Pediatric Cancer

Current Projects
Marissa Rashkovan, PhD

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, accounting for 10-15% of pediatric and 25% of adult ALL cases. While survival rates have improved with intensified treatment regimens, 25% of pediatric T-ALL cases still relapse because of refractory disease. Furthermore, the intensity of these treatment regimens has led to increased secondary effects in these children later in life. This underscores the need for the development of efficient, targeted and highly specific anti-leukemic therapies to treat T-ALL. Dr. Rashkovan studies a distinct subgroup of immature T-ALL, ETP-ALL, which phenotypically resembles early thymic progenitors (ETPs), has been associated with early relapse, and poor prognosis. There is a particularly urgent need for targeted therapies for ETP-ALL, which is notoriously difficult to treat. She will assess the metabolic vulnerabilities of ETP-ALL in order to propose new, targeted therapies which could be beneficial for the treatment of this high-risk leukemia group.

Project title: "Targeting metabolic vulnerabilities in ETP-ALL"
Institution: Columbia-Presbyterian Medical Center
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Adolfo A. Ferrando, MD, PhD
Cancer Type: Blood, Pediatric
Research Area: Cancer Genetics
Yadira M. Soto-Feliciano, PhD

Pediatric acute myeloid leukemia (AML) has the lowest survival rate among all pediatric cancers. MLL gene rearrangements (MLL-r) occur in about 20% of children diagnosed with AML. This subtype of leukemia is exquisitely sensitive to inhibition of the interaction between MLL and the chromatin adaptor Menin. Dr. Soto-Feliciano is combining genetic, genomics, and mouse modeling approaches to identify factors that regulate the function of Menin in MLL-r and non-MLL-r leukemia. The identification of cellular mechanisms that mediate the response to Menin-MLL inhibitor-based therapies (already in pre-clinical studies), will inform us about the molecular mechanisms driving acute leukemia. She anticipates that the results of these experiments will provide a better understanding of gene expression programs and chromatin landscapes governing the leukemic state. In addition, this project has the potential to identify novel dependencies that can lead to development of novel drug targets for the treatment of pediatric leukemia.

Project title: "Dissecting the role of Menin in acute leukemia"
Institution: The Rockefeller University
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): C. David Allis, PhD
Cancer Type: Blood, Pediatric
Research Area: Epigenetics
Kathryn R. Taylor, PhD

Dr. Taylor is investigating the impact of neural activity on pediatric high-grade glioma (pHGG) invasion. The innate ability of pHGGs to diffusely infiltrate healthy brain tissue is a classical hallmark of the disease, which represents a major contributor to the devastating prognosis. Using optogenetic techniques to stimulate neuronal activity, she will directly and noninvasively test the effect of activity-dependent secreted proteins on tumor cell invasion in human cancer cells and animal models. She plans to confirm the pro-infiltrative effect of candidate proteins on pHGG and subsequently uncover the mechanisms by which they alter the molecular dynamics of the tumor cell. Her hope is to highlight a novel means by which the neural microenvironment drives glioma progression and most importantly identify a new set of therapeutic targets to limit glioma spread.

Project title: "The effect of neuronal activity on pediatric glioma invasion"
Institution: Stanford University
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Michelle L. Monje, MD, PhD
Cancer Type: Other Cancer, Pediatric, Brain
Research Area: Developmental Biology
Ly P. Vu, PhD

Dr. Vu is studying childhood acute myeloid leukemia (AML), a complex and heterogeneous disease. Despite exciting advances in our understanding of AML and the availability of more aggressive treatment regimens, ~30% of children still eventually relapse from this disease and there are yet no approved targeted therapies for children with AML. Her project aims to uncover the role of Syncrip, a novel RNA binding protein, in maintaining the leukemia stem cell in AML. The study will provide insights into the mechanism underlying the cause and development of AML and may lead to innovative therapeutic strategies and improved clinical outcomes for this deadly childhood disease.

Project title: "Uncovering the role of RNA-binding protein Syncrip in acute myeloid leukemia (AML)"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Michael Kharas, PhD, and Ross L. Levine, MD
Cancer Type: Blood, Pediatric
Research Area: Stem Cell Biology
Angela J. Waanders, MD

Dr. Waanders is committed to developing more effective treatments for the many children diagnosed with brain tumors each year. Brain tumors are the leading cause of cancer-related death in children. Mutations in BRAF, an oncogene that can drive cancer growth, are prevalent in pediatric astrocytomas. By studying how mutated BRAF can be targeted by the newest classes of cancer drugs, she hopes to understand why and how these tumors develop in children and which treatments might work best. Her preliminary research has shown that different BRAF mutations identified in pediatric astrocytomas respond differently to targeted BRAF treatments. These studies will be the basis for moving novel, targeted treatment strategies into the clinic to treat the many children afflicted by this devastating cancer.

Project title: "Preclinical models for therapeutic targeting of pediatric astrocytomas"
Institution: Children's Hospital of Philadelphia
Award Program: Dale Frey Scientist
Cancer Type: Pediatric, Brain
Research Area: Signal Transduction
Mark W. Zimmerman, PhD

Dr. Zimmerman studies neuroblastoma, a tumor of the peripheral sympathetic nervous system. In high-risk neuroblastoma tumors, which account for 15% of all childhood cancer deaths, the chromatin remodeling gene CHD5 is often deleted and its loss is associated with poor prognosis. The gene expression program regulated by CHD5 has strong tumor suppressive effects and has thus emerged as a very attractive target for potential anti-cancer therapeutics. CHD5 expression is also altered in other cancer types, indicating a potential role in many different adult and pediatric malignancies. His research elucidating the CHD5 pathway in a zebrafish model of neuroblastoma will lead to significant advances in our understanding of how CHD5 functions as a tumor suppressor

Project title: "Elucidating the mechanism of CHD5-mediated tumor suppression in neuroblastoma"
Institution: Dana-Farber Cancer Institute
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): A. Thomas Look, MD
Cancer Type: Other Cancer, Pediatric
Research Area: Chromatin Biology
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