Pediatric Cancer

Current Projects
Özlem Aksoy, PhD

Dr. Aksoy is establishing a human stem-cell based model of medulloblastoma brain tumors that can be rapidly manipulated, allowing insights into how genetic mutation contributes to medulloblastoma tumorigenesis and how these mutations cooperate in tumor formation. She will study the highest-risk subtype of medulloblastoma, with the goal of understanding the possible role of translational control in this cancer. She will test both novel and existing mTOR inhibitors as a potential therapeutic strategy for patients.

Project title: "Understanding the role of translational control in humanized mouse models for medulloblastoma"
Institution: University of California, San Francisco
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Davide Ruggero, PhD
Cancer Type: Pediatric, Brain
Research Area: Cancer Genetics
Challice L. Bonifant, MD, PhD

Dr. Bonifant is studying how best to direct the immune system to combat acute myeloid leukemia (AML), a blood cancer of both children and adults. By specifically directing T immune cells to AML, she hopes to make therapy stronger and more effective, while also reducing toxicity. She is exploring the activity of T cells targeting multiple AML-specific antigens that do not affect normal cells. The ultimate goal of the work is to develop new strategies to treat AML.

Project title: "Dual-antigen targeting by ENG-T cells as improved anti-AML therapy"
Institution: University of Michigan, Ann Arbor
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Pavan Reddy, MD
Cancer Type: Blood, Pediatric, All Cancers
Research Area: Immunotherapy
Kristopher R. Bosse, MD

Neuroblastoma is a cancer of the nervous system that occurs in young children and is often lethal. An improved understanding of neuroblastoma tumorigenesis is urgently needed to catalyze development of innovative and effective therapies. Recent immunotherapy advances have provided optimism for the use of this treatment type in children with neuroblastoma. However, there is a desperate need for new molecules that can be safely and specifically targeted with immune-based therapeutic approaches. Recent work showed that a protein called glypican-2 (GPC2) is abundant on neuroblastoma cells, but not found on normal cells, and that GPC2 helps neuroblastomas grow aggressively. Thus, GPC2 may be an ideal cell surface molecule to target with immune-based therapies. Dr. Bosse seeks to validate GPC2 as a candidate for engineered targeted immune cells in high-risk neuroblastoma. This research will also define how GPC2 promotes cancer growth, thus providing additional critical knowledge for the therapeutic exploitation of an important tumor-sustaining pathway. Finally, this work will help establish a robust pipeline for the identification of novel tumor-specific molecules for immunotherapeutic targeting in pediatric cancer. This blueprint will allow for the rapid translation of prioritized molecules to a clinically available targeted immunotherapeutic, with an aim to make meaningful differences in the clinical care of children with high-risk pediatric malignancies.

Project title: "GPC2 as an oncogene and immunotherapeutic target in high-risk neuroblastoma"
Institution: Children's Hospital of Philadelphia
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): John M. Maris, MD
Cancer Type: Other Cancer, Pediatric
Research Area: Immunotherapy
Robert L. Bowman, PhD

Dr. Bowman focuses on acute myeloid leukemia (AML), which can be characterized by successive development of genetic mutations. While some mutations are found in nearly every cell of the disease, others are found in sub-populations and are thought to arise at later stages of disease development. It remains unclear if these late mutations are necessary for leukemic progression and are actionable therapeutic targets. He aims to develop models to test the oncogenic dependency of one of the most commonly mutated genes in AML, FLT3. Further models will be developed to understand the role of mutation order in disease development.

Project title: "Interrogating the subclonal architecture and functional contributions of mutation order in FLT3-ITD mutant AML"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Sohn Fellow
Cancer Type: Blood, Pediatric
Research Area: Animal Models/Mouse Models
Stacy L. Cooper, MD

Dr. Cooper focuses on developing novel therapies for acute myeloid leukemia (AML), which has an approximately 50% mortality rate. Her work focuses on C/EBPalpha, a protein that is decreased in more than half of all AML patients. By determining how the production of this protein is regulated, she aims to understand the mechanisms for its reduction in leukemia and to develop strategies to target C/EBPalpha as a novel therapy for AML.

Project title: "The Cebpa +37kb enhancer is a critical target of transformation in acute myeloid leukemia"
Institution: The Johns Hopkins University
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Alan D. Friedman, MD
Cancer Type: Blood, Pediatric
Research Area: Epigenetics
Amanda Balboni Iniguez, PhD

Dr. Balboni Iniguez studies Ewing sarcoma, a rare pediatric solid tumor containing a characteristic chromosomal translocation that fuses the EWSR1 gene to the FLI1 gene. The resulting EWS/FLI fusion protein initiates an oncogenic gene expression program, thus promoting tumorigenesis. EWS/FLI represents an attractive tumor-specific therapeutic target; however, it has been difficult to pharmacologically inhibit. Her work will focus on elucidating a novel approach to selectively target EWS/FLI by utilizing a small-molecule inhibitor against the transcriptional regulator proteins CDK12/13. This research will contribute to our understanding of Ewing sarcoma cell biology and has important clinical implications for other cancers driven by similar transcription factor fusion proteins.

