Nuclear Receptor Tyrosine Kinases Mediating Chromatin Remodeling & Checkpoint Adaption
Background: Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. The alveolar subtype is noticeably more aggressive than the embryonal subtype of rhabdomyosarcoma. This disease often responds to chemotherapy, but in many patients the available treatments fail – a deadly outcome. We identified how a cancer-causing fusion gene called Pax3:Foxo1 may lead to treatment failure: by turning on growth factor genes late in the process of tumor cell duplication. We believe this pro-growth, pro-survival process allows tumor cells to endure chemotherapy and radiation and allow tumor recurrences.
Project Goal: We want to determine if FGFR1 (a growth factor related to Pax3:Foxo1) is a suitable target for drug development for children with alveolar rhabdomyosarcoma and will help limit treatment resistance in tumor cells.
Project Update 2021: Our previous study revealed Pax3:Foxo1 promotes resistance to radiation treatment. In this study, we find that FGFR1, a growth factor receptor highly expressed in rhabdomyosarcoma, may mediate this tumor survival. We have found clues of specific survival mechanisms induced by FGFR1, and we are testing whether FGFR1 is a suitable target of drug development to help children with alveolar rhabdomyosarcoma. Ultimately, we did not observe the hallmarks of radiation resistance led by FGFR1 activation in rhabdomyosarcoma. Instead, fortunately, we observed significant function of nuclear FGFR1 in osteosarcoma, which we believe has clinical trial applications.
