Funding Childhood Cancer Research
The Andrew McDonough B+ Foundation® is proud to announce the recipients of the Fall 2019 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
Dr. Andy Kolb
Dr. Julie R. Park
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
Dr. Michael Jensen
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
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
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
Recent B+ Grants Awarded to:
Dr. Lamia Barakat – The Children’s Hospital of Philadelphia, Philadelphia, PA
Clinical Trial Decision Aid (DECIDES) for Adolescents and Young Adults with Cancer and their Caregivers
Adolescents and young adults (AYA) with cancer have lower rates of participation in therapeutic clinical trials; they have limited involvement in decision-making, do not fully understand clinical trials, and are vulnerable to acute distress undermining their decision processes. We developed a decision support tool (DECIDES = AYA Deciding about Enrolling on a Clinical Intervention Trial: Decision Aid for Education and Support) to increase collaboration among AYA, primary caregivers, and providers in clinical trial decision-making. DECIDES is based on decision theory, findings from our qualitative studies of AYA decision-making, evidence-based decision tools in adult oncology, and feedback from CHOP AYA Patient Steering Committee, caregivers, and Scientific Advisory Committee. Content/format includes information on cancer clinical trials and a value clarification exercise in a web-based format with written information, games, video, and animation. We will use a hybrid design to pilot test and identify implementation strategies with newly diagnosed or relapsed AYA: DECIDES alone (n=20), DECIDES+coach (n=20), and Usual Care (n=10). Hypotheses: (1) DECIDES will be acceptable and feasible; (2) DECIDES groups will have more knowledge about cancer clinical trials, open clinical trial attitudes, positive decision processes, and collaborative decision-making than the usual care group. Interviews with participants will provide feedback on DECIDES for future, larger scale implementation.
Dr. Christine Brown – Beckman Research Institute of the City of Hope, Duarte, CA
Overcoming Resistance of CAR T Cells Immunotherapy with CBP/ß-catenin Antagonists in Pediatric Glioma and Ependymoma
Brain tumors are the second most common cancer in children, accounting for 20% of all pediatric cancers. Our research aims to improve treatment for two types of deadly brain tumors: ependymoma and glioma. While some young patients can be successfully treated using radiation and surgery, far too many children fail to respond to therapy or relapse. The emerging field of immunotherapy has shown great promise in treating various cancers, and one type in particular uses cells from the patient’s own immune system to fight cancer. The method entails isolating a patient’s immune cells (T cells) and genetically engineering them to recognize and kill brain tumor cells using a chimeric antigen receptor (CAR). By infusing these CAR T cells back into the patient, the engineered cells seek out and eliminate malignant cells. Two previous first-in-human clinical trials by our team at City of Hope demonstrated the safety and feasibility of this approach and suggested that it could be effective against brain tumors, provided barriers presented by the tumor can be overcome. One common therapeutic barrier is that the tumors typically present an environment that suppresses the immune response. We postulate that resistance to chimeric antigen receptor T (CAR T) cell therapy involves activation of the Wnt/ß-catenin signaling pathway. We hypothesize that the Wnt/CBP/ß-catenin pathway selective inhibitor ICG-001 can safely overcome tumor resistance and synergize with CAR T cell treatment via two mec.
Dr. Samuel Henry Cheshier – University of Utah, Salt Lake City, UT
Stimulating Macrophages to Eat Pediatric Brain Cancer: Combining Anti-CD47 and Irradiation to Enhance the Treatment of Group 3 Medulloblastoma
We devolved a therapy that allows macrophages (a type of white blood cell) to specifically “eat” tumor cells by a process called phagocytosis. The therapy, anti-CD47 treatment, blocks a signal on tumor cells called a “Don’t Eat Me” signal. There are also signals on tumor cells that promote phagocytosis of tumor cells called “Eat Me” signals. We know that increasing “Eat Me” signals (when the “Don’t Eat Me” signal is being suppressed by anti-CD47) greatly enhances the ability of macrophages to “eat” tumor cells. Irradiation is well known to enhance the expression of “Eat Me” signals on tumor cells, and we have preliminary data show that the combination of anti-CD47 and irradiation can enhance eating of malignant brain tumor by macrophages in the test tube, as well as in a live animal. Here, we propose to use this combination (anti-CD47 + irradiation) to kill the deadly pediatric brain tumor, Group 3 Medulloblastoma. We will determine the dose of irradiation needed to enhance anti-CD47 meditated eating of Group 3 Medulloblastoma cells by macrophages in test tubes and live animals. In addition, we will determine how irradiation with anti-CD47 can impact the levels of “Eat Me” and “Don’t Eat Me” signals on Group 3 medulloblastoma tumor cells. Our goal is to utilize this combination to dial down the amount of irradiation needed to treat the children with Group 3 medulloblastoma. This will allow for a more effective therapy that is also safer.
