Pediatric Cancer

Current Projects
Jessie A. Brown, PhD

Dr. Brown studies acute lymphoblastic leukemia (ALL), an aggressive leukemia and one of the most common malignancies in children and adolescents. Despite significant progress, relapse is associated with high rates of drug resistance and poor prognosis. As a result, relapsed ALL is the leading cause of cancer-related death in children. Dr. Brown will use large-scale genetic (DNA) and transcriptomic (RNA) data and leukemia animal models to dissect how a small number of ALL cells are able to escape the cytotoxic effects of chemotherapy. These cells then undergo genetic and epigenetic changes that allow them to generate resistance to chemotherapy and proliferate, causing relapse of this devastating childhood disease. Understanding this process may lead to novel therapeutic approaches for relapsed ALL.

Project title: "Master regulators of drug resistance in relapsed acute lymphoblastic leukemia" 
Institution: Columbia University
Named Award: Candy and William Raveis Fellow of the Damon Runyon-Sohn Foundation Pediatric Cancer Fellowship Award
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Adolfo A. Ferrando, MD, PhD
Cancer Type: Blood, Pediatric
Research Area: Chemoresistance
Kiara C. Eldred, PhD

Dr. Eldred is focusing on retinoblastoma, a tumor of the eye that primarily occurs in children. She is developing three-dimensional tissue cultures that replicate the complexity of the human retina. Using these retinal “organoid” models, Dr. Eldred will generate mutations of the retinoblastoma (RB1) gene in previously healthy tissue to observe the effects of different mutations on the formation and growth of retinoblastoma. She hopes this will also shed light on the roles of tumor-causing oncogenes and tumor suppressors involved in retinoblastoma progression. A deeper understanding of specific RB1 mutations may guide the prevention, diagnosis, and development of individualized treatment plans for patients with retinoblastoma and other cancers involving mutations in the RB1 pathway.   

Project title: "Dissecting the mechanisms of tumorigenesis in the human retina"
Institution: University of Washington
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Thomas Reh, PhD
Cancer Type: Other Cancer, Pediatric, All Cancers
Research Area: Cell Biology
Katherine E. Gadek, PhD

Dr. Gadek focuses on the Sonic Hedgehog (Shh) signaling pathway, which can be altered in rhabdomyosarcoma (RMS) patients. RMS is the most common soft-tissue sarcoma in children, but survival rates and treatments for high-risk patients have not improved in three decades. Dr. Gadek will examine the timing of tumor development and the role of Shh signaling in tumor location and formation. This may lead to diagnostic markers and tools for identifying high-risk patients with altered Sonic Hedgehog signaling, which could improve treatment options and outcomes.

Project title: "Defining endothelial progenitor cell pliancy in rhabdomyosarcoma" 
Institution: St. Jude Children's Research Hospital
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Mark Hatley, MD, PhD, and Stacey Ogden, PhD
Cancer Type: Head and Neck Cancer, Pediatric, Sarcoma
Research Area: Developmental Biology
Lillian M. Guenther, MD

Ewing sarcoma is an aggressive bone tumor that occurs in children and young adults. Cure rates, particularly when disease has spread, are low with currently available treatments. Dr. Guenther aims to identify critical genes on which Ewing sarcoma cells are dependent for survival, with the goal of discovering weaknesses in these cancer cells that may be exploited to stop cancer growth. CITED2 is of particular interest as a Ewing sarcoma-specific dependency gene based on a genome-wide screen in hundreds of cancer cell lines. In some other cancers, CITED2 is described as important for helping cells repair damage and survive stress, such as when they are exposed to chemotherapy. She has found that CITED2 is present in higher levels in Ewing sarcoma cells than in other types of cancer, and when CITED2's function is turned off in Ewing sarcoma cells, they grow more slowly. She aims to first confirm that CITED2 is critical for Ewing sarcoma survival. She will also investigate what makes CITED2 important in cancer cells, including specific features of Ewing sarcoma cells that contribute to its high levels of activity.  Additionally, she wants to understand CITED2's function in Ewing sarcoma cells, including any role for CITED2 in the repair of damage to DNA after chemotherapy or stress. The goal of this work is to develop new directed cancer therapies for patients with this devastating disease. She hopes that these studies will have an additional impact on the treatment of other cancers where CITED2 has been shown to play a role, including acute myeloid leukemia.

