Pediatric Cancer

Current Projects
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: The Johns Hopkins University School of Medicine
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Donald Small, MD, PhD
Cancer Type: Blood, Pediatric, All Cancers
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
Sponsor(s) / Mentor(s): Ross L. Levine, MD
Cancer Type: Blood, Pediatric
Research Area: Animal Models/Mouse Models
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
Srinjoy Chakraborti, PhD

Dr. Chakraborti is developing technologies to facilitate the rapid identification of individual, specific, safely targetable tumor antigens, and to engineer tumor chimeric antigen receptors (CARs) to specifically recognize and kill cancer cells within a clinically relevant timeline. Dr. Chakraborti also plans to use these technologies to investigate the role of helper T cells in enhancing the activity of anti-cancer killer T cells. These technologies, although applicable to adult cancers as well, will focus on antigens derived from pediatric cancer tissues because conventional therapies (such as chemotherapy and radiation) hold long-term health risks. 

Project title: Mining pHLA and T cell receptors (TCR) specificities by phage display for de novo TCR engineering and personalized cancer therapy
Institution: Albert Einstein College of Medicine
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Jonathan R. Lai, PhD
Cancer Type: Pediatric, All Cancers
Research Area: Immunotherapy
Adam D. Durbin, MD, PhD

Dr. Durbin is developing new ways to target neuroblastoma, using chemical inhibitors and genetic techniques to disrupt small RNA species and enzymes that neuroblastoma cells require for survival. These new factors will also be inhibited in animal models of human neuroblastoma, alone and in combination with drugs similar to those entering clinical trials. These studies aim to identify new levels of gene regulation and methods to inhibit the genes involved in formation of neuroblastoma, with minimal side effects.

Project title: Interrogation of neuroblastoma dependencies and non-coding RNAs on the core-regulatory circuitry for therapeutic inhibition
Institution: Dana-Farber Cancer Institute
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): A. Thomas Look, MD
Cancer Type: Other Cancer, Pediatric
Research Area: Epigenetics
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
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Kimberly Stegmaier, MD
Cancer Type: Pediatric, Sarcoma
Research Area: Cell Biology
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
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
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
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