Pediatric Cancer Grants That We Have Funded

Children's Oncology Group


Children’s Oncology Group, Monrovia, CA

With advancements in technology, data is often getting ahead of our human capacity to manage it, parse it, and share it. It does us no good to have mountains of data that is out of the reach of the researchers. For that reason, The B+ Foundation® has funded a Masters-level biostatistician at the COG. This investment will not only help one researcher but, potentially, dozens as critical data is shared with numerous investigators.

Dana-Farber cancer institute

Zebrafish Models of Human AML

Dana-Farber/Harvard Medical Center, Boston, MA

Zebrafish present an exciting way to cost-effectively accelerate the learning of drug development effectiveness. The B+ Foundation® is proud to have provided multiple research grants to Dr. Evisa Gjini in Dr. Thomas Look’s lab at Dana-Farber/Harvard Medical Center.


Children's Oncology Group

Reversing NK Cell Dysfunction in Pediatric Cancer

Case Western Reserve University, Cleveland, OH

Natural Killer (NK) cells are immune cells in our body, which can kill cancer cells. Cancer cells often escape from NK cells mostly due to insufficient number and low activity of NK cells in cancer patients. Transforming Growth Factor beta is a protein produced by cancer cells, which make NK cells less active. We will study the role played by this protein in suppressing NK cell activity in pediatric AML patients and use methods to neutralize Transforming Growth Factor beta to enhance NK cell activity and thus develop better treatment for pediatric AML.

Project EveryChild

Children’s Oncology Group, Philadelphia, PA

The Children’s Oncology Group (COG) is the preeminent body who oversees non-governmental research funded by the National Cancer Institute (NCI). The COG is made up of institutions in North America, Australia, New Zealand, and part of Europe. Ninety percent of children treated for cancer in the United States are treated at COG hospitals. The COG is led by internationally known pediatric oncologist, Dr. Peter Adamson of the Children’s Hospital of Philadelphia (CHOP).

Dr. Adamson has been a great supporter of The B+ Foundation® and we are proud to support a long-overdue initiative in Project EveryChild.

This project strives to capture tissue/blood/tumor samples from every pediatric cancer patient in the country and store them in a bio-repository in Columbus, OH. By gathering this information, we can significantly assist researchers as they require ample samples of these “rare” childhood cancers.

Project EveryChild will likely have a profound effect on childhood cancer research and, like ALL of the other research that we fund, it will benefit the entire childhood cancer community as collaboration is a requirement of ours.

Project: Everychild
B+ Heroes

Phase II Ewing’s Sarcoma Clinical Trial

Nemours/A.I. DuPont Hospital, Wilmington, DE

The B+ Foundation® supported Dr. Andy Kolb’s work on the Phase II Ewing’s Sarcoma Clinical Trial in conjunction with the COG Bone Sarcoma Disease Committee.

MD Anderson Cancer Center

Pediatric Colon Cancer Phase I Clinical Trial

MD Anderson, Houston, TX

Under the direction of Dr. Andrea Hayes-Jordan, The B+ Foundation® is proud to support the Phase I Trial of Oxaliplatin and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Children and Adolescents with Extensive Colon Carcinoma.


Epigenetic Therapy in AML

Nemours/A.I. DuPont Hospital, Wilmington, DE

The B+ Foundation® supported Dr. Sonali Barwe’s work to lay the foundation to allow the use of a new drug combination in the clinic to treat children with AML.

Pediatric Cancer Genome Project

St. Jude Children’s Research Hospital, Memphis, TN

St. Jude Children’s Research Hospital, in collaboration with Washington University of St. Louis, are engaged in an unprecedented effort to identify the genetic changes that give rise to some of the world’s deadliest childhood cancers. The team has joined forces to decode the genomes of more than 600 childhood cancer patients.

The St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project is the largest investment to date aimed at understanding the genetic origins of childhood cancers. Scientists involved in the project are sequencing the entire genomes of both normal and cancer cells from each patient, comparing differences in the DNA to identify genetic mistakes that lead to cancer.

