Current Funded Grants by Kids Beating Cancer

Children’s Hospital of Los Angeles

$300,000 Grant

Yong-Mi Kim, MD, PhD
Professor, Division of Hematology-Oncology, Departments of Pediatrics and Pathology
Children’s Hospital Los Angeles and University of Southern California, Keck School of Medicine

Today, many children with leukemia are being cured. This is due, in part, to the development of revolutionary new treatments such as CAR T-cells. Unfortunately, for a percentage of pediatric patients, every treatment, which includes bone marrow transplants, ultimately fails and the leukemia returns. Our inspiration to help these children comes from a form of leukemia that is found in older adults, named Multiple Myeloma. Since 2015, patients with this disease have been treated with a specific antibody that binds to a protein called CD38 . As of this point, there is extensive clinical experience with this approach in adults. Leukemia cells coated with the antibody are flagged for killing by specialized immune cells: natural killer cells, macrophages, and neutrophils. T-cells, another type of immune cells, have not been involved in this approach. More recently, investigators at City of Hope developed a unique antibody that pulls many subsets of T-cells together with adult acute myeloid leukemia cells through CD38. This is a stimulus for the T-cells to efficiently kill them. Based on preliminary experiments we have completed with acute lymphoblastic leukemia cells; we are confident that this antibody can be used to kill a variety of pediatric leukemia cells including those from patients who did not respond to other treatments. This project seeks to explore the impact of this antibody further and provide robust evidence for its success with the most challenging forms of pediatric leukemia.

Dana-Farber/Boston Children’s Hospital Cancer and Blood Disorders Center

$200,000 Grant

Amy Sexauer, MD, PhD
Attending in Pediatric Hematology/Oncology/Stem Cell Transplant
Dana-Farber/Boston Children’s Hospital Cancer and Blood Disorders Center

Acute T-cell lymphoblastic leukemia (T-ALL) is a lethal hematologic malignancy affecting children and young adults. T-ALL continues to have higher rates of both induction failure as well as higher rates of relapse as compared to B-ALL, with very poor survival rates in both scenarios. Compared to B-ALL, T-ALL has not benefitted from the same immune-mediated therapies and continues to pose an ongoing treatment challenge with an unmet therapeutic need. This research studies the metabolic dependencies in T-ALL to identify novel therapeutic targets. Using data from the Dependency Map project, we identified DHODH (dihydroorotate dehydrogenase) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of denovo pyrimidine nucleotide synthesis. Therefore, inhibiting DHODH via small molecule inhibitors (DHODHi) rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage.
In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, cell cycle arrest, and ultimately death. DHODH has been highlighted as a potential therapeutic target in many hematologic and solid tumor malignancies including AML, neuroblastoma, glioblastoma, pancreatic cancer, and breast cancer (and others). Malignant T-lymphoblasts appear to be particularly and exquisitely sensitive to nucleotide starvation following DHODH inhibition.  This sensitivity has been confirmed in vitro as well as in vivo in three murine models of T-ALL, including an aggressive NOTCH driven model in syngeneic recipients and two human patient derived xenografts. Additionally, we have identified that certain subsets of T-ALL seem to have an increased reliance on oxidative phosphorylation when treated with DHODHi.  In addition to these studies, we are interested in understanding the effects of nucleotide starvation on developing T-cells, an area which has received little attention. Given the goal of making DHODHi therapy available to young children with relapsed/refractory T-ALL, we must understand the longer-term effects, if any, of nucleotide starvation on the developing thymus and other hematopoietic progenitors. Preliminary studies suggest that while DHODHi treatment does lead to significant changes in thymic populations in juvenile mice,
these changes are reversible with time.
The goal of this research is to better understand why T-lymphoblasts are so sensitive to DHODHi, and to develop new therapeutic combinations for patients with T-ALL using DHODH inhibitors. The availability of clinical-grade DHODH inhibitors currently in human clinical trials speaks to the potential for rapidly advancing this work into the clinic.

