In an ambitious effort to crack the code of several aggressive childhood cancers lacking definitive treatments, the Beau Biden Cancer Moonshot program has awarded grants to two research teams led by scientists at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Only four grants in total were awarded for this initiative.
One team, receiving $12.5 million over five years, is led jointly by Kimberly Stegmaier, MD, co-director of the Pediatric Hematologic Malignancy Program and vice chair of Pediatric Oncology at Dana-Farber, and Scott Armstrong, MD, PhD, chairman of Pediatric Oncology at Dana-Farber/Boston Children’s. Other Dana-Farber team members are Nathanael Gray, PhD, and Eric Fischer, PhD, in the Chemical Biology Program, and Project Manager Jennifer Perry, PhD. Collaborators are at Massachusetts General Hospital and other centers.
Heading the other team, which is receiving $10.5 million over five years, is Cigall Kadoch, PhD, of Dana-Farber/Boston Children’s and the Broad Institute of MIT and Harvard. Co-investigator is Ali Shilatifard, PhD, of Northwestern University. Kadoch’s team will work with Sirano Dhe-Paganon, PhD, director of the Longwood Center for Structural and Chemical Biology.
The research teams were chosen among a competitive nationwide pool of applications for their expertise and resources relevant to the challenge of studying these rare pediatric cancers, which include Ewing sarcoma, the second-most common bone cancer in teens and young adults; synovial sarcoma; alveolar rhabdomyosarcoma; ependymoma, and acute myeloid leukemia specifically with NUP98 fusion proteins.
Last year the Blue-Ribbon panel advising the Moonshot project listed several priorities for research, one of which is “to intensify research on the drivers of childhood cancer.”
The cancers being tackled by the research teams are all driven by “fusion oncoproteins” – abnormally joined proteins in cells that act as powerful stimulators of malignant growth. These fusion proteins are formed by accident when two genes on separate chromosomes break and merge, forming a renegade partnership that disrupts normal gene regulation and turns on multiple cell-growth genes that should be inactive. Over many years, Armstrong has produced a series of pioneering discoveries about the role of fusion proteins involving the MLL (mixed lineage leukemia) gene and protein in causing acute leukemias with a poor prognosis.
The team led by Stegmaier and Armstrong aims to develop precise drug strategies to treat Ewing sarcoma, for which there is no targeted drug therapy, only chemotherapy. It’s known that at the root of Ewing sarcoma is the breaking and joining of parts of two genes, EWSR1 and FL1, to form a fusion oncoprotein EWS/FLI. But exactly how that oncoprotein disrupts the normal molecular circuitry of the cell, driving an array of genes into malignant overdrive, is one of the questions the scientists hope to answer. It’s likely that the oncoprotein interacts with complex molecules that regulate chromatin – the material that packages the DNA in cells and controls which genes are transcribed into proteins – and the research team will focus on dissecting that interaction, with the aim of finding targets for drugs.
Transcription factors, like the EWS/FL1 protein involved in Ewing sarcoma, are notoriously difficult to target with drugs. A recently developed approach called protein degradation can eliminate desired proteins from cells. Stegmaier says that method will be investigated as a potential treatment, with Gray and Fischer from the Chemical Biology Program leading that effort.