Pediatric Cancer Grants That We Have Funded
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.
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.
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.
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.
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.
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.
‘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.
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.
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
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.
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.
UT Southwestern Medical Center
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.
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.
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.
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.