The investment in the overall project exceeds $50,000,000.  The B+ Foundation® is proud to support Dr. Tanja Gruber’s work in this very worthwhile project.  The Pediatric Cancer Genome Project will yield valuable information that will be the foundation of childhood cancer research for decades.


St. Jude Children's Research Hospital
Cincinnati Children's Hospital

‘Eyes Absent’ Gene Investigation in Ewing’s Sarcoma Patients

Cincinnati Children’s Hospital, Cincinnati, OH

Based on laboratory investigation at Cincinnati Children’s Hospital, researchers have found that a gene called ‘Eyes Absent’ (EYA) plays a critical role in Ewing’s sarcoma and, more importantly, may provide a promising new target for treating Ewing’s sarcoma patients. Dr. Hegde, with the support of Drs. Pressey and Szabo, intend to determine the role of EYA in tumor growth, spread, and resistance to conventional chemotherapy. They will also study promising new agents that inhibit the function of EYA.

Ultimately, they anticipate that their findings may shed light on the biology underlying Ewing’s sarcoma and translate into the discovery of improved treatments for Ewing’s sarcoma and other cancers. This project will pair Cincinnati Children’s Hospital’s pediatric oncology sarcoma physicians with expert pathologists and world-class laboratory scientists, offering hope to the many Ewing’s sarcoma patients that are diagnosed each year.

Cincinnati Children's Hospital

MicroNRA Regulation of Cancer Stem Cells in Nervous System Tumors

Baylor College of Medicine, Houston, TX

One of the reasons that curing cancer is so difficult is that tumors are made up of many different types of cells, each with its own behavior and drug susceptibility. Researchers are beginning to appreciate that a small population of tumor cells, called cancer stem cells, are more aggressive and able to survive chemotherapy. Our goal is to understand how cancer stem cells acquire the properties that enable them to persist and metastasize, and to discover new ways to treat cancer by targeting them. In addition to improving treatment efficacy, therapies that target specific molecular pathways are better tolerated by patients. We previously showed that neural progenitors – stem cells that give rise to the nervous system during development – depend on the function of a gene, called microRNA-302 (miR-302); without miR-302, the nervous system does not form properly resulting in death. Our preliminary work in a brain cancer model of glioma shows that miR-302, ordinarily non-active after birth, is turned on in glioma, the most common type of brain cancer. Because miR-302 is active in stem cells, we hypothesize that miR-302 marks the cancer stem cell population in glioma and other related cancers. In this project, we will use multiple cancer models and experimental techniques to test the function of miR-302 in cancer stem cells, specifically on the aggressiveness of brain-related cancers, and will dissect the molecular pathways that control cellular behavior.

Defining Actionable Apoptotic Dependencies in Pediatric CNS Tumors

John B. Little Center for Radiation Sciences, Harvard Chan School, Boston, MA

Central nervous system (CNS) tumors comprise a diverse group of cancer types and are a leading cause of cancer-related death in children. In addition to surgery, radiation and chemotherapy are the mainstays of treatment and although tumors frequently respond initially, tumor recurrence and treatment resistance is common. Importantly, radiation and chemotherapy treatments also damage healthy developing tissues in children and can cause life-long and devastating toxicities. When effective, most anti-cancer therapies induce apoptosis (programmed cell death) in cancer cells. However, CNS tumors frequently increase their expression of key pro-survival proteins from the BCL-2 family (BCL-2, BCL-XL and MCL-1) to block this form of cell death and support the development of resistance. The recent development of novel medicines that block pro-survival protein function has created an unprecedented opportunity to enhance the chemosensitivity of cancer cells and have already been approved for use in other malignancies. We propose to use cutting-edge tools to measure dependence on pro-survival proteins within pediatric CNS cancer cells in order to determine which cancers are most sensitive to these new therapies. In addition, we will comprehensively define the most effective strategies for combining these new medicines with existing treatments to inhibit the development of therapy resistance and improve cure rates while also reducing toxicities.

