AML) each year in the United States. While most children initially respond to standard chemotherapy, nearly 40% ultimately relapse, making AML the deadliest blood cancer in childhood. Despite significant advancements in the treatment of other kinds of acute pediatric leukemia—such as B-cell Progenitor Acute Lymphoblastic Leukemia (BCP-ALL)— in recent years, clinical outcomes in pediatric AML have remained poor for decades, with the majority of mortalities attributable to relapsed disease. To better characterize why some pediatric AML patients ultimately relapse while others do not, the proposed project will use state-of-the-art molecular profiling approaches to characterize millions of primary AML cells and their computational “alignment” with the different stages of healthy blood cell development. These data will be used to develop a method of predicting at diagnosis which patients have a high risk of relapse and which patients have a low risk of relapse. Successful completion of this research will identify the most prognostically important cell populations in pediatric AML as well as potential therapeutic targets in the management of this poorly-understood childhood illness.
Dr. Alan Friedman - Johns Hopkins University School of Medicine, Baltimore, MD
Activation of NF-kB in Neuroblastoma Myeloid Cells
Malignant tumors develop means to evade the immune system. An exciting recent advance is the use of checkpoint inhibitors to reactivate T cells within the immune system, which has led to major responses in several cancers. Myeloid cells are a second key component of the immune system. Cancers attract myeloid cells and stimulate them to adopt tumor-promoting M2 features. Conversion of tumor myeloid cells to the anti-cancer M1 state would represent a new immunotherapy strategy. Myeloid cells that lack a protein called NF-?B p50 adopt M1 features and cannot be directed to become M2 by cancers. Several cancers grow slower in mice lacking p50, and when we treat mice with myeloid cells lacking p50, several types of tumors respond. This proposal seeks to use mouse models to validate and optimize p50-deficient myeloid cell therapy against neuroblastoma, a pediatric cancer that is often highly aggressive in patients over 18 months of age. Aim 1 will determine whether neuroblastoma grows slower in mice lacking p50. Aim 2 will determine whether infusion of myeloid cells lacking p50 slows neuroblastoma tumor growth. In both aims, we will also evaluate whether combining T cell checkpoint inhibitors or agents that modify DNA to stimulate the immune response with myeloid cells lacking p50 benefits therapy of neuroblastoma. Successful completion of these studies will encourage us to test the utility of myeloid cells lacking NF-kB p50 as a novel immunotherapy for patients with neuroblastoma.
Dr. Siddhartha Mitra – University of Colorado Denver, AMC and DC, Aurora, CO
Overcoming Innate Immune Evasion in Pediatric High Grade Glioma
Few therapies have been aimed at stimulating the myeloid arm of the immune system to attack tumors. As one of the earliest immunologic defense mechanisms of the developing fetus, the innate immune system, which begins developing during the first trimester of gestation, is a potent cell scavenger within children. We previously showed that anti-CD47 monoclonal antibody activates the innate immune system showing significant activity against high-grade glioma including pediatric glioblastoma and Diffuse intrinsic pontine glioma. However for phagocytosis to occur eat-me signals are required to be exposed on the outer surface of the cells. Depending on the initiating stimulus such as Irradiation, cancer cell death can be immunogenic as they lead to surface expression changes termed, Damage Associated Molecular Patterns which acts as eat me signals marking them for clearance by macrophages. Therefore, there is an overlap in the signals that induce anti-tumor activity in the standard of care therapy and anti-CD47 therapy. Here We hypothesize that irradiating pediatric high-grade glioma tumors, activates DAMP pathways, leading to increased pro-phagocytosis signals on tumor cell surface, making them more susceptible to macrophage-mediated phagocytosis by overcoming the immune evasion mechanisms. Performing these studies we will facilitate a new clinical paradigm.
Dr. Michele Redell – Baylor College of Medicine, Houston, TX
Targeting Signaling Pathways that Confer Cytarabine Resistance in Pediatric AML
Nearly 40% of children with acute myeloid leukemia (AML) relapse, and many of them die of progressive AML. Current treatments still use the same old drugs, including cytarabine. Patients with detectable AML after one cycle of treatment have a very high risk of relapse. This residual leukemia is the focus of our proposal. Our goal is to identify and block the processes that allow some AML cells to survive treatment. Interactions between AML cells and the bone marrow environment support survival of a small number of AML cells, but scientists have not yet figured out how to overcome this problem. Studies with AML patients and with mice that received cytarabine have shown that residual AML cells are changed in ways that favor cytarabine resistance. Our experiments confirm that AML cells from mice treated with cytarabine have higher activity of a survival protein, STAT3, than AML cells from mice treated with placebo. We hypothesize that resistance processes are enhanced in AML cells that survive cytarabine, and blocking these processes reduces residual disease and prolongs survival. We will engineer changes in AML cells to interrupt the processes that promote cytarabine resistance, and compare the effectiveness of cytarabine in mice with engineered AML cells compared to normal AML cells. Also, we will test drugs that block resistance processes in mice with human AML. This research will lead to novel strategies to overcome cytarabine resistance so that more children will be cured.
Dr. Jean-Francois Rual - The Regents of the University of Michigan, Ann Arbor, MI
L3MBTL3, A Therapeutic Target in Acute Myeloid Leukemia
Billions of white blood cells are formed every day in the bone marrow. Leukemia occurs when cell proliferation becomes uncontrolled. As part of a complex ensemble of regulators of blood cells, the “Notch signaling pathway” helps maintain the balanced generation and proliferation of white blood cells. Several labs observed that increasing Notch signaling in Acute Myeloid Leukemia (AML) cells impairs their proliferation and may thus provide therapeutic benefit for AML patients. What mechanisms contribute to switching Notch signaling off in blood cells? Could these mechanisms be targeted for the therapeutic benefit of leukemia patients? The Rual lab recently discovered that the L3MBTL3 gene is a repressor of Notch signaling. We hypothesize that the inhibition of L3MBTL3 in AML cancer cells and the associated “de-repression” of Notch signaling could provide therapeutic benefit in AML. With the support of the B+ Foundation, we propose to test this hypothesis by studying the extent to which inhibiting L3MBTL3 modulates cancer progression in mouse models of AML. Our study could offer critical mechanistic insights on the role of the L3MBTL3 in AML that could be harnessed in the future for the therapeutic benefit of AML patients.