Project title: "Investigation of CITED2 as a novel dependency in Ewing sarcoma"
Institution: Dana-Farber Cancer Institute
Named Award: William Raveis Charitable Fund Physician-Scientist
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Kimberly Stegmaier, MD
Cancer Type: Pediatric, Sarcoma
Research Area: Cell Biology
Jennifer M. Kalish, MD, PhD

Dr. Kalish is studying a rare hereditary syndrome called Beckwith-Wiedemann syndrome (BWS), which increases the risk of children developing kidney and liver cancers. These individuals have epigenetic changes on chromosome 11 that are found in other types of cancers. Epigenetic markers modify DNA so gene expression is turned on or off; changes in this process can cause cancer. By understanding how cancer is triggered in BWS, Dr. Kalish aims to identify pathways that can be targeted for the development of new treatments both for BWS patients and for others with cancers that have similar epigenetic changes. As a physician-scientist, Dr. Kalish established the BWS Registry, which compiles both clinical data and patient samples, and created the first human cell-based models of BWS. Dr. Kalish works under the mentorship of Marisa Bartolomei, PhD, at Children’s Hospital of Philadelphia, Philadelphia.

Project title: "Epigenetic and genetic mechanisms of cancer in Beckwith-Wiedemann Syndrome"
Institution: Children's Hospital of Philadelphia
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Marisa S. Bartolomei, PhD, and Garrett A. Brodeur, MD
Cancer Type: Kidney and Bladder, Other Cancer, Pediatric
Research Area: Epigenetics
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
Sarah Naomi Olsen, PhD

Dr. Olsen is investigating new therapeutic options to treat acute myeloid leukemia (AML), an aggressive form of childhood cancer. One subtype of AML is characterized by a chromosomal translocation involving the MLL (KMT2A) and the AF9 gene, resulting in an abnormal MLL-AF9 fusion protein. Dr. Olsen is targeting the MLL-AF9 fusion protein using a newly developed protein degradation approach. Characterizing the consequences of direct MLL-AF9 degradation will provide important mechanistic insight into how this mutant protein modulates leukemia and help guide the development of combination therapeutic approaches for long-term responses in pediatric AML patients.

Project title: "Targeted degradation of the MLL-AF9 fusion oncoprotein in acute myeloid leukemia"
Institution: Dana-Farber Cancer Institute
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Scott A. Armstrong, MD, PhD
Cancer Type: Blood, Pediatric
Research Area: Epigenetics
Anand G. Patel, MD, PhD

Dr. Patel studies rhabdomyosarcoma (RMS), a fast-growing childhood cancer that can spread from muscles to other parts of the body. Dr. Patel has discovered that each RMS tumor consists of different subpopulations of cells that mimic different stages of early muscle development. He will characterize how chemotherapy or radiation therapy selects for specific subpopulations of resistant cancer cells that survive treatment within both patient tissue and in patient-derived models of cancer. Using this information, Dr. Patel aims to test whether directing therapy against resistant cell subpopulations improves treatment outcomes. Ultimately, the goal of this research is to uncover novel therapeutic targets and drugs for the treatment of pediatric RMS.

Project title: "Targeting the developmental architecture of rhabdomyosarcoma"
Institution: St. Jude Children's Research Hospital
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Michael A. Dyer, PhD
Cancer Type: Pediatric, Sarcoma
Research Area: Chemoresistance
Maxim Pimkin, MD, PhD

Dr. Pimkin is identifying and characterizing the most critical transcription factors (proteins that regulate the function of genes), called core regulatory circuitries (CRCs), in various types of AML. This will provide new insights into the most critical mechanisms of AML survival and identify new targets for drug development. Preliminary data show that CRCs can accurately and reliably predict critical genes necessary for AML cancer cell survival, suggesting a practical way of identifying potential therapeutic targets. Dr. Pimkin hopes to create a unified understanding of the common and different ways in which AML subtypes arise, as well as create an unprecedented way of predicting common and subtype-specific AML vulnerabilities. 

Project title: "Divergent core transcriptional circuitries highlight context-specific vulnerabilities in AML"
Institution: Harvard Medical School
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Stuart Orkin, MD
Cancer Type: Blood, Pediatric
Research Area: Genomics
Zulekha A. Qadeer, PhD

Dr. Qadeer investigates the mechanisms underlying medulloblastoma (MB), the most common form of malignant brain tumors in children. Group 3 MB is a particularly aggressive subgroup, for which there are few actionable targets for therapies. Dr. Qadeer aims to understand how the genes and pathways regulated by the proteins MYC and TGFb mediate the transformation of neural precursor cells to malignant group 3 MB tumors. This work may also help elucidate tumor heterogeneity and resistance to current alkylating chemotherapies. The overall goal of this research is to identify more effective therapies to treat patients by targeting the mutations that drive tumor formation.

Project title: "Targeting TGFb pathway dependencies in Group 3 Medulloblastoma" 
Institution: University of California, San Francisco
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): William A. Weiss, MD, PhD
Cancer Type: Pediatric, Brain
Research Area: Invasion and Metastasis
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