University of Louisville

Tumorigenesis of a Pediatric Liver Cancer

The Rockefeller University, New York, NY

Many cancers are the consequence of a change in activity of a particular kind of protein called a kinase.  A kinase works by modifying other proteins by adding on to them a particular compound called a phosphate. In some cancers, there is an increase in the amount of the kinase that is made; in other cancers the kinase is trapped in the “on” position and is not properly regulated by the cell. Drug therapies that inhibit kinases that add phosphates to proteins on the amino acid tyrosine, have already been approved by the FDA for treatment of non-small cell lung cancer, renal cell carcinoma, chronic myelogenous leukemia (CML), human epidermal growth factor (Her2+) breast cancer, myelofibrosis, gastrointestinal stromal tumor (GIST), and melanoma.  While there are kinases that add phosphates to other amino acids, they have not been studied as potential drivers of cancer. We are studying a specific pediatric cancer that forms in the liver, fibrolamellar hepatocellular carcinoma (FLHCC). We discovered that the only alteration in the tumor cells is the formation of a variant of a kinase which adds phosphates onto the amino acids serine or threonine. We want to understand how such a kinase can cause cancer.  If we know how it is working, then we are in a better position to block it without affecting the normal functioning of the cells. With support of The B+ Foundation® we are developing the technology for studying the changes that result from an altered kinase in the cell.  This will provide both better understanding of fibrolamellar, provide targets for treatment the disease, but also develop a new way to study the many cancers that are the consequence of an altered kinase in the cell.


Phase I Polio Oncolytic Virotherapy (PVS-RIPO) of Pediatric High-Grade Glioma

Duke University Medical Center, Durham, NC

The B+ Foundation® is pleased to support this exciting new immunotherapy for children with deadly brain tumors conducted at Duke University. Oncolytic viruses are capable of stimulating immune responses against tumor-associated antigens that can produce lasting immunologic control of cancers. 

PVS-RIPO is a polio-derived oncolytic virus engineered to selectively kill brain tumor cells, and has shown some dramatic responses without toxicity in adults with universally fatal recurrent glioblastoma. This has garnered the attention of the oncology research community and was highlighted by 60 minutes in March 2015, and now will be available to pediatric patients in mid-2016. This pediatric trial will enroll 10-15 children with recurrent high-grade gliomas, and the PVS-RIPO poliovirus is directed to the tumor by convection-enhanced delivery. The researchers will determine the optimum dose and any toxicities

There are promising therapies in adults that The B+ Foundation® has worked hard to make available to children with deadly tumors and no options. Given the promising results in adults, expectations are high this will be very effective in children as well.  Read more about the development of this oncolytic virus.

The B+ Foundation provided the essential support to this exciting work, summed up by oncologist Dr. Henry Friedman: “This, to me, is the most promising therapy I’ve seen in my career, period.”


Seattle Children’s Hospital

Seattle, WA

Immunotherapy may be the most exciting area of research in childhood cancer today.  In short, a patient’s T-cells are removed from their body, re-programmed to fight their particular type of cancer, and re-inserted into the body.  Immunotherapy could potentially replace chemotherapy for some patients, or at least reduce the use of side-effect-causing chemotherapy. There are a few centers of excellence that are working on immunotherapy right now, and The B+ Foundation® has provided multiple grants to Dr. Michael Jensen’s lab at the Ben Towne Center for Childhood Cancer Research at Seattle Children’s Hospital.  In the initial group of patients, the doctors are seeing survival rates for relapsed leukemia increasing from 15% to 91%!  Read the full article. The B+ Foundation® has purchased a Nuance Imaging System and a Droplet PCR machine for the lab.  Our contribution to this exciting work was described by a lead investigator as “game changing”!


