Treatment of blood complications in FA kids using bone marrow transplantation has seen great improvement over the past decade. However, after a successful bone marrow transplantation, those kids affected with FA must now face nonblood malignancies in subsequence adolescent life which defy conventional therapeutics due to their aggressive course and global sensitivity to conventional treatments. Squamous cell carcinomas (SCCs) are the most common solid tumors in FA patients, and the high risk of FA SCC is further increased by conditioning protocols that are required for bone marrow transplant. Once diagnosed, outcomes and quality of life of such kids are dismal due to tumor progression and recurrence, and treatment-related toxicities and major damage to adjacent healthy tissue by conventional X-ray radiation or chemotherapy remains a serious limitation. In contrast, proton based radiation therapies are known for the benefit of precision targeting of the tumor, with limited damage to surrounding tissues.
To date, the molecular and cellular responses to proton radiation remain largely unknown. In this project, we will first define FA-dependent sensitivity, toxicity and biological response to the proton in HNSCC cells compared with normal skin cells in 3-dimension cell culture in a dish that mimics real tumors. Subsequently, we will define the therapeutic effects of proton irradiation in mouse xenograft models and design new drugs combination approaches based on the FA cell responses to proton therapy.