Combination of Sulindac and Bexarotene for Prevention of Intestinal Carcinogenesis in Familial Adenomatous Polyposis.
Charles M BowenLewins WalterEster BorrasWenhui WuZuhal OzcanKyle ChangPrashant V BommiMelissa W TaggartSelvi ThirumurthiPatrick M LynchLaura Reyes-UribePaul A ScheetKrishna M SinhaEduardo VilarPublished in: Cancer prevention research (Philadelphia, Pa.) (2021)
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in ApcMin/+ and ApcLoxP/+-Cdx2 mice. Finally, the reported data suggest miRNA-21 could serve as a predictive serum biomarker for polyposis burden in patients with FAP. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for patients with FAP. PREVENTION RELEVANCE: This study identified a novel chemopreventive regimen combining sulindac and bexarotene to reduce polyposis in patients with FAP using in silico tools, ex vivo, and in vivo models. This investigation provides the essential groundwork for moving this drug combination forward into a clinical trial.
Keyphrases
- chronic rhinosinusitis
- clinical trial
- cell proliferation
- oxidative stress
- emergency department
- single cell
- mouse model
- rna seq
- randomized controlled trial
- risk assessment
- metabolic syndrome
- climate change
- machine learning
- case report
- study protocol
- drug delivery
- insulin resistance
- skeletal muscle
- electronic health record
- big data
- binding protein
- induced pluripotent stem cells
- drug induced
- data analysis
- double blind