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

Cancer Prev Res (Phila). 2021 Sep;14(9):851-862. doi: 10.1158/1940-6207.CAPR-20-0496. Epub 2021 Jul 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / drug therapy*
  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli / pathology
  • Adenomatous Polyps / drug therapy
  • Adenomatous Polyps / genetics
  • Adenomatous Polyps / pathology
  • Adult
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bexarotene / administration & dosage*
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Case-Control Studies
  • Cells, Cultured
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / pathology
  • Intestinal Neoplasms / prevention & control*
  • Male
  • Mice
  • Mice, Transgenic
  • Sulindac / administration & dosage*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Sulindac
  • Bexarotene