In-Vivo Organogenesis Approach to Elucidate Drivers of Medulloblastoma Development and Identify Therapeutic Targets

University of California, San Francisco, CA

Medulloblastoma is a brain tumor that primarily affects children and is the leading cause of cancer-related deaths in children. Currently, 30-40% of children with medulloblastoma die and therapies for treating medulloblastoma have not majorly changed since the 1980s. Recent research has shown that medulloblastoma actually represents many different types of tumors and potential factors driving medulloblastoma development have been proposed. However, these insights have not translated into improved patient outcomes because an efficient approach for validating these findings and for testing new therapies is lacking. We propose to address this critical need by developing an approach that will dramatically accelerate the identification of drivers of medulloblastoma and the testing of new therapies.

university hospital

Preclinical Development of Novel Immunotherapies for Pediatric Acute Myeloid Leukemia (AML)

Children’s Hospital of Philadelphia, Philadelphia, PA

Many children with acute myeloid leukemia (AML) are resistant to chemotherapy and/or will relapse. New treatments are needed to improve outcomes for these patients. We are testing new “killer T cell” immunotherapies in specialized pediatric AML mouse models with the goal of rapid translation into clinical trial testing for children with relapsed/refractory AML. We hypothesize that creation of an armamentarium of chimeric antigen receptor (CAR)-engineered T cell immunotherapies is necessary to improve cure rates substantially given the underlying biologic and genetic heterogeneity of childhood AML. Our first laboratory studies testing a new CAR T cell therapy in our AML mouse models have directly informed the development of two soon-to-open clinical trials at Penn and CHOP that will test the effectiveness of this immunotherapy in adults and children with relapsed AML.

University of Louisville

UT Southwestern Medical Center

Dallas, TX

The genomics era was anticipated to bring with it the capacity to use molecular biology tools to identify specific cancer-causing mutations and translate that information into better therapy. For most children with cancer, especially diseases like rhabdomyosarcoma which harbors few identifiable mutations, this promise has not been fully realized. Researchers in the Skapek laboratory at UT Southwestern Medical Center have developed a new computational pipeline to identify candidate rhabdomyosarcoma “drivers” that foster tumor formation or progression. With funding from The Andrew McDonough B+ Foundation®, the Skapek laboratory team is carrying out functional studies of the candidate drivers to validate the utility of the new analysis pipeline and identify those drivers that could represent new therapeutic targets for rhabdomyosarcoma.

TARGET Pediatric AML Initiative

Children’s Oncology Group

The TARGET Pediatric AML Initiative was identified by the Children’s Oncology Group acute myeloid leukemia (AML) leadership team as the highest potential and greatest need effort in our research portfolio to benefit children, adolescents and young adults fighting AML.  The goal of this initiative is to uncover the genetic drivers of AML in young people and maximize the use of both existing and emerging therapies, and accelerate the discovery new ones.

What is the TARGET Pediatric AML Initiative?

AML is also a highly complex, diverse group of diseases driven by multiple genetic mutations, some occurring in combinations that can be patient-specific. As such, “one size fits all” or single-agent therapeutic strategies may be less effective against this disease.  The goal of this initiative is to use the most advanced tools available to establish a rapid discovery platform and identify the right “targets” for new and existing drugs and therapies.  Developing a robust list of pediatric AML target mutations mapped to a “toolbox” of weapons (drugs & therapies) will be key.  These discoveries are the very foundation of personalized/precision medicine and are urgently needed in AML research to reduce treatment-related toxicities.

What needs to get done?

The Children’s Oncology Group will roll out this initiative in two phases.  Phase 1 will include deep genomic sequencing on patient samples, hiring computational staff to fully analyze data, testing and verification to determine if a target is in fact driving the cancer, and sequencing sick kids now for disease monitoring, early relapse detection, and treatment option discovery.  This will help us better understand why responders to therapy responded, while others did not.

Phase 2 of the initiative will entail expanding sequencing, analysis, and target discovery to a much larger patient population in order to generate a comprehensive list of targets and biomarkers for AML in young people.  This will allow us to design targeted, patient-specific treatments geared towards the patient’s specific cancer profile.

