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Imatinib: a new chemopreventive option in adenomatous polyposis?

ABSTRACT: Patients with adenomatous polyposis, usually defined as patients with >10 adenomatous polyps in the colorectum, are at increased risk for colorectal cancer (CRC). Since surgical and endoscopic treatment do not completely eliminate the potential for future polyps or extraintestinal neoplasms, there is an unmet medical need to identify pharmacological agents to delay major surgical interventions. We present two cases of patients with adenomatous polyposis who developed chronic myelogenous leukaemia and were treated with imatinib as part of their chemotherapy. A sustained regression of the colonic polyps documented in both cases was observed after the initiation of the tyrosine kinase inhibitor. Despite the presence of potential confounders, we hypothesise the potential role of imatinib as a chemopreventive agent in patients with familial adenomatous polyposis.

SUBMITTER: Tobon A

PROVIDER: S-EPMC7778759 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Imatinib: a new chemopreventive option in adenomatous polyposis?

Tobon Angelica A Olivas Pol P Ocaña Teresa T Pellisé María M Balaguer Francesc F

BMJ open gastroenterology 20201201 1

Patients with adenomatous polyposis, usually defined as patients with >10 adenomatous polyps in the colorectum, are at increased risk for colorectal cancer (CRC). Since surgical and endoscopic treatment do not completely eliminate the potential for future polyps or extraintestinal neoplasms, there is an unmet medical need to identify pharmacological agents to delay major surgical interventions. We present two cases of patients with adenomatous polyposis who developed chronic myelogenous leukaemi ...[more]

PMID: 33376108

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Project description:BackgroundFamilial 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.MethodsThis 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.DiscussionThe 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 registrationClinicalTrials.gov ( https://clinicaltrials.gov/ ): NCT05402891 (June 1, 2022) and the EU Clinical Trials Register: EuraCT 2022-000240-30 (January 1, 2022).

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Imatinib: a new chemopreventive option in adenomatous polyposis?

Publications

Imatinib: a new chemopreventive option in adenomatous polyposis?

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