Pediatric Cancer

Current Projects
Lucas Farnung, PhD

About 70% of pediatric leukemias and 10% of adult leukemias are caused by a genetic disruption in which the mixed lineage leukemia (MLL) 1 gene breaks off and attaches to a different chromosome. This event, known as a chromosomal translocation, gives rise to a distinct subset of leukemias called MLL-rearranged acute myeloid and lymphoblastic leukemias (AML or ALL). Novel treatments for these cancers represent a major unmet medical need. However, the development of therapeutics is hampered by a lack of basic understanding of how the MLL translocations disrupt the function of affected cancer cells. Dr. Farnung will use biophysical and structural biology approaches to visualize how MLL translocations function at the atomic level and influence the important process of gene transcription. His work will elucidate the precise molecular mechanisms that drive acute leukemias and provide a platform for the development of novel therapeutic strategies against these cancers.

Project title: "Understanding the mechanistic basis of gene expression regulation by MLL complexes in cancers"
Institution: Harvard Medical School
Award Program: Innovator
Cancer Type: Blood, Pediatric
Research Area: Structural 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: St. Jude Children's Research Hospital
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Mark E. Hatley, MD, PhD
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.

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 M. Brodeur, MD
Cancer Type: Kidney and Bladder, Other Cancer, Pediatric
Research Area: Epigenetics
Nora Kory, PhD

Cancer cells rely on efficient uptake, conversion, and exchange of nutrients and vitamins to support their rapid growth and survival. The molecular transport channels that allow passage of nutrients between the different cellular compartments are critical for the survival of cancer cells and are thus promising as potential drug targets. However, drug discovery efforts are hampered by a lack of basic understanding of these channels' identities, functions, and regulation inside cancer cells. Dr. Kory's research aims to identify transporters central to cancer cell nutrient supply and detoxification pathways and determine their role in the emergence, survival, and aggressiveness of cancer. Her research is relevant to all cancers, but particularly pediatric, blood, and breast cancers.

Project title: "Targeting mitochondrial transporters in cancer"
Institution: Harvard T.H. Chan School of Public Health
Award Program: Innovator
Cancer Type: Blood, Pediatric, Breast, All Cancers
Research Area: Metabolism
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
Elvin Wagenblast, PhD

Age is the greatest risk factor for developing cancer due to the continuous and life-long accumulation of DNA mutations. Although we have identified causes of childhood cancer, including the inheritance of cancer-predisposing genes, other major contributing factors have not yet been identified. Blood cancer is the most common cancer in children and sequencing data indicate that the first genetic mutations occur during fetal development. Dr. Wagenblast will use human blood stem cells and CRISPR/Cas9-mediated genome engineering to model leukemia evolution and identify biological processes that specifically contribute towards cancer development in children. The goal is to leverage this understanding to identify novel therapeutic targets against childhood blood cancer.

Project title: "Untangling the evolutionary dependency of childhood leukemia"
Institution: Icahn School of Medicine at Mount Sinai
Award Program: Innovator
Cancer Type: Blood, Pediatric
Research Area: Stem Cell Biology
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