Children's Oncology Group
university hospital

Improving Brain Tumor Targeted Antigen Receptor T Cell Function

City of Hope, Duarte, CA

Chimeric Antigen Receptor (CAR) T cells, recently approved by the FDA, have revolutionized leukemia treatment. However, CAR T cell solid tumor therapy has been disappointing, because myriad inputs contribute to make solid tumors resistant to immune attack. Indeed, despite our very encouraging initial clinical results using IL13Ra2-targeted CAR T cells in glioblastoma multiforme, benefit is only temporary; CAR T cells vanish from patients within 7 days of administration, and rapidly lose the ability to kill brain tumor cells in culture. Improving CAR T cell persistence will vastly improve their efficacy in treating brain tumors.

Doing this requires us to understand and manipulate protein-level events in CAR T cells, as proteins are the ultimate effectors of cellular function. Identifying proteins responsible for T cell persistence will be critical to keeping CAR T cells from disappearing. The best way to do that is with protein-focused techniques like mass spectrometry and mass cytometry.

I pioneered a groundbreaking technique for using mass spectrometry on small numbers of cells, which has not been possible before. We will use this and other protein-focused techniques, as well as biological models of brain tumors and the immune system, to identify a unique protein signature corresponding to T cell survival and persistence. We hypothesize that these activated protein circuits can be leveraged to improve CAR T cell persistence and efficacy.

University of Louisville

Targeting Beta-Catenin Mediated Activity in Metastatic Osteosarcoma

Baylor College of Medicine, Houston, TX

Metastatic disease, which is when the cancer has spread throughout the body, is responsible for about 90% of all cancer related deaths. For children afflicted with metastatic osteosarcoma, the most common bone tumor in the pediatric population, it often means a very aggressive cancer that is associated with an extremely poor outcome. Unfortunately, one reason for this unacceptable outcome is due to our lack of understanding the biology of the metastatic state and identifying better treatment options.

Recently our laboratory has created a new mouse model of metastatic osteosarcoma (OS) that mimics the human tumor development and progression. Using the tumors from this model, we have been able to analyze genes and determine pathways that are functioning abnormally, including the identification of key alterations within metastatic tumors in a key pathway in the cell known as the Wnt cascade.

Our proposal will continue to investigate the exact role of Wnt signaling during metastatic development, or evolution, through both innovative pre-clinical models as well as functional and therapeutic studies. Furthermore, using these models we will test a new therapeutic agent designed to target this pathway that one day can be brought to the clinical care of these patients. Therefore, by gaining a better understanding of the detailed role of Wnt signaling during metastatic development, we will elucidate novel molecular aberrations and further identification of novel therapies.


Targeting MEK and CDK4/6 in DIPG

Lurie Children’s Hospital, Chicago, IL

Diffuse intrinsic pontine glioma, or DIPG, is an incurable brain cancer that mostly strikes young children. The median survival rate is less than one year after diagnosis. To date, there are no chemotherapeutic or targeted agents that have proven to be beneficial for treatment of these cancers. Dr. Becher leads one of very few laboratories around the world that focus exclusively on this type of deadly brain cancer. He is using a novel DIPG mouse model to study the function of proteins that drive tumor growth and to determine how novel anti-cancer drugs can inhibit tumor growth. His goal is to identify the most effective drugs against this type of brain cancer and then translate these findings by testing the drugs in clinical trials for children afflicted with this type of brain cancer. In this application, Dr. Becher is proposing to evaluate the anti-cancer activity of two novel cancer drugs alone and in combination in the newly developed improved DIPG mouse models.

MD Anderson Cancer Center

Epigenetic Drivers in Rhabdomyosarcoma

University of Washington, Seattle, WA

Rhabdomyosarcoma (RMS) is a devastating pediatric sarcoma. There is still no effective treatment for children with relapsed or wide-spread disease. In contrast to adult cancers, RMS has fewer DNA mutations, suggesting that other molecular changes may be driving tumor growth and progression. We have identified 40 potential candidate genes that function to alter DNA structure and packaging in the cells without causing DNA mutations. Previous data suggest that these genes may play a role in RMS. Some of these genes may work together to exert biological effects. My proposed research will apply genome engineering technology to target each individual candidate gene and gene combinations in RMS cells to identify the ones that are essential for RMS tumor growth. New targets identified from the study will be the basis for novel therapy designs to improve survival of RMS patients with advanced disease.


