Safety and Tolerability of Metformin and Naproxen for Cancer Prevention in Fanconi Anemia

Fanconi Anemia, Head and Neck Cancer, Squamous Cell Carcinoma, Squamous Cell Cancer of Head and Neck (SCCHN)

metformin, naproxen, Rockefeller, Minnesota, Fanconi anemia, Cancer prevention

Finding effective ways to slow down or prevent the development of cancer in people with Fanconi anemia (FA) is a critical medical priority. Individuals with FA are at dramatically higher risk of developing aggressive cancers, particularly of the head and neck, and these cancers are difficult to treat with standard therapies such as surgery, chemotherapy or radiation. Because options for treatment are limited and outcomes are often poor, prevention strategies are urgently needed. In this study, the investigators will test two widely available drugs, metformin and naproxen, to evaluate whether they can lower the risk of cancer in FA patients. Metformin is commonly prescribed for type 2 diabetes, while naproxen is a nonsteroidal anti-inflammatory drug (NSAID) frequently used for pain and inflammation. Both have shown potential in previous research to influence biological pathways linked to cancer development. By repurposing these well-known drugs, this trial aims to explore a safe, practical approach to cancer prevention in this vulnerable population. The study, conducted at the Rockefeller University and the University of Minnesota, has several goals. First, the investigators will carefully assess the safety and tolerability of metformin and naproxen when used in participants with FA. Because these individuals can be more susceptible to metabolic disorders like diabetes compared to the general population, and may have genitourinary abnormalities related to their underlying condition, monitoring for side effects and adverse events is especially important. Second, investigators will evaluate whether intervention affects visible or microscopic changes in the mouth, where cancers often arise. This will involve performing small biopsies of oral tissue to look for cancerous or pre-cancerous lesions. Third, investigators will investigate early molecular changes using an exploratory less invasive technique: collecting cells with a soft brush, similar to a toothbrush. These samples will allow the investigators to analyze biomarkers-biological signals that can indicate increased or reduced cancer risk-before and after intervention. Together, these approaches will provide information on whether metformin or naproxen are safe and well-tolerated in the FA population. As an additional outcome, by combining direct tissue analysis with biomarker studies, the investigators aim to detect subtle changes that precede cancer, giving us an early indication of whether the drugs are working as preventive agents. Although this is an early-phase study, its potential significance is considerable. Demonstrating that well-tolerated, inexpensive, and widely accessible drugs may have potential to reduce cancer risk would represent a major advance for FA patients, who currently face limited options for prevention and treatment. This work may also offer insights relevant to broader cancer prevention efforts in other high-risk groups. Ultimately, our study seeks to take an important step toward changing the outlook for people with Fanconi anemia by moving the focus from late-stage treatment toward early prevention.

Fanconi anemia (FA) patients have a 500-700-fold higher risk of head and neck squamous cell carcinoma (HNSCC) than the general population, with early onset and poor survival due to the aggressive nature of these tumors and intrinsic constitutional sensitivity of FA patients to chemo- and radiotherapy. Given this risk and the paucity of viable treatments, cancer prevention is a critical priority. Metformin, a widely used anti-diabetes drug, has shown promise in FA-related cancer prevention. In preclinical studies, metformin improves defective hematopoiesis and delays tumor development in Fancd2-/-/Trp53+/- mice. Metformin also showed preventive efficacy in oral cancer in patients with oral premalignancies in a Phase IIA clinical trial (NCT02581137), with an ongoing Phase IIB randomized, placebo- controlled trial (NCT05237960) further evaluating its effectiveness. Outside FA, but in the setting of high cancer predisposition syndrome, the MILI Precision-Prevention trial (ISRCTN16699730) and a parallel NIH study will assess metformin in a non-placebo-controlled Phase II trial in adults with Li-Fraumeni Syndrome undergoing annual MRI-based cancer surveillance. Finally, a clinical trial for treatment of cytopenia in FA (NCT03398824) concluded that metformin was safe, well-tolerated, and may provide therapeutic benefit in nondiabetic patients with FA with a median age of 9.4 years. Naproxen, another widely-used and well-tolerated drug, has shown promise in cancer prevention. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be associated with reduced metastasis across cancer types and to inhibit proliferation and drive apoptosis of cancer cells. Naproxen has shown promise in animal studies by inhibiting lung adenocarcinoma formation in mice, suggesting a chemopreventive role. In a study of 80 participants in Lynch syndrome with a predisposition to multiple cancer types, daily administration of naproxen for six months promoted immune activation, with no statistically significant difference in the total number of adverse events when comparing treatment arms to placebo, with excellent tolerance of the intervention. Another NSAID, the COX-2 selective agent celecoxib has also shown cancer preventive potential. In the FA-setting, combination of atorvastatin and celecoxib delayed tumor formation in Fancd2-/-/Trp53+/- mice. More recently, Markus Grompe's lab found that in a Fanct-/-/Trp53+/-/ADH5-/- mouse model, the number of dysplastic tongue lesions decreased following intervention with atorvastatin/celecoxib or celecoxib alone (Markus Grompe lab, SU2C team project led by Dr. Smogorzewska, unpublished). Evidence from large observational studies suggests that naproxen has a better cardiovascular safety profile compared to other NSAIDs like celecoxib. The major innovation in this trial will be the use of molecular biomarkers to assess potential anti-mutagenic effects of these agents. Ongoing unpublished studies in our lab have shown that 55% of 38 FA patients exhibited at least one molecular alteration in normal-appearing oral mucosa. Clinically significant TP53 Single Nucleotide Variants (SNVs) were identified in 10 of 38 FA patients (26%), with 19 unique SNVs detected in 222 (8.5%) brush biopsy samples from normal-appearing, non-lesional mucosa. Copy Number Variants (CNVs) were present in 20 of 38 FA patients (53%) and detected in 56 of 171 samples (33%). These preliminary results indicate that a large proportion of FA patients are likely to have potentially oncogenic somatic genomic variants. This gives us an opportunity to follow these biomarkers, in patients without lesions and eventually forgo the use of surgical biopsies to assess efficacy of treatment. The investigators will also incorporate buccal swab brushing followed by targeted NanoSeq analysis of variants in a panel of 239 cancer genes. This is being performed through a collaboration with Dr. Iñigo Martincorena (Sanger Institute, UK). The high sensitivity of this method for low frequency variants will give us a richer picture of mutational landscape in patients with Fanconi anemia, and by increasing sensitivity of variant detection, will increase the number of eligible participants. Some participants who may not have variants identifiable by brushing, may have variants detectable by buccal swab. Building on these findings, the investigators propose an open-label crossover design phase 1 clinical trial testing the feasibility of metformin and naproxen, administered separately, to prevent oral cancer in FA patients. Adult FA patients with at least one oral lesion or the presence of a biomarker (described above) will be included. The investigators hypothesize that metformin and naproxen are safe, feasible, well-tolerated in patients with FA, and may reduce or reverse genetic lesions associated with cancer development in FA patients. This is a multi-site single IRB study with Rockefeller serving as IRB of Record for the University of Minnesota (UMN) using the SMART IRB Master Reliance Agreement. The University of Minnesota site will carry out the same protocol at their site under the direction of Dr. Rachel Uppgaard, DDS (Relying Site PI).

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