University of North Carolina at Chapel Hill

$126,200 grant

Scott Elton, PhD Co-Principal Investigator, Pediatric Neurosurgery, University of North Carolina Hospital
Shawn Hingtgen, PhD Co-Principal Investigator UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
Oleh Taratula, PhD Co-Principal Investigator, College of Pharmacy, Oregon State University
James Baumgartner, MD Co-Principal Investigator, Pediatric Neurosurgery

Stem Cell-delivered Particles for Hyperthermia Therapy to Treat Glioblastoma

Glioblastoma (GBM) is the most common primary brain tumor and one of the deadliest forms of cancer¹. Median survival is little more than 12 months and has not improved significantly in over three decades. We propose an exciting new approach to GBM therapy that could mean a big leap towards finding a cure: tumor-homing cell-based hyperthermia therapy. We propose an exciting new approach to GBM therapy that could mean a big leap towards finding a cure: tumor-homing cell-based hyperthermia therapy. We hypothesize that engineered metal-loaded iNSC/oscillating magnetic field hyperthermia therapy will achieve GBM-selective homing and therapeutic efficacy that will prevent GBM progression. Across three Aims, we will convert human skin tissues into next-generation tumor-homing neural stem cell drug carriers termed iNSCs. We will load the iNSCs with custom-developed metal nanoparticles and investigate the fate, migration, efficacy of this novel strategy in clinically-relevant preclinical models of GBM. Our rationale is that iNSC drug carriers derived from the patient’s own skin will avoid immune rejection, seek out residual tumor foci that chemotherapy and radiation cannot reach, and effectively eradicate the tumor once a magnetic field is applied to generate heat that will selectively and efficiently induce tumor kill. We propose to test this hypothesis, defining the efficacy of this novel treatment and develop strategies to support translation into human clinical trials. We will investigate particle loading, impacts on iNSC viability, homing, and GBM kill. We will modulate a variety of parameters to optimize the therapeutic strategy, focusing first on the iNSC carrier then on maximizing GBM kill. All testing will be done using our validated nanoparticles, unique ex vivo living tissue brain slice model, and novel surgical resection models of patient-derived CD133+ human GBM cells to maximize the clinical relevancy of our finding and understand the impact of the immune system on iNSC treatment durability. If successful, this transformative platform will advance the field of cell therapy, shift NSC therapy for GBM towards a personalized hyperthermia-based approach and develop a broadly applicable patient-specific cell therapy strategy that could shape the future of clinical GBM therapy.

Children’s Hospital of Philadelphia

$300,000 grant

Margaret Chou, PhD Principal Investigator, Children’s Hospital of Philadelphia
Associate Professor of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania

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Making cold tumors hot: Multi-faceted Immunostimulatory Therapy for Ewing Sarcoma (MITES)

Ewing sarcoma (ES), the second most common bone cancer in children, remains a significant challenge in pediatric oncology.  Survival rates for patients with recurrent or metastatic disease have not improved for decades, and no targeted treatments have succeeded for broad clinical use.  Immunotherapy has revolutionized cancer treatment in recent years, but it has been poorly explored in the context of ES.  Recent studies show that some ES patients exhibit high infiltration of cytotoxic immune cells, and that this is associated with greatly prolonged survival. Yet, the tumor-intrinsic factors that drive this favorable, “hot” immune phenotype spontaneously in some patients is a mystery. Children’ Hospital of Philadelphia’s research has identified such a factor, USP6, which has potent and pleiotropic immunostimulatory effects in jumpstarting the immune system, triggering infiltration of immune cells into the tumor, and stimulating their ability to kill the cancer cells.  Concordantly, high USP6 levels are associated with dramatically improved survival in ES patients. These findings will be exploited to develop a novel immunotherapeutic agent to prevent ES recurrence and improve survival.

Washington University in St. Louis School of Medicine

$100,000 grant 

Nathan Singh, MD, PhD, Principal Investigator
Assistant Professor of Medicine; Division of Oncology, Washington University School of Medicine in St. Louis

Defining the epigenetic and transcriptional signatures of chimeric antigen receptor T cell dysfunction

Chimeric antigen receptors (CARs) are engineered proteins that re-direct a patient’s immune system to target their cancer.  T cells, the “killers” of the immune system, that are engineered to express CARs have demonstrated unprecedented results in the treatment of pediatric acute lymphoblastic leukemia, with ~9/10 patients becoming disease-free after treatment.  Despite these exciting initial results, follow-up now shows that only half of patients treated will remain disease-free long-term.  These clinical failures often result from failed T cell activity against leukemia cells. Washington University School of Medicine has recently identified that prolonged interaction between CAR T cells and leukemia cells can lead to T cell failure, however the biology responsible for this remains unclear.  This research aims to identify the ways in which CARs promote T cell failure.  Understanding this process will reveal strategies to engineer CAR T cells that are resistant to failure, resulting in more durable responses.

University Of Cincinnati

Emerging Scientist $7,000 grant 

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