Dr. Robert Schnepp – Emory University - Winship Cancer Institute, Atlanta, GA
Uncovering the Contribution of RNA Binding Proteins to Neuroblastoma Aggression
High-risk neuroblastoma is an extremely aggressive pediatric cancer of the developing sympathetic nervous system. Unfortunately, fewer than 50% of patients survive and survivors experience multiple treatment-related side effects, including decreased growth/development, bone damage, and an increased risk of developing other cancers. Thus, novel targets and therapies must be developed for this disease.
This study focuses on a poorly characterized class of proteins known as RNA binding proteins (RBPs). These proteins bind RNA, which contains the direct instructions to make proteins (proteins carry out many key functions in cells). We have now discovered that the RBP, Musashi 2 (MSI2), is highly expressed in neuroblastoma, causing uncontrollable growth. We will determine how MSI2 causes neuroblastoma to act aggressively, studying its function in cell line and animal models and determining other signaling networks with which MSI2 communicates. MSI2 constitutes a promising drug target and our studies will help build the initial foundation for potentially drugging this protein directly or indirectly. In addition, there are approximately 1550 other RBPs and we will use a “high-throughput” technique that will allow us, for the first time, to determine how RBPs contribute to neuroblastoma aggression. We believe that our focused studies on MSI2 as well as our more global studies on the 1550 other RBPs will nominate new therapeutic targets for this aggressive disease.
Dr. Jeffrey Skolnick – Georgia Tech Research Corporation, Atlanta, GA
A Novel Approach to Target ACVR1 as a Treatment to Pediatric Cancer
Brain cancers are the leading cause of cancer-related deaths in childhood. Each year about 300 children in the US are diagnosed with Diffuse Intrinsic Pontine Gliomas (DIPGs), which accounts for 10% of childhood cancer patients. Due to the delicate location of these tumors, surgical resection is not practical, and these patients also do not respond well to current cancer therapies. The survival rate for DIPG patients is less than 20% two years after the initial diagnosis. Therefore, there is a pressing need to develop new, effective therapeutics for DIPGs. Recently, several independent whole-genome sequencing studies on the DIPG tumor tissues have found a new cancer-driver gene known as ACVR1. About 30% of DIPG patients harbor deleterious genetic mutations in their ACVR1 genes, which are believed to contribute to the cause of the disease. Here, the goal is to target ACVR1 in a series of combined computational and experimental studies. By using high-resolution structural data, state-of-the-art virtual screening tools, and experimental validation, two strategies will be adopted to alleviate the deleterious effects of ACVR1 mutations. First, the team will look for novel inhibitors that target ACVR1 mutants found in DIPG patients. Second, the team will look for small-molecule compounds that may restore the regulation of ACVR1. The outcome of the study will suggest possible therapies using repurposed FDA approved drugs for compassionate use or novel small-molecule compounds for clinical trials.
Dr. Xiaolei Su - Yale University, New Haven, CT
Molecular Mechanism of CAR Activation in Targeting B Cell Leukemia
Childhood cancer is the #1 disease killer of children in the United States. Among all the childhood cancers, Leukemias, cancers of bone marrow and blood, are the most common type. The development of chimeric antigen receptors (CARs) marked a new era for leukemia therapy. CAR-mediated therapy has been successfully adopted in treating pediatric acute lymphoblastic leukemia and other childhood leukemias. Meanwhile, significant challenges remain including cytokine release syndrome, neurotoxicity, and incomplete patient response. This raises the necessity to understand CAR function at the molecular level so that new tools for CAR therapy could be developed to improve its therapeutic effect. In this proposal, I aim to reveal how a tumor antigen could activate CAR to induce immune responses towards cancer. It will provide guidelines for selecting antigens for building CARs targeting more types of childhood cancers. Moreover, I will explore how phase separation, an emerging biophysical principle in organizing biomolecules, promotes CAR activity. This will establish phase separation as a new target for increasing the efficacy of CAR’s killing tumors.
Dr. Yanbin Zheng - UT Southwestern Medical Center, Dallas, TX
Developing A Novel Therapeutic Strategy for Rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Even with intensive treatment, outcome for patients with metastatic or recurrent disease remains poor. The 5-year survival rate of children with high-risk RMS is only 20% – 30%, with very little improvement over the last 30 years. Therefore, new therapy based on better understanding of this disease is urgently needed. In this proposal, our goal is to develop an effective therapeutic strategy for RMS.
To achieve this aim, my colleagues and I recently combined a new computational approach (iExCN algorithm) and an experimental tool (CRISPR/Cas9-based screen) to identify cancer disease genes in RMS. We have successfully identified 29 RMS disease genes whose expression is driven by copy-number variations and have validated more than half of them. We then applied another computational approach (rFBA algorithm) to predict synergistic drug combinations targeting two RMS disease genes. We found the drug combination targeting both EZH2 and CDK4/6 is promising and our preliminary data support it. Here, we are going to further test the synergistic drug combination in preclinical models, and study the pharmacodynamics of the drug combination. The drug combination we are studying is either FDA-approved drug or drug currently in single-agent clinical trials in children. Therefore, upon completion of this work, we will be able to rapidly advance this promising combination to clinical trials for patients with RMS.