Dr. Agnieszka Czechowicz – Stanford University, Stanford, CA
Development of anti-KIT antibodies and immunotoxins as therapeutics and HSCT conditioning agents for pediatric acute myeloid leukemia
Acute myeloid leukemia (AML) is a frequent and devastating type of cancer that affects thousands of children worldwide. Patients diagnosed with AML are generally treated with harsh conventional chemotherapy and/or blood-forming (hematopoietic) stem cell transplantation (HSCT). Unfortunately, regardless of the therapy used, most children have sub-optimal outcomes: overall survival is only ~60% and children who do survive have many severe co-morbidities from the toxic treatments used. Thus, better therapeutic options for these patients are desperately needed. We have pioneered several new antibodies that could become very powerful therapies to safely cure AML. These antibodies target a specific protein, KIT (CD117), which is found on bone marrow stem cells and cells that are thought to start and maintain AML. These anti-KIT therapies may kill the leukemic cells by: 1) depriving the cells of key nutrient stem cell factor (SCF) needed for cell growth and survival, or 2) delivering an additional toxin to kill the cells directly. We propose to test these therapies as stand-alone drugs and in combination with HSCT in models of pediatric AML. If our results are promising, we believe these antibodies could rapidly turn into important drugs for both pediatric and later adult AML treatment. In addition, such work could encourage broader exploration of an entire new class of therapies that target both stem cells and AML cells, which could further improve safety and efficacy of HSCT.
Dr. Heike Elisabeth Daldrup-Link – Stanford University, Palo Alto, CA
Artificial Intelligence for Pediatric Cancer Imaging
Imaging tests are essential for diagnosing cancers in children and for monitoring tumor response to therapy. By combining magnetic resonance imaging (MRI) and positron emission tomography (PET), pediatric cancers can be imaged with 80% reduced radiation exposure compared to traditional imaging tests. However, the acquisition of combined MRI and PET scans takes about 3-4 times longer (60-90 minutes) compared to traditional combined PET and computed tomography (CT) scans (20-30 minutes). These long acquisition times are a major bottleneck for clinical translation of PET/MRI technologies. To achieve faster diagnoses and higher throughput, we propose to develop novel deep convolutional neural networks (Deep-CNN) that can accelerate PET/MR image data acquisition and interpretation. The goal of our project is to develop Deep-CNNs for accelerated PET and MR image data acquisition of children with cancer. We will accomplish this goal by using deep convolutional neural networks (Deep-CNN) to reconstruct high resolution MR and PET images from low resolution inputs. In addition, we will train our Deep-CNN to classify responders and non-responders based on the image data. To the best of our knowledge, this is the first attempt to apply Deep-CNN to pediatric oncology applications. Results will be readily translatable to the clinic and thereby, will have major and broad health care impact.
Dr. Gregory Friedman – The University of Alabama at Birmingham, Birmingham, AL
Boosting Immunovirotherapy with Tumor Vaccination to Treat Pediatric Malignant Brain Tumors
Medulloblastoma, the most common pediatric brain tumor, is a leading cause of cancer-related death and injury. New, improved treatments are greatly needed. We are currently conducting a clinical trial of a cold-sore virus that has been altered to target and kill brain tumor cells while not harming normal brain cells and to stimulate the child’s own immune system to attack the tumor. Results of the trial have been very promising. In the trial, we have learned that a critical obstacle to achieving more long-term responses from the virus therapy is maintaining an immune system attack on the tumor. We will overcome this obstacle by combining a new, improved altered cold-sore virus with a unique tumor vaccine. The new virus produces a substance that attracts more immune cells to the tumor, stimulates an even greater attack on the tumor and is currently in an adult clinical trial at UAB. The novel vaccine, which greatly improves on current technologies, is designed to increase the immune attack against the tumor and increase the amount of tumor cell killing by the virus. We plan to rapidly translate this research from the lab to the clinic, and we anticipate that we will see even better outcomes in children with brain cancer using these exciting therapies. Importantly, this combination treatment can be applied to treat other pediatric brain tumors and solid tumors outside the brain, increasing the overall potential impact for children with cancer and their families.
Dr. Xingguo Li – University of Rochester, Rochester, NY
Arginine methylation as a potential therapeutic target in high-risk neuroblastoma
Neuroblastoma, an embryonal malignancy of the developing sympathetic nervous system, remains a leading cause of childhood cancer deaths. The goal of this project is to develop novel targeted therapies for high-risk neuroblastoma based on specific, rational molecular vulnerabilities we have uncovered. We have recently discovered a novel regulatory pathway involved in the cancerous properties of neuroblastoma cells. Our preliminary studies have further confirmed the therapeutic potential of using drugs to inhibit this pathway’s role in neuroblastoma cancer cells. In this project, we propose a paradigm-shift approach to determine the role of this pathway in the development of sympathetic nervous system and neuroblastoma tumorigenesis. By better understanding this regulatory pathway, we ultimately aim to improve the treatment of patients with neuroblastoma and other malignancies.
Dr. Benjamin Stanton – The Research Institute at Nationwide Children’s Hospital, Columbus, OH
Polycomb inhibition sensitizes AML to anthracycline therapy
Childhood acute myeloid leukemia (AML) is an aggressive blood cancer driven from undifferentiated populations of myeloid cells that inappropriately proliferate and fail to differentiate. The major genetic drivers of childhood AML include mutations to epigenetic machinery, which functions to organize the DNA inside of the cell. Undifferentiated tumors, including subtypes of childhood AML with stem-like characteristics, are associated with high expression levels of Polycomb genes, encoding proteins which can epigenetically silence regions of DNA. This proposal builds on my hypothesis that drugs targeting Polycomb/EZH2 can help lower the dose of co-administered anthracyclines which are a toxic therapy for childhood AML. My preliminary data indicates that across cell models for several AML subtypes, inhibiting EZH2 enables lowering the effective dose of anthracycline by more than 5-fold. This proposed study aims to understand why we are observing this effect, to connect basic questions about the organization of DNA inside the leukemia cells to translational studies with patient-derived samples at Nationwide Children’s Hospital. This proposal will build on a collaboration with AML clinicians and physican-scientists, including Dr. Terri Guinipero, Dr. Huifei Liu and Dr. Ryan Roberts. We will define how DNA accessibility affects the function of anthracyclines in childhood AML.
Dr. Samuel Volchenboum – The University of Chicago, Chicago, Illinois
Pediatric Cancer Data Commons
Worldwide, about 300,000 young people are diagnosed with cancer each year. Thanks to decades of medical research, about 80% will survive. A major roadblock to better outcomes for the remaining 20% is the siloed nature of research’s best hope: data. Data from clinical trials are difficult to collect and share across research groups because each group collects data according to their own preferences and definitions. This limits researchers’ ability to analyze patients’ clinical data and to pair it with data from new techniques, like genomic testing, to make discoveries.
The Pediatric Cancer Data Commons (PCDC) designs better ways to collect and store clinical data (and connect clinical data to other types, such as imaging and genomic data) by developing consensus among researchers to develop a common data language and sharing those standards widely. The PCDC is dedicated to gathering as much data as possible from around the world into a “data commons”—a single place where researchers everywhere can go to access and explore uniform data in pursuit of their research questions.
Funding from The Andrew McDonough B+ Foundation will allow the PCDC to build the tools and systems necessary for collecting, storing, analyzing, and sharing these data. Your funding will supplement work supported by the St. Baldrick’s Foundation and your investment will be maximized by generous matching funds provided by an anonymous foundation.
Dr. Xiaofeng Wang – Trustees of Dartmouth College, Lebanon, NH
Understanding the role of SMARCD1(BAF60A) in malignant rhabdoid tumors
SWI/SNF chromatin remodeling complexes are groups of proteins with numerous roles in the organization and activation of DNA. These complexes are vital to the health and development of our cells, and disruption of their activity can lead to a range of diseases. Nearly 20% of all human cancers are thought to arise from mutations in the compositional subunits of SWI/SNF complexes. Malignant rhabdoid tumors (RTs) and atypical teratoid rhabdoid tumors (ATRT) are aggressive forms of pediatric cancer that typically stem from inactivating mutations in a prominent SWI/SNF chromatin remodeling complex subunit known as SMARCB1. It is widely accepted that SMARCB1 acts as a tumor suppressor when functional, but less clear how mutations in the subunit might fuel the growth of cancer cells. Unearthing the molecular mechanisms that are responsible for tumor growth in SMARCB1-mutant cancers could yield new therapies for patients suffering from rhabdoid tumors. We hypothesize that one subunit in particular, SMARCD1, is essential for maintaining the functionality of the residual complex. Further characterizing this interaction could open doors to cancer treatments targeting the residual complex via SMARCD1. We hope to identify the specific genes or features of the genome that SMARCD1 and the residual complex are targeting in cancer cells, with the ultimate goal of finding new ways to eliminate these tumors and generate better treatments for this pediatric cancer.