Childhood Cancer

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Nuclear Receptor Tyrosine Kinases Mediating Chromatin Remodeling & Checkpoint Adaption

Children’s Cancer Therapy Development Institute
Charles Keller, MD
Grant Type: 
Innovation Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

Alveolar rhabdomyosarcoma is a cancer of the soft tissues. 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
For this project, learning how to better use growth factor inhibitors could pave the way to new designs of evidence-based clinical trials that prevent treatment relapse and could save lives.

Project Update 2020
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. The aggressiveness of alveolar rhabdomyosarcoma results from the Pax3:Foxo1 mutation. 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.

Co-funded by: 
Northwestern Mutual Foundation