Disrupting Neuroblastoma Tumor-Initiating Cells

University of Rochester, Rochester, NY

Neuroblastoma is a common and deadly childhood cancer with an overall 5-year survival of less than 50% for high-risk tumors. Tumor initiating cells may drive therapeutic resistance and relapse, which accounts for the majority of deaths in neuroblastoma. We have recently discovered a novel regulatory pathway involved in the cancerous properties of neuroblastoma tumor initiating 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 will determine the role of this pathway in the development of neuroblastoma and devise an approach to inhibit its cancerous activity with the long-term goal of improving neuroblastoma treatments for children diagnosed with this terrible disease.

Molecular Mechanism of CAR Activation in Targeting B Cell Leukemia

Yale University, New Haven, CT

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.

University of Louisville

Predicting Post-Treatment Relapse in Pediatric AML Using Single-Cell Proteomics

Stanford University, Stanford, CA

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.


Targeting Signaling Pathways that Confer Cytarabine Resistance in Pediatric AML

Baylor College of Medicine, Houston, TX

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.

MD Anderson Cancer Center

Developing A Novel Therapeutic Strategy for Rhabdomyosarcoma

UT Southwestern Medical Center, Dallas, TX

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.


Targeting RNA Processing Defects of Ewing Sarcoma

UT Health Science Center at San Antonio, San Antonio, TX

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.

university hospital

L3MBTL3, A Therapeutic Target in Acute Myeloid Leukemia

The Regents of the University of Michigan, Ann Arbor, MI

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.

University of Louisville

Overcoming Innate Immune Evasion in Pediatric High Grade Glioma

University of Colorado Denver, AMC and DC, Aurora, CO

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.


A Novel Approach to Target ACVR1 as a Treatment to Pediatric Cancer

Georgia Tech Research Corporation, Atlanta, GA

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.

MD Anderson Cancer Center

Uncovering the Contribution of RNA Binding Proteins to Neuroblastoma Aggression

Emory University – Winship Cancer Institute, Atlanta, GA

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.


Activation of NF-kB in Neuroblastoma Myeloid Cells

Johns Hopkins University School of Medicine, Baltimore, MD

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.

university hospital

Clinical Trial Decision Aid (DECIDES) for Adolescents and Young Adults with Cancer and their Caregivers

Children’s Hospital of Philadelphia, Philadelphia, PA

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.

University of Louisville

Artificial Intelligence for Pediatric Cancer

Stanford University, Palo Alto, CA

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.


Pediatric Cancer Data Commons

University of Chicago, Chicago, Illinois

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. 

MD Anderson Cancer Center

Arginine methylation as a potential therapeutic target in high-risk neuroblastoma

University of Rochester, Rochester, NY

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.


Polycomb inhibition sensitizes AML to anthracycline therapy

The Research Institute at Nationwide Children’s Hospital, Columbus, OH

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.

university hospital

Development of anti-KIT antibodies and immunotoxins as therapeutics and HSCT conditioning agents for pediatric acute myeloid leukemia

Stanford University, Stanford, CA

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.

University of Louisville

Understanding the role of SMARCD1(BAF60A) in malignant rhabdoid

Trustees of Dartmouth College, Lebanon, NH

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.

MD Anderson Cancer Center

Boosting Immunovirotherapy with Tumor Vaccination to Treat Pediatric Malignant Brain Tumors

University of Alabama at Birmingham, Birmingham, AL

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.



Overcoming Resistance of CAR T Cells Immunotherapy with CBP/ß-catenin Antagonists in Pediatric Glioma and Ependymoma

Beckman Research Institute of the City of Hope, Duarte, CA

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.


Stimulating Macrophages to Eat Pediatric Brain Cancer: Combining Anti-CD47 and Irradiation to Enhance the Treatment of Group 3 Medulloblastoma

University of Utah, Salt Lake City, UT

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.