Combination of Sulindac and Bexarotene for Prevention of Intestinal Carcinogenesis in Familial Adenomatous Polyposis

Abstract

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.

Identification of an m6A-Related Long Noncoding RNA Risk Model for Predicting Prognosis and Directing Treatments in Patients With Colon Adenocarcinoma

“…In addition, m6A-LPS was used to investigate potential chemotherapeutic drugs and immunotherapeutic targets. The IC 50 values of chemotherapeutic drugs available on the GDSC website were calculated, which indicated that the low-risk group was more sensitive to almost all the drugs, including olaparib, bexarotene, and doxorubicin, which were reported to be helpful for preventing or treating COAD ( Bowen et al, 2021 ; de Castro e Gloria et al, 2021 ; Pan et al, 2021 ). Afatinib, metformin, and GW.441756 are more useful for low-risk patients.…”

Wnt/β-Catenin Signaling Pathway in the Development and Progression of Colorectal Cancer

“…Bowen et al demonstrated that the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach can prevent colorectal carcinogenesis of FAP through the Wnt/β-catenin pathway. 105 Possibly, there is a role for aspirin or NSAIDs as primary prevention in those patients with a defined hereditary predisposition (eg, Lynch syndrome and FAP). 106 However, the serious adverse reactions of traditional NSAIDs as anti-cancer drugs cannot be ignored.…”

Blocking the Wnt/β‑catenin signaling pathway to treat colorectal cancer: Strategies to improve current therapies (Review)

“…More importantly, repeated use of 2,5-dimethyl celecoxib was able to significantly reduce the size and number of tumors without any drug toxicity, suggesting that 2,5-dimethyl celecoxib is a new potential anticancer treatment. Of note, the combination of an NSAID (sulindac) and rexinoid (bexarotene) resulted in a durable amelioration of familial adenomatous polyposis, thereby preventing the development of CRC (74). Furthermore, a clinical trial is currently investigating the role of aspirin as an adjunctive drug for the prevention of postoperative CRC recurrence and metastasis (NCT02607072).…”