Current therapies for children with Fanconi anemia (FA) and squamous cell carcinoma (SCC) (commonly seen in older and/or post-transplant (HCT) patients) include radiation and chemotherapy, which are associated with significant morbidity and mortality. Thus, there is clearly a need for a novel approach that has fewer and less severe side effects. Animal and humans studies indicate that reactive-oxygen species (ROS) play a key role in the pathogenesis of SCC in these children. Our long-term goal is to interdict the development of SCC in post- HCT patients with FA. Our overall objective, is to develop, at a phase 2 level, a novel approach to treatment of SCC in FA that is safer and more efficacious compared to existing approaches. It is our central hypothesis that treatment with the ROS scavenger quercetin will modulate systemic and salivary/mucosal ROS levels in patients with FA, which in turn will ameliorate development of SCC. In non-FA setting, Quercetin is shown to prevent or modulate SCC formation in mice. Our own preliminary data show that quercetin reverses the ill effects of ROS on FA SCC tumor cells and kills them in a dose dependent fashion. Buccal brushing samples from children with FA showed decreased number of micronuclei (marker of DNA damage/tumor formation) after treatment with oral Quercetin. These data strongly suggest that quercetin will be beneficial in decreasing ongoing DNA damage and preventing SCC in children with FA. Our multidisciplinary team is well prepared and will have access to sufficient number of patients. Quercetin is a naturally occurring anti-oxidant, and was well tolerated and able to achieve biologically relevant in patients with FA in our recent Phase 1 pilot study. In this Phase 2 study, we will test the above hypothesis with the following specific aims: 1.Determine the efficacy of Quercetin in reducing buccal micronuclei (a surrogate marker of DNA damage and susceptibility to SCC due to genomic instability) in post-HCT patients with FA. Thirty eight post-HCT FA patients will receive oral quercetin for a total of 24 months and be followed with assessment of serial buccal micronuclei. 2. Measure the impact of Quercetin therapy on additional potential surrogate markers Peripheral blood ROS and salivary ROS, Salivary total antioxidant capacity, Biomarkers measured via Exhaled Breath Condensate (EBC) - anti-oxidants, aldehydes etc., Oral microbiome, and Skin elasticity. The impact of quercetin on reduction of buccal micronuclei and blood as well as salivary ROS will serve as surrogate markers for prevention of SCC. Additionally, effect on improving salivary total antioxidant capacity, oral microbiome and skin elasticity will be quantified. Expected outcomes include the demonstration that long-term quercetin therapy decreases buccal micronuclei (a surrogate marker of DNA damage and susceptibility to squamous cell carcinoma due to genomic in-stability) in post-HCT patients with FA. Expected positive impact is that success will lead to a new first line therapy for post-HCT FA patients, obviating the need for radiation and chemotherapy. The proposed research is innovative, as it incorporates micronuclei as a novel therapeutic target, in a feasible approach for SCC prevention with a unique intervention of oral quercetin.
By any measure, Fanconi anemia (FA) is an orphan disease, with an overall prevalence of 1 to 5 per million and an estimated carrier frequency of 1 in 200 to 1 in 300 in most populations, with limited therapeutic options for associated potentially fatal squamous cell carcinoma (SCC). This Phase 2 study will be the first step in developing quercetin, a naturally occurring anti-oxidant, as a simpler, safer and novel therapeutic approach for prevention of SCC in FA, ultimately gaining FDA approval for the same. This project is relevant to the FDAs mission, to advance the evaluation and development of products (drugs, biologics, devices, or medical foods) that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions. This study is also consistent with a congressionally mandated program that calls for preclinical and early clinical development of new drugs for rare and neglected diseases, and development of new technologies and paradigms to improve the efficiency of therapeutic development for these diseases, as well as the Integrated National Strategy to Accelerate Research and Product Development for Rare Diseases created by NIH and the Institute of Medicine (IOM).
