Targeting Fusion-driven Sarcomas
Co-Principal Investigators
Kimberly Stegmaier, MD, Dana-Farber Cancer Institute
Olivier Delattre, MD/PhD, Institut Curie
Co-investigators
Scott A. Armstrong, MD/PhD, Dana-Farber Cancer Institute
Alexander J. R. Bishop, DPhil, University of Texas, Health Science Center San Antonio
Brian D. Crompton, MD, Dana-Farber Cancer Institute
Lee J. Helman, MD, Children’s Hospital Los Angeles
Heinrich Kovar, PhD, St. Anna Children’s Cancer Research Institute
Andrew L. Kung, MD/PhD, Memorial Sloan Kettering Cancer Center
Marc Ladanyi, MD, Memorial Sloan Kettering Cancer Center
Beth Lawlor, MD/PhD, University of Michigan
Stephen L. Lessnick, MD/PhD, Nationwide Children’s Hospital
Miguel N. Rivera, MD, Massachusetts General Hospital
Poul Sorensen, MD/PhD, BC Cancer Research Centre, Vancouver
Project Summary: A number of aggressive childhood malignancies are characterized by fusion proteins whose presence and function are essential for the survival of cancer cells. Strategies aimed at the inactivation of such cancer-associated fusion proteins have resulted in major clinical success stories, either through inhibition of a specific activity of the fusion as in sarcomas with NTRK fusions or through the induction of degradation of the fusion protein as in acute promyelocytic leukemia. We believe that such strategies can now be more broadly applied to target other fusion-positive malignancies. Indeed, the availability of highly-efficient new genome editing technologies and the availability of large drug libraries indicate that a global strategy aimed at acting on fusion proteins function and/or stability can be conducted on a large scale. We propose to use such technologies to tag the fusion proteins in cancer cells from three major fusion-driven sarcomas: Ewing sarcoma, alveolar rhabdomyosarcoma and synovial sarcoma. These tags will enable us to: 1) precisely and easily quantify the amount of the fusion in the sarcoma cells and thus to identify destabilizing effects of drugs or of gene alterations and 2) purify these proteins and characterize their binding partners which may constitute outstanding targets for therapies as recently demonstrated in some leukemias. These cell models will be made broadly available to the research community to be used in multiple drug and genetic screens and will hence fuel the next phase of drug discovery efforts focused on these difficult to treat pediatric cancers.
Project Update 2020: The goal of this initiative is the generation of panels of modified cell lines from two fusion-driven sarcomas: Ewing sarcoma (EWS) and alveolar rhabdomyosarcoma (ARMS). The proposed modifications will enable researchers to measure the amount of the fusion protein present in a sarcoma cell or purify more effectively each fusion protein and the other proteins they bind. Over the first phase of this research initiative, we have made successful strides into generating fusion gene tagged of at least one EWS and one ARMS cell line. The next phase of our work will focus on establishing the remaining cell lines and validating and characterizing these cell line resources with the transfer of these resources to the research community for their use in fueling the next phase of discovery efforts focused on these difficult to treat pediatric cancers.