Project title: "Targeting the EWS-FLI oncoprotein in Ewing sarcoma with CDK12/13 inhibitors"
Institution: Dana-Farber Cancer Institute
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Kimberly Stegmaier, MD
Cancer Type: Pediatric, Sarcoma
Research Area: Experimental Therapeutics
Carolyn C. Jackson MD, MPH

Kaposi sarcoma (KS), a potentially fatal cancer especially in immunodeficient individuals, is caused by human herpes virus-8 (HHV-8), a carcinogenic agent declared by the World Health Organization. Human genetic variability may account for the variability in the clinical outcome of HHV-8 infection. Dr. Jackson aims to discover novel genetic alterations underlying childhood KS and to understand how specific gene defects drive KS in conjunction with HHV-8. This work will identify molecular pathways of impaired antiviral immunity or tumor suppression, consequently broadening our understanding of virus-driven cancers. The genetic study of KS in childhood may provide new insights into the pathogenesis of KS, and aid in developing potential future therapeutics. It will also benefit children at risk of KS in regions of the world where the prevalence of HHV-8 is high.

Project title: "Genetic dissection of pediatric classic Kaposi sarcoma"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Jean-Laurent Casanova, MD, PhD
Cancer Type: Pediatric, Sarcoma
Research Area: Cancer Genetics
Michael A. Koldobskiy, MD, PhD

Dr. Koldobskiy studies the ways that cancer cells rely on “epigenetic” modifications, or chemical marks that modify the expression of genes without a change in the genetic sequence itself. Variability of epigenetic marks allows cancer cells flexibility in turning genes on and off, and may account for resistance to treatment. By dissecting the mechanisms of epigenetic modification in pediatric acute lymphoblastic leukemia (ALL), the most common cancer in children, he aims to identify new targets for treatment.

Project title: "DNA methylation stochasticity in pediatric pre-B cell acute lymphoblastic leukemia"
Institution: The Johns Hopkins University
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Andrew P. Feinberg, MD
Cancer Type: Blood, Pediatric
Research Area: Epigenetics
Loretta S. Li, MD

Approximately 10-15% of pediatric and adult patients with B-cell acute lymphoblastic leukemia (B-ALL) have a high-risk form of the disease characterized by rearrangements of a gene called CRLF2. Alterations of this gene result in increased expression of the CRLF2 protein and promote leukemia development. When treated with conventional chemotherapy, patients with CRLF2 gene alterations do poorly. Their leukemias are dependent on an enzyme called JAK2 for survival, yet no targeted therapies with proven efficacy are currently available. Dr. Li has unique access to a new drug called CHZ868, which turns off JAK2 enzyme activity, potently kills B-ALL cells, and improves overall survival in mice with JAK2-dependent B-ALL. Treatment with CHZ868 alone is not curative, however, and all mice eventually succumb to progressive leukemia. Using JAK2-dependent B-ALL cells and mouse models, she will study how leukemia becomes resistant to JAK2 inhibitors. Her goal is to identify combinations of agents that can prevent or overcome resistance to a single therapy and also guide the development of new JAK2 inhibitors for patients.

Project title: "Mechanisms of disease and resistance in CRLF2-rearranged B-cell acute lymphoblastic leukemia"
Institution: Dana-Farber Cancer Institute
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): David M. Weinstock, MD
Cancer Type: Blood, Pediatric
Research Area: Cancer Genetics
Cara A. Rabik, MD, PhD

Dr. Rabik is examining how mutations in the WT1 gene result in methylation changes in acute myeloid leukemia (AML). WT1 recruits the machinery necessary for demethylation to its target genes, ultimately regulating gene expression. When WT1 is mutated, these genes remain methylated and inactive, preventing normal hematopoiesis. She is identifying WT1 target genes and mapping their methylation landscape both in leukemic and normal settings. She will also test drugs designed to cause demethylation to evaluate if these drugs can treat the leukemia caused by mutations in WT1.

Project title: "Determination of the role of WT1 in hematopoiesis and leukemogenesis"
Institution: The Johns Hopkins University
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Patrick A. Brown, MD
Cancer Type: Blood, Pediatric
Research Area: Epigenetics
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