The CHAMP-study: the CHemopreventive effect of lithium in familial AdenoMatous Polyposis; study protocol of a phase II trial

Jasmijn D G Linssen, Sanne M van Neerven, Arthur S Aelvoet, Clara C Elbers, Louis Vermeulen, Evelien Dekker, Jasmijn D G Linssen, Sanne M van Neerven, Arthur S Aelvoet, Clara C Elbers, Louis Vermeulen, Evelien Dekker

Abstract

Background: Familial adenomatous polyposis (FAP) is a rare autosomal dominant disease characterized by germline mutations in the Adenomatous Polyposis Coli (APC) gene, resulting in the development of numerous colorectal adenomas. As these patients have a high risk of developing colorectal cancer (CRC), guidelines suggest prophylactic colectomy during early adulthood, however, adenoma development is still observed in the remaining intestinal tract. Therefore, FAP patients would benefit from chemoprevention strategies reducing the development of adenomas. Recent work in mice reveals a chemopreventive effect of lithium on the development of adenomas by inhibiting the expansion of Apc mutated intestinal stem cells (ISCs) within the crypts of normal intestinal mucosa. Here, we aim to investigate the effect of lithium on the spread of APC mutant cells within the human intestinal epithelium.

Methods: This prospective phase II single arm trial has a duration of 18 months. FAP patients (18-35 years) with a genetically confirmed APC mutation who did not undergo colectomy will be treated with lithium carbonate orally achieving a serum level of 0.2-0.4 mmol/l between month 6 and 12. Colonoscopy with biopsies of normal intestinal mucosa will be performed at baseline and every six months. The primary endpoint is the effect of lithium on the spread of APC mutant cells within intestinal crypts over time by using APC specific marker NOTUM in situ hybridization. Secondary endpoints include change in adenoma burden, patient reported side effects and safety-outcomes. Total sample size is 12 patients and recruitment will take place in the Amsterdam UMC, location AMC in the Netherlands.

Discussion: The outcome of this study will function as a proof-of-concept for the development of novel chemoprevention approaches that interfere with the competition between normal and mutant ISCs.

Trial registration: ClinicalTrials.gov ( https://ichgcp.net/clinical-trials-registry/NCT05402891" title="See in ClinicalTrials.gov">NCT05402891 (June 1, 2022) and the EU Clinical Trials Register: EuraCT 2022-000240-30 (January 1, 2022).

Keywords: Chemoprevention; Colorectal adenomas; Familial adenomatous polyposis; Lithium carbonate.

Conflict of interest statement

L.V. received consultancy fees from Bayer, MSD, Genentech, Servier, and Pierre Fabre, but these had no relation to the content of this publication. E.D. has endoscopic equipment on loan of FujiFilm and received a research grant from FujiFilm. She has received honorarium for consultancy from FujiFilm, Olympus, GI Supply, PAION and Ambu, and speakers' fees from Olympus, GI Supply, Norgine, IPSEN, PAION and FujiFilm.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Crypt fixation and chemoprevention with lithium treatment. APC = adenomatous polyposis coli tumor-suppressor gene. DKK2 = Dickkopf WNT Signaling Pathway Inhibitor 2. ISCs = intestinal stem cells. WIF1 = WNT Inhibitory Factor 1. ISCs reside at the bottom of the crypts of the epithelium of the colon where they engage in ongoing neutral competition with each other for a position in the crypt. These neutral dynamics are disturbed whenever an ISCs acquires a second mutation in the APC allele. APC-mutant ISCs have a competitive advantage by secreting Wnt antagonists (e.g. NOTUM, WIF1, DKK2) that drive the differentiation of WT ISCs, thereby resulting in mutant crypt fixation and the development of premalignant adenomas. In this study, we propose that boosting the Wnt pathway in WT ISCs using lithium diminishes this competitive advantage and prevents adenoma formation. This figure was created by using Adobe Illustrator 2022 (version 26.0.3)
Fig. 2
Fig. 2
NOTUM in situ hybridization (ISH) in human FAP adenomatous lesion. Fluorescent staining of human intestinal adenomas was visualized with a SP8X confocal microscope using Leica Application Suite software (version 3.5.7)
Fig. 3
Fig. 3
Flowchart of the study design (as of May 2, 2022). 1Hematology: haemoglobin, thrombocytes, leukocytes. 2Chemistry: GFR, creatinine, urea, sodium, potassium, calcium and TSH (if deviating T4). 3A pregnancy test is required for participants with the female gender. 4Urine sample: urine osmolality and urine creatinine. This figure was created by using Adobe Illustrator 2022 (version 